The American Association for Cancer Research (AACR) organizes an annual meeting program covering some of the most recent discoveries in cancer research. The conference aims to highlight work from the best minds in research and medicine from institutions all over the world. Oncotarget, exhibited by its publisher Impact Journals, will be participating virtually at the AACR Annual Meeting this year. 
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As of June 2020, Scopus released their latest 2019 Journal Rankings on Oncology. Oncotarget is among their highest rated (Q1) journals and ranked number one in total citations in oncology. The journal has published outstanding papers and reviews by authors including Bert Vogelstein, Peter K. Vogt, Pier Paolo Pandolfi, Arnold J. Levine, Brian Druker, and Carol Prives. Founding Oncotarget Editorial Board members include Nobel Laureates Andrew V. Schally and Gregg L. Semenza; Lasker Award recipients Alexander Varshavsky, Brian J. Druker, and Gregg L. Semenza; and 16 members of the US National Academy of Sciences. Oncotarget is indexed and archived in PubMed, PubMed Central, Scopus, EMBASE, and META (Chan Zuckerberg Initiative).

The 2021 AACR conference, a two-week online event, will take place from April 10-15 and May 17-21, 2021. Topics include population science and prevention, cancer biology, translational and clinical studies, survivorship, and advocacy. 

In 2019, Oncotarget participated in the AACR Annual Meeting at the Georgia World Congress Center in Atlanta, Georgia, USA, and "AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics," at the Hynes Convention Center in Boston, Massachusetts, USA. The total registration count from the 2019 AACR Annual Meeting was over 21,000—nearly 16,000 of which were scientific attendees from all over the world. 

Follow the Oncotarget Twitter account (@Oncotarget) for live updates about the conference using the #AACR21 hashtag.

About Oncotarget:

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Oncotarget

Oncotarget: Participating in the AACR Annual Meeting

The profound impact of the COVID-19 pandemic, caused by the SARS-CoV-2 virus, has been felt across various domains, including the realm of cancer research and treatment. As scientists delve deeper into the intricate mechanisms of this viral pathogen, intriguing revelations have emerged regarding its potential influence on cellular processes pivotal to cancer development and progression. 

In a new study, researchers Wafik S. El-Deiry and Shengliang Zhang from Brown University and Lifespan Health System shed light on the intricate interplay between the SARS-CoV-2 spike protein and the tumor suppressor p53, a key guardian of genomic integrity. On May 3, 2024, they published their new research paper in Oncotarget’s Volume 15, entitled, “Transfected SARS-CoV-2 spike DNA for mammalian cell expression inhibits p53 activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2 proteins in cancer cells and increases cancer cell viability after chemotherapy exposure.”

In this study, researchers El-Deiry and Zhang uncovered a hitherto unknown facet of the SARS-CoV-2 spike protein’s impact on cancer cells. Their findings, meticulously detailed in their research paper, have ignited a newfound curiosity within the scientific community.

Full blog - https://www.oncotarget.org/2024/05/09/sars-cov-2-spike-protein-disrupts-p53-tumor-suppressor-pathway/

Paper DOI - https://doi.org/10.18632/oncotarget.28582

Correspondence to - Wafik S. El-Deiry - wafik@brown.edu

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Keywords - cancer, SARS-COV2 spike, p53, MDM2, chemotherapy

About Oncotarget 

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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SARS-CoV-2 Spike Protein Disrupts p53 Tumor Suppressor Pathway

BUFFALO, NY - January 21, 2025 – A new #research paper was #published in Oncotarget's Volume 16 on January 20, 2025, titled “Anti-correlation of KLRG1 and PD-1 expression in human tumor CD8 T cells."

The study, authored by Dr. Steven A. Greenberg from Harvard Medical School, has discovered a potential new way to improve cancer treatment by studying two key molecules found in immune cells: KLRG1 and PD-1. Analysis of data from cancer patients and healthy individuals revealed that these molecules work in opposite ways in cancer-fighting cells, suggesting that targeting both at the same time could enhance the effectiveness of cancer immunotherapy.

“Much effort in the field of immuno-oncology has involved the study of combination therapies, including combinations involving blockade of more than one T cell inhibitory receptor.”

The immune system helps fight cancer through specialized cells called T cells. Treatments known as checkpoint inhibitors, which block proteins like PD-1, have been successful in helping these cells attack cancer. However, combining different checkpoint inhibitors has not always provided the expected improvements. 

This new research focuses on KLRG1, a lesser-known protein, and its relationship with PD-1. The findings suggest that targeting both markers simultaneously could create a stronger and more effective immune response against cancer. Most existing immunotherapy treatments focus only on blocking PD-1, which is commonly found in “exhausted” T cells that struggle to fight cancer. In contrast, KLRG1 is linked to more active, mature T cells that are better at attacking tumors. By blocking both PD-1 and KLRG1, new treatment strategies could help patients with hard-to-treat cancers, such as lung cancer, melanoma, and colorectal cancer.

KLRG1 has not been widely studied in cancer immunotherapy, but this research highlights its potential to revolutionize treatment strategies. While current combinations of checkpoint inhibitors have shown only limited improvements, using therapies that target both PD-1 and KLRG1 could lead to more significant and long-lasting benefits.

“Whereas much of the T cell inhibitory drug development efforts over the last decade have been focused on combinations of expression-correlated inhibitory receptor targets, the targeting of anti-correlated inhibitory receptors has greater potential to produce supra-additive benefit, and KLRG1 has this distinct property.”

Further studies and clinical trials are needed to explore how combining PD-1 and KLRG1 treatments could benefit different types of cancer. If successful, this strategy could open the door for the creation of new combined immunotherapies.

DOI - https://doi.org/10.18632/oncotarget.28679

Correspondence to - Steven A. Greenberg - sagreenberg@bwh.harvard.edu

Video short - https://www.youtube.com/watch?v=PME2xfyYN18

About Oncotarget 

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Anti-Correlation Between KLRG1 and PD-1 in Tumor CD8 T Cells

BUFFALO, NY - January 22, 2025 – A new #review was #published in Oncotarget's Volume 16 on January 20, 2025, titled “Evolving concepts in HER2-low breast cancer: Genomic insights,
definitions, and treatment paradigms."

Researchers Whitney L. Hensing, Emily L. Podany, James J. Sears, Shaili Tapiavala, and Andrew A. Davis from the University of Missouri-KC School of Medicine and Washington University in St. Louis School of Medicine explore HER2-low breast cancer, a recently recognized type of breast cancer that is changing the way clinicians should approach treatment. The review explains what makes HER2-low breast cancer different and highlights new treatment options that are helping patients.

“Breast cancer, which has been historically classified as HER2-positive versus HER2-negative, is currently facing a paradigm shift in both the definition of HER2 status and in the existing treatment algorithms.”

Breast cancer is usually classified into two main types based on the HER2 protein: HER2-positive or HER2-negative. HER2-low breast cancer falls somewhere in between. Thanks to new targeted treatments, such as a drug called trastuzumab deruxtecan, patients with HER2-low breast cancer now have more options and better chances of responding to treatment.

The review looks at recent studies on the genetics of HER2-low breast cancer. Researchers found that these tumors are often hormone receptor (HR)-positive, meaning they respond to hormones like estrogen. Some tumors also carry a common genetic change called a PIK3CA mutation, which could affect how well treatments work. However, experts say HER2-low breast cancer is not a completely separate breast cancer type but rather an opportunity for more personalized treatment.

“Despite evidence from existing literature that HER2-low breast cancer does not represent a distinct biologic and prognostic subtype, the introduction of HER2-low expression as a therapeutic target has expanded patient eligibility for a potent class of anti-HER2 drugs, HER2-directed ADCs, with potential for significant efficacy.”

Despite these advances, diagnosing HER2-low breast cancer can still be difficult. Current testing methods are not always accurate, and different laboratories may get different results. The review calls for better detection methods to make sure patients who can benefit from these new treatments are correctly identified.

With cancer treatments becoming more personalized, the review also explains how clinicians can fit HER2-low treatments into existing guidelines to help patients. The success of targeted therapies is changing how breast cancer is treated, especially for patients whose cancer has metastasized.

In conclusion, experts believe ongoing research will continue to improve the way HER2-low breast cancer is diagnosed and treated. However, they stress the need for better detection methods and continued exploration of new therapies to help patients get the best possible care.

DOI - https://doi.org/10.18632/oncotarget.28680

Correspondence to - Andrew A. Davis - aadavis@wustl.edu

About Oncotarget 

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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HER2-Low Breast Cancer: Genomic Insights and Evolving Treatment Paradigms

BUFFALO, NY - February 10, 2025 – A new #casereport was #published in Volume 16 of Oncotarget on February 5, 2025, titled “A case report of donor cell–derived hematologic neoplasms 9 years after allogeneic hematopoietic cell transplantation."

In this case report, Aleksandra Mroczkowska-Bękarciak and Tomasz Wróbel from Wroclaw Medical University describe a rare and serious complication after a stem cell transplant. The case involves a patient who, nine years after receiving a stem cell transplant for acute myeloid leukemia (AML), developed a new, aggressive blood cancer originating from donor cells. Despite receiving treatment, the disease progressed to myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), ultimately leading to the patient’s death.

Stem cell transplants are a life-saving treatment for many blood cancers, including AML. While relapse of the original cancer is the most common concern, this case highlights another rare but serious complication: the development of donor cell-derived hematologic neoplasms (DCHN).

The report details the case of a 23-year-old woman who remained in remission for nearly 10 years following a successful hematopoietic stem cell transplant from an unrelated donor. However, she later developed a new form of leukemia, driven by genetic mutations in the ASXL1, SETBP1, and EZH2 genes—biomarkers linked to highly aggressive blood cancers. Over the next two years, the disease progressed despite intensive treatment, ultimately proving fatal.

This case highlights the need for continued monitoring of transplant recipients, even years after the procedure. Although DCHN is extremely rare, its occurrence raises critical questions about the process by which donor cells transform into leukemia.

Some stem cell donors may unknowingly carry genetic mutations that are harmless in their own bodies but could trigger cancer in recipients. Additionally, factors such as immunosuppressive therapy, bone marrow stress, and transplantation procedures may contribute to these rare but deadly outcomes.

“Early diagnosis and intervention are crucial to improving patient prognosis.” 

Ongoing research is focused on improving donor screening methods to help predict and prevent these complications. In the future, routine genetic testing for stem cell donors could become a standard part of the transplant process, helping clinicians identify potential risks before transplantation.

More studies are needed to fully understand why donor-derived cancers develop and how they can be prevented. With continued progress in precision medicine and genetic diagnostics, researchers aim to make stem cell transplants safer and more effective for all patients.

DOI - https://doi.org/10.18632/oncotarget.28686

Correspondence to - Aleksandra Mroczkowska-Bękarciak - omroczkowska@interia.pl

Video short - https://www.youtube.com/watch?v=G2zd0UqWzeE

About Oncotarget 

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Rare Case of Donor Cell-Derived Blood Cancer Discovered Nine Years After Stem Cell Transplant

BUFFALO, NY – February 14, 2025 – A new #review was #published in Oncotarget, Volume 16, on February 12, 2025, titled “SETDB1 amplification in osteosarcomas: Insights from its role in healthy tissues and other cancer types.”

Authors Elodie Verdier, Nathalie Gaspar, Maria Eugenia Marques Da Costa, and Antonin Marchais from the Gustave Roussy Cancer Campus analyzed recent studies on a gene called SETDB1, which may play a key role in osteosarcoma, a type of bone cancer that mostly affects teenagers and young adults. Their review highlights how SETDB1 helps cancer cells grow, resist treatment, and avoid the immune system. Because of this, blocking SETDB1 could be a promising new way to treat osteosarcoma.

Osteosarcoma is a fast-growing bone cancer that is usually treated with surgery and chemotherapy. However, if the cancer spreads or returns, treatment options are very limited. Scientists are searching for new ways to stop this disease, and recent studies have found that osteosarcoma cells often have extra copies of the SETDB1 gene. This seems to make the cancer more aggressive and harder to treat.

“Whole exome sequencing of osteosarcoma samples from both diagnosis and relapses has highlighted several factors, including SETDB1, that are amplified in the most aggressive forms of the disease.”

SETDB1 is involved in epigenetics, meaning it affects how genes are turned on and off without changing the DNA itself. The review explains that SETDB1 helps tumors hide from the immune system, making it difficult for the body to fight the cancer naturally. The researchers believe that blocking SETDB1 could help the immune system recognize and attack osteosarcoma cells. Some experimental drugs that target SETDB1 are already being tested in the lab.

The review also describes how SETDB1 influences key cancer pathways, such as Wnt signaling, which helps cancer cells grow, and epithelial-mesenchymal transition (EMT), a process that allows cancer to spread. The authors suggest that combining SETDB1-blocking drugs with immunotherapy or radiation could be an effective new strategy for treating osteosarcoma.

Another key finding is that SETDB1 may help cancer cells become resistant to chemotherapy, making treatment less effective. This means that drugs targeting SETDB1 could not only slow cancer growth but also make existing treatments work better.

While more research is needed, this review brings attention to SETDB1 as a potential treatment target. Scientists hope that a deeper understanding of SETDB1 will lead to new therapies that improve survival rates for osteosarcoma patients.

DOI - https://doi.org/10.18632/oncotarget.28688

Correspondence to - Antonin Marchais - antonin.marchais@gustaveroussy.fr, and Maria Eugenia Marques Da Costa - jenny.marquescosta@gustaveroussy.fr

Video short - https://www.youtube.com/watch?v=f9WgaDoEubs

About Oncotarget 

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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SETDB1 Amplification Identified as a Potential Target for New Osteosarcoma Treatment

BUFFALO, NY - February 18, 2025 – A new #researchpaper was #published in Oncotarget, Volume 16, on February 12, 2025, titled “Could Panitumumab with very low dose Capecitabine be an option as a maintenance regimen."

In this study, researchers Doaa A. Gamal, Aiat Morsy, and Mervat Omar from Assiut University Hospital, evaluated a new maintenance treatment for metastatic colorectal cancer (mCRC). Their findings suggest that a combination of two drugs—Panitumumab, a targeted therapy that blocks a protein called epidermal growth factor receptor to slow cancer growth, and low-dose Capecitabine, a chemotherapy drug that converts into 5-fluorouracil (5-FU) inside the body to stop cancer cells from growing and dividing—could help extend survival in patients with mCRC. This regimen appears to be both effective and well-tolerated, especially for patients with wild-type KRAS mCRC who had previously responded to treatment.

Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. Standard treatment often involves a combination of chemotherapy and targeted therapies, but many patients face challenges related to treatment toxicity and resistance, which can lead to treatment interruptions. This study tested whether a lower-intensity maintenance treatment could help keep the cancer under control after initial treatment.

The study involved 25 mCRC patients with wild-type KRAS and BRAF, who first received six rounds of standard 5-FU-based chemotherapy with Panitumumab. Patients who responded well then switched to a maintenance treatment of Panitumumab every two weeks and a low, continuous dose of Capecitabine. The results showed that patients had a median progression-free survival of 18 months and a median overall survival of 45 months, indicating a strong potential benefit.

Patients with metastases detected at the same time as the primary tumor showed a longer progression-free survival than those with metastases appearing later. The treatment was also well tolerated, with only 8% of patients experiencing severe side effects such as skin rash or diarrhea, which were managed with standard treatments.

"In our research, the toxicity profile was very acceptable, and no patients needed to stop treatment or had a dose modification due to toxicity."

Finding a way to keep cancer under control while reducing side effects is a major goal in cancer treatment. While other maintenance therapies like Bevacizumab and Cetuximab have been studied, this research suggests that Panitumumab with low-dose Capecitabine could be a promising new option. Panitumumab is already an FDA-approved drug, but its role in maintenance therapy had not been extensively explored. The results of this study suggest that this combination may help delay disease progression while keeping side effects manageable, ultimately improving patients’ quality of life.

Although larger studies are needed, these findings open the door for further clinical trials to confirm the benefits of this regimen. If validated, this approach could change the standard of care for mCRC patients, particularly those who cannot tolerate more intensive chemotherapy.

DOI - https://doi.org/10.18632/oncotarget.28687

Correspondence to - Doaa A. Gamal - doaaalygamaal@gmail.com

Video short - https://www.youtube.com/watch?v=wuPSS0EdK-8

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Panitumumab with Low-Dose Capecitabine as a Maintenance Regimen: A Viable Option?

BUFFALO, NY - February 24, 2025 – A new #research paper was #published in Oncotarget, Volume 16, on February 18, 2025, titled “Robust p53 phenotypes and prospective downstream targets in telomerase-immortalized human cells."

Researchers Jessica J. Miciak, Lucy Petrova, Rhythm Sajwan, Aditya Pandya, Mikayla Deckard, Andrew J. Munoz, and Fred Bunz from the Sidney Kimmel Comprehensive Cancer Center and Johns Hopkins University School of Medicine studied the tumor-suppressing protein p53, which plays a key role in preventing cancer. Their findings reveal how p53 affects cancer cell growth, treatment resistance, and potential drug targets, providing new insights that could improve future cancer therapies.

The p53 protein plays a crucial role in preventing cancer by stopping uncontrolled cell growth. However, many cancers mutate or suppress p53, allowing tumors to develop and resist treatment. In this study, researchers restored p53 function in colorectal cancer cells, which led to slower cellular growth, increased cellular aging (senescence), and greater sensitivity to radiation therapy. These findings suggest that p53 status influences cancer progression and response to treatment, making it a promising target for new therapies.

The study also examined hTERT-RPE1 cells; a type of non-cancerous human cell used in research. When the TP53 gene was disrupted in these cells, they grew faster and became more resistant to radiation, reinforcing the idea that p53 helps prevent cancerous growth.

Another key discovery was a previously unnoticed p53 mutation (A276P) found in a subset of hTERT-RPE1 cells. This mutation weakened p53’s ability to regulate certain genes but did not affect its ability to control calcium signaling, a process important for cell survival. The unexpected appearance of this mutation suggests that even non-cancerous cells can acquire genetic changes that mimic early cancer development. This insight could help scientists better understand how cancers evolve and become resistant to treatment.

"Cancers that retain wild type TP53 presumably harbor other clonal alterations that permitted their precursors to bypass p53-mediated growth suppression."

A breakthrough in the study was the identification of two new p53-regulated genes that could be important for cancer treatment. The first, ALDH3A1, helps detoxify harmful substances and may impact cancer cell resistance to oxidative stress. The second, NECTIN4, is a protein found in many aggressive cancers, including bladder and breast cancer. Notably, NECTIN4 is the target of enfortumab vedotin, an FDA-approved drug for bladder cancer. These discoveries provide new potential drug targets and could lead to improved therapies for cancers that still retain some p53 function.

In conclusion, this research highlights the critical role of p53 in cancer biology and suggests that restoring p53 function could make tumors more vulnerable to radiation and chemotherapy. The discovery of new p53-controlled genes provides new opportunities for targeted cancer therapies. With further research, these findings could lead to new precision medicine strategies that leverage p53’s natural tumor-suppressing abilities.

DOI - https://doi.org/10.18632/oncotarget.28690

Correspondence to - Fred Bunz - fredbunz@jhmi.edu

Video short - https://www.youtube.com/watch?v=Psxj3ctbTuk

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Researchers Identify New p53 Targets to Combat Cancer Growth

BUFFALO, NY - March 11, 2025 – A new #editorial was #published in Oncotarget, Volume 16, on March 10, 2025, titled “EXPOSOMES and GENES: The duo influencing CANCER initiation and progression."

In this editorial, Drs. Uzma Saqib, Katherine E. Ricks, Alexander G. Obukhov, and Krishnan Hajela from Devi Ahilya Vishwavidyalaya (DAVV) in Indore, India, discuss how environmental factors, known as exposomes, interact with genes to influence cancer risk. The authors highlight how pollution, diet, infections, and chronic stress can trigger genetic alterations that may lead to cancer. Understanding these connections could play a crucial role in cancer prevention and public health strategies.

Genes store the instructions for how the body functions, but they can be damaged by harmful exposures. Polluted air, radiation, tobacco smoke, and processed foods can lead to DNA damage, interfering with the body’s natural ability to repair itself. Over time, these genetic changes can increase the risk of cancer development. The authors emphasize that nearly everyone is exposed to cancer risk factors daily. 

“According to the Global Air Quality Guidelines of World Health Organization (WHO), nearly all of the global population (>99%) breathes polluted air that exceeds guideline limits.”

For example, air pollution has been linked to lung cancer, while UV radiation is a leading cause of skin cancer. Processed meats contain harmful chemicals that can damage DNA, and excessive alcohol consumption has been shown to raise the risk of liver cancer by causing toxic buildup in cells. Even chronic stress and hormone imbalances can weaken the body’s natural defenses against cancer by altering key genetic pathways.

Infections also play a critical role in cancer risk. The Helicobacter pylori bacterium can cause stomach cancer by damaging stomach cells, while human papillomavirus (HPV) is strongly linked to cervical cancer. Other bacteria, viruses, and fungi can introduce genetic instability that contributes to tumor growth.

Despite these risks, scientists estimate that up to 40% of cancers could be prevented through lifestyle changes such as a healthy diet, regular exercise, and avoiding harmful exposures. Advances in research technology are helping scientists better understand how environmental factors alter genes, leading to new strategies for cancer detection and prevention.

“Understanding the exposome-gene-cancer research axis will have a significant impact on public health and the development of more effective strategies for prevention and treatment of diseases.”

The editorial underscores the urgent need for greater public awareness and policy action to reduce exposure to harmful environmental risks. As scientists continue to explore the connection between exposomes and genetic changes, their findings could revolutionize public health efforts and cancer prevention strategies.

By recognizing the long-term impact of environmental exposures, individuals, communities, and policymakers can take meaningful steps toward reducing cancer risk and promoting healthier environments for future generations.

DOI - https://doi.org/10.18632/oncotarget.28696

Correspondence to - Krishnan Hajela - hajelak@gmail.com

Video short - https://www.youtube.com/watch?v=kE4XX9ULHBQ

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How Environmental Exposures Affect Genes and Increase Cancer Risk

BUFFALO, NY – March 12, 2025 – A new #editorial was #published in Oncotarget, Volume 16, on March 10, 2025, titled “COMETgazing – interesting insights, lessons for clinical practice and a call for more precision using the biomarkerSCOPE.”

Dr. Mangesh A. Thorat, affiliated with Queen Mary University of London, Homerton University Hospital, and King’s College London, discusses new findings suggesting that some women diagnosed with early-stage breast cancer may not need immediate surgery. The editorial is based on results from the COMET trial, which studied women with low- to intermediate-grade ductal carcinoma in situ (DCIS). The findings raise questions about the necessity of surgery and highlight the importance of more precise screening methods for DCIS, ensuring that only those who truly need treatment receive it.

Breast cancer screening programs are designed to detect cancer early, but this editorial reinforces the concern that some detected cancers may never become a real threat. The COMET trial compared two strategies for treating breast cancer: standard treatment, which includes surgery and possible additional therapy, versus active monitoring, where patients are closely observed without immediate intervention.

The results indicate that many of the invasive cancers diagnosed in the monitoring group were likely present from the start rather than developing from DCIS over time. Dr. Thorat points out that these invasive cancers were often slightly larger, but they did not appear to be aggressive. These findings challenge the assumption that immediate treatment is necessary for all cases of DCIS. Researchers estimate that at least half of the invasive breast cancers in this study either take years to progress or may never progress at all.

“The planned long-term follow-up of the trial may shed more light on the median length of lead-time and the proportion of IBCs regressing as well as DCIS progression under different lead-time assumptions.”

Current methods for evaluating DCIS rely heavily on histological grading, which has limitations. Dr. Thorat emphasizes the need for more precise tools to determine which DCIS cases require treatment. His previous research suggests that biomarkers, such as multi-clonal estrogen receptor (ER) expression and tumor-infiltrating lymphocytes (TILs), may help predict which DCIS cases are truly at risk of becoming invasive.

The editorial also highlights that many women prefer to avoid surgery when possible. In a related study, only 52% of patients in the standard care group followed through with it, indicating that more individuals are willing to consider alternatives to surgery. This fact underscores the importance of developing accurate biomarkers to guide treatment decisions and ensure that patients receive appropriate care without unnecessary interventions.

As researchers continue to follow patients from the COMET trial, they hope to learn more about how invasive breast cancers behave over time. Finally, Dr. Thorat encourages clinicians and scientists to rethink breast cancer treatment and develop better ways to identify which patients truly need surgery—and which do not.

DOI - https://doi.org/10.18632/oncotarget.28698

Correspondence to - Mangesh A. Thorat - m.thorat@qmul.ac.uk

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Rethinking Breast Cancer Screening: New Insights on Overdiagnosis

BUFFALO, NY - March 18, 2025 – A new precision oncology paper was #published in Oncotarget, Volume 16, on March 12, 2025, titled “Worldwide Innovative Network (WIN) Consortium in Personalized Cancer Medicine: Bringing next-generation precision oncology to patients."

Led by Oncotarget Editor-in-Chief Dr. Wafik S. El-Deiry and a global team of researchers, this special publication highlights the groundbreaking work of the Worldwide Innovative Network (WIN) Consortium, a global collaboration dedicated to transforming cancer care through personalized medicine. By leveraging artificial intelligence (AI), molecular profiling, and innovative clinical trials, WIN is helping clinicians tailor treatments to each patient’s unique cancer profile—moving beyond the traditional one-size-fits-all approach.

The WIN Consortium is a fast-moving, non-profit organization bringing together nearly 40 academic, industry, and research institutions, along with patient advocacy groups, across 18 countries and five continents. Founded in 2010 in France by Dr. John Mendelsohn (MD Anderson Cancer Center) and Dr. Thomas Tursz (Gustave Roussy), WIN has been led by different renowned experts. Currently under Dr. El-Deiry’s leadership, WIN continues to break barriers in cancer research, ensuring cutting-edge treatments reach patients worldwide.

“The WIN global consortium is ready to take up the challenge by bringing the best possible Precision Oncology trial to patients.”

One of WIN’s most significant contributions is the development of N-of-1 clinical trials, a revolutionary approach that personalizes cancer treatment based on a patient’s specific tumor characteristics. Unlike traditional trials that test drugs on large groups, N-of-1 trials focus on finding the best therapy for an individual patient using AI-driven algorithms, genomic analysis, and real-world data. WIN’s WINTHER trial was one of the first to use both DNA and RNA analysis to match patients with the most effective therapies, while the WINGPO trial builds on this approach by integrating AI and liquid biopsies to refine treatment selection. These innovations are helping clinicians make more precise treatment decisions and improving outcomes for cancer patients.

While advancing research, the WIN Consortium is also addressing major challenges in precision oncology, including drug accessibility, regulatory barriers, and disparities in global healthcare. By working closely with governments, pharmaceutical companies, and advocacy organizations, WIN is aiming to ensure that life-saving treatments are accessible to all patients, regardless of location or financial status.

WIN’s mission is clear: to accelerate the future of precision oncology by delivering the latest scientific advancements into real-world cancer care. As the field continues to evolve, WIN remains at the forefront, developing next-generation trials and leveraging AI-driven insights to improve patient outcomes. Through global collaboration and groundbreaking research, the WIN Consortium is shaping a future where every cancer patient receives the most effective, personalized treatment possible.

DOI - https://doi.org/10.18632/oncotarget.28703

Correspondence to - Wafik S. El-Deiry - wafik@brown.edu

Video short - https://www.youtube.com/watch?v=XAdYfFoMvUM

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WIN Consortium Leading the Future of Precision Cancer Medicine

BUFFALO, NY - March 21, 2025 – A new #editorial was #published in Oncotarget, Volume 16, on March 13, 2025, titled “No disease left behind."

In this editorial, Dr. Muzamil Arshad from the University of Chicago Medical Center and colleagues highlight a growing concern in cancer care: radiotherapy may leave behind microscopic cancer even when scan images suggest the tumor is gone. The authors argue that this “residual disease” is more common than expected and is linked to worse long-term outcomes. Their perspective calls for a rethinking of how treatment success is judged and how cancer is followed up after therapy.

Radiotherapy, especially a form known as stereotactic ablative radiotherapy (SABR), is widely used to treat cancers in the lung, liver, prostate, and other organs.  SABR delivers high-dose radiation with outstanding precision and often shows excellent results on scans. However, the authors highlight that relying only on imaging may not provide a complete picture. Months or even years later, follow-up biopsies frequently reveal cancer cells that scan imaging tests were unable to identify.

“Residual cancer is identified on histology in 40% of lung, 57–69% of renal cell, 7.7–47.6% of prostate and 0–86.7% of hepatocellular carcinoma.”

This gap between what scans show and what tissue analysis finds can have serious consequences. Studies across several cancer types have shown that patients with residual disease—even if small—are more likely to experience cancer recurrence and shorter survival. This pattern holds true for rectal, cervical, prostate, and liver cancers, among others. In some cases, not  destroying the tumor completely may allow it to spread to distant organs.

The authors point out that a complete response on scan imaging does not necessarily indicate the complete disappearance of the tumor. This mismatch can mislead both clinicians and patients into thinking treatment was more successful than it truly was. The editorial encourages more regular use of biopsy-based tests and new strategies to increase the true effectiveness—or “ablative power”—of SABR.

They also discuss promising approaches to improve outcomes, including increasing radiation doses and combining radiotherapy with other therapies, such as immune checkpoint inhibitors. While some trials have shown better tumor control with these combinations, results have not been consistent, and more research is needed to refine these strategies.

In summary, this editorial encourages the cancer care community to look beyond the scan images. Residual cancer may remain even when imaging looks clear, and recognizing this hidden threat is key to improving long-term outcomes. The goal is not just to shrink tumors on screen but to fully eliminate the disease.

DOI - https://doi.org/10.18632/oncotarget.28700

Correspondence to - Muzamil Arshad - muzamil.arshad@uchicagomedicine.org

Video short - https://www.youtube.com/watch?v=XC0XNjJjC2o

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Clear Scans Can Be Misleading: Residual Cancer Linked to Worse Outcomes

BUFFALO, NY - April 2, 2025 – A new #research paper was #published in Oncotarget, Volume 16, on March 21, 2025, titled “NSD2-epigenomic reprogramming and maintenance of plasma cell phenotype in t(4;14) myeloma."

Researchers Andrea Gunnell, Scott T. Kimber, Richard Houlston, and Martin Kaiser from The Institute of Cancer Research, London, studied how a gene called NSD2 affects the behavior of multiple myeloma (MM) cells. Their findings reveal that NSD2 plays a key role in helping cancer cells retain their identity as plasma cells—white blood cells that normally help the immune system fight infections. This discovery could shape future treatment strategies for patients with a high-risk form of MM known as t(4;14) myeloma.

Multiple myeloma is a type of blood cancer that begins in plasma cells found in the bone marrow. About 20% of patients have a genetic change called t(4;14), which makes the NSD2 gene highly active. The research team compared two types of myeloma cells: one with high NSD2 activity and one where NSD2 was turned off. They found that when NSD2 is active, it changes how DNA is folded and how genes are switched on or off, especially genes that help the cells act like plasma cells. When NSD2 was turned off, important markers like CD38 were reduced, and other genes normally silent in plasma cells were activated.

The study indicated that NSD2 does not directly affect the main genes responsible for plasma cell creation. Instead, it influences many other genes that help maintain the cancer cell’s identity, which contributes to cancer growth and survival. 

The researchers also observed physical changes in the cancer cells. Cells with active NSD2 looked and behaved more like typical plasma cells, while cells without NSD2 appeared more immature and lost important surface markers. These changes were linked to differences in how the DNA was organized inside the cells.

These findings are especially important as new drugs are being developed to block NSD2. The study suggests that turning off NSD2 could change how MM cells respond to existing treatments. For example, if NSD2 is blocked and CD38 levels drop, the change might affect therapies that target CD38. However, the rise of other immune-related genes might make certain immunotherapies more effective.

“Identifying the biological consequences of NSD2 over-expression in MM is not only relevant to informing new therapeutic interventions through indirect targeting of downstream effectors, but also to anticipate possible consequences of targeting NSD2 directly.”

In summary, this study shows how NSD2 helps myeloma cells keep their cancerous identity by reorganizing the DNA and influencing gene activity. Understanding this role could help researchers design better treatment approaches and possibly overcome resistance to current therapies in t(4;14) myeloma.

DOI - https://doi.org/10.18632/oncotarget.28706

Correspondence to - Andrea Gunnell - andrea.gunnell@icr.ac.uk

Video short - https://www.youtube.com/watch?v=hibkjUpRq7I

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NSD2 Gene Drives Cancer Cell Identity in Multiple Myeloma

BUFFALO, NY - April 4, 2025 – A new #research paper was #published in Oncotarget, Volume 16, on March 27, 2025, titled “Imipridones ONC201/ONC206 + RT/TMZ triple (IRT) therapy reduces intracranial tumor burden, prolongs survival in orthotopic IDH-WT GBM mouse model, and suppresses MGMT."

Researchers from Brown University, led by first author Lanlan Zhou and corresponding author Wafik S. El-Deiry, have shown that combining a new class of drugs called imipridones with standard glioblastoma treatments significantly improves outcomes in mice. The study tested ONC201 and its analog ONC206 in combination with radiation therapy and the chemotherapy drug temozolomide (TMZ), a regimen referred to as IRT. This triple therapy slowed tumor growth and extended survival in a mouse model of glioblastoma, offering a potential new strategy for one of the most aggressive and treatment-resistant brain cancers.

Glioblastoma is a fast-growing brain tumor with a poor prognosis and limited treatment options. Standard care typically includes surgery, radiation, and TMZ, but most patients still face a short life expectancy. While ONC201 and ONC206 are currently being studied in clinical trials as single agents, there has been limited information on how they interact with standard therapies. This study is the first to show that both drugs work synergistically with radiation and TMZ, strengthening their overall effects.

The results showed that in both laboratory-grown tumor cells and mice, the triple therapy significantly slowed cancer cell growth, reduced tumor size, and prolonged survival compared to using any single or double treatment. Mice treated with IRT lived an average of 123 days, with some surviving more than 200 days—far longer than the 44 to 103 days observed with other treatment combinations. In addition to directly killing tumor cells, ONC201 and ONC206 lowered the expression of MGMT, a protein that helps tumors resist chemotherapy, making the treatment more effective.

The researchers also found that the triple therapy reshaped the tumor environment. It decreased levels of harmful molecules that promote tumor growth and immune evasion while increasing signals that activate the immune system. This dual action—directly attacking tumors and boosting immune responses—adds to the potential impact of this treatment approach.

“Overall, our preclinical findings support further exploration of the ONC201 and ONC206 IRT regimen as a potential treatment for GBM and diffuse gliomas with H3K27M mutations.”

While these findings are based on preclinical mouse models, they offer strong support for advancing this triple therapy to clinical trials. ONC201 and ONC206 are promising due to their ability to cross the blood-brain barrier and enhance the effects of standard treatment. This combination could lead to more effective therapies for glioblastoma and other hard-to-treat brain tumors.

DOI - https://doi.org/10.18632/oncotarget.28707

Correspondence to - Wafik S. El-Deiry - wafik@brown.edu

Video short - https://www.youtube.com/watch?v=Q_mXy8mana0

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Triple Therapy Slows Glioblastoma Growth and Extends Survival in Preclinical Study

BUFFALO, NY - April 8, 2025 – A new #editorial was #published in Oncotarget, Volume 16, on April 4, 2025, titled “Deep learning-based uncertainty quantification for quality assurance in hepatobiliary imaging-based techniques."

Dr. Yashbir Singh from Mayo Clinic and his colleagues discussed how artificial intelligence (AI) can improve liver imaging by recognizing when it might be wrong. This approach, called “uncertainty quantification,” helps clinicians better detect liver cancer and other diseases by pointing out areas in medical scans that need a second look. The authors explain how these AI tools could make imaging results more accurate and reliable, which is especially important when diagnosing serious conditions like liver tumors.

Liver and bile duct imaging is difficult because of the organ’s complex structure and differences in image quality. Even skilled radiologists can struggle to identify small or hidden tumors, especially in patients with liver damage or scarring. The editorial explains how new AI models not only read medical images but also measure their own confidence. When the AI system is unsure, it can alert clinicians to take a closer look. This extra layer of information can reduce missed diagnoses and improve early detection of liver cancer.

One of the most advanced tools described in the editorial is called AHUNet (Anisotropic Hybrid Network). This AI model works with both 2D and 3D images and can highlight which parts of a scan it is most confident about. It performed well when measuring the entire liver and showed how its confidence dropped when scanning smaller or multiple lesions. This feature helps clinicians know when more testing or review is needed.

The authors also looked at other AI models used in liver imaging. Some tools were able to analyze liver fat using ultrasound images and give clinicians both a result and a confidence score. Others improved the speed and accuracy of liver magnetic resonance imaging (MRI) scans, helping to create clear images in less time. These advancements could help hospitals work faster and provide better care.

The editorial highlights how this technology can be especially helpful in smaller clinics. If they do not have liver specialists, they could still use AI systems that flag uncertain results and send them to larger centers for review. Such an approach could improve care in rural or less-resourced areas.

“Radiology departments should develop standardized reporting templates that incorporate uncertainty metrics alongside traditional imaging findings.”

By using AI tools that know when to second-guess themselves, clinicians may soon have more reliable methods for detecting liver cancer and monitoring liver disease. The authors suggest that uncertainty-aware AI may soon become a vital part of everyday medical imaging, supporting faster and more accurate decisions in liver disease care.

DOI: https://doi.org/10.18632/oncotarget.28709

Correspondence to: Yashbir Singh — singh.yashbir@mayo.edu

Video short - https://www.youtube.com/watch?v=Zm0QASQ_YSI

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Keywords: cancer, deep learning, uncertainty quantification, radiology, hepatobiliary imaging

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AI That Measures Its Own Uncertainty Could Improve Liver Cancer Detection

BUFFALO, NY - April 11, 2025 – A new research perspective was published in Oncotarget, Volume 16, on April 4, 2025, titled “GSK3β activation is a key driver of resistance to Raf inhibition in BRAF mutant melanoma cells."

In this work, first author Diana Crisan and corresponding author Abhijit Basu from the University Hospital Ulm led a team that presents experimental evidence pointing to the protein GSK3β as a key contributor to drug resistance in melanoma. Their findings suggest that GSK3β becomes increasingly active in cancer cells during treatment, helping them survive and adapt despite ongoing therapy with BRAF inhibitors.

Melanoma is a type of skin cancer in which nearly half of patients have mutations in the BRAF gene that accelerate tumor growth. While treatments targeting BRAF, known as BRAF inhibitors, initially work well, tumors often find ways to fight back. This research perspective explores how GSK3β, a protein involved in metabolism and cell survival, becomes more active in melanoma cells that develop resistance to BRAF inhibitors.

Researchers treated melanoma cells with a common BRAF mutation using Dabrafenib, a widely used BRAF inhibitor. Over time, the cancer cells developed resistance and showed a marked increase in GSK3β levels. This pattern was confirmed across multiple melanoma cell models, suggesting that the finding is consistent and reliable.

Importantly, the researchers observed that treating resistant cancer cells with a GSK3β inhibitor significantly reduced their growth. This result suggests that blocking this protein could restore sensitivity to treatment, highlighting GSK3β as a promising therapeutic target and supporting the idea of combining GSK3β inhibitors with existing melanoma therapies.

“Remarkably, treatment of BRAFi-resistant melanoma cells with the GSK3 inhibitor LY2090314 for three weeks could overcome resistance and significantly decreased melanoma cell growth, confirming the causal role of GSK3 activation for BRAFi resistance development.”

The research perspective adds to ongoing efforts to understand and overcome melanoma drug resistance. It shows that resistance is not driven only by genetic mutations but may also involve adaptive changes in the cell’s internal signaling and survival mechanisms. By identifying GSK3β as a potential contributor, the authors offer a new direction for improving the durability of targeted treatments in melanoma.

As research continues, GSK3β may be a critical factor in the long-term success of melanoma therapy, particularly for patients who have stopped responding to standard BRAF-targeted drugs.

Continue reading: DOI: https://doi.org/10.18632/oncotarget.28711

Correspondence to: Abhijit Basu — abhijit.basu@alumni.uni-ulm.de

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Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Protein GSK3β Offers New Angle on Overcoming Melanoma Drug Resistance

BUFFALO, NY - April 15, 2025 – A new #research paper was #published in Oncotarget, Volume 16, on April 4, 2025, titled “Association between two single nucleotide polymorphisms of the Prostaglandin-Endoperoxide Synthase 1 and 2 genes and cell proliferative prostatic diseases in Lebanon."

The team of researchers led by first author Brock J. Sheehan and corresponding author Ruhul H. Kuddus, from Utah Valley University, discovered that a specific genetic variation in the PTGS2 gene is associated with a higher risk of benign prostate hyperplasia (BPH), a common condition in aging men. The study, which focused on Lebanese men, suggests that the C allele of the -765 G>C polymorphism in the PTGS2 gene may increase risk to this non-cancerous but problematic prostate condition. This finding could help identify men at greater risk earlier and lead to better treatment choices.

Benign prostate hyperplasia and prostate cancer are two common conditions that involve abnormal cell growth in the prostate gland. While prostate cancer is malignant and potentially life-threatening, BPH is a non-cancerous enlargement that can still significantly affect quality of life. Both conditions are widespread in older men, with BPH affecting over 70% of men above 60. Researchers have long suspected that inflammation-related genes may play a role in their development. In this study, the focus was to study PTGS1 and PTGS2, genes that help produce enzymes involved in inflammation.

Using DNA samples from 168 Lebanese men, including 61 with prostate cancer, 51 with BPH, and 56 healthy controls, the researchers analyzed two common gene variants. They found no link between the PTGS1 variant and either condition. However, the PTGS2 variant showed a strong association with BPH. Men carrying the C version of this gene were more than twice as likely to have BPH compared to those without it. While a similar trend was observed in men with prostate cancer, the results were less conclusive.

"The C allele of SNP-765G>C of the PTGS2 gene was significantly associated with an increased risk of BPH (OR = 2.30, p-value = 0.01)."

This is the first study to report a genetic link between the C allele of the -765 G>C polymorphism in the PTGS2 gene and BPH in Lebanese men. It builds on earlier findings that associated this gene variant with various cancers, including prostate, colon, and stomach cancers. Although based on a relatively small and specific population, the study offers new insight that could help improve genetic screening and guide prevention strategies.

The research also points to the potential benefits of COX-2 inhibitors—drugs already used to treat prostate conditions—which may be more effective for men with certain PTGS2 gene types. Further studies in larger and more diverse groups are needed to confirm these results and explore how this gene variant influences prostate disease. In the future, simple genetic tests could help identify men at higher risk before symptoms appear, allowing for earlier and more personalized care.

Continue reading: DOI: https://doi.org/10.18632/oncotarget.28710

Correspondence to: Ruhul H. Kuddus — ruhul.kuddus@uvu.edu

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Gene Variant Linked to Benign Prostate Hyperplasia Risk in Lebanese Men

BUFFALO, NY - April 28, 2025 – A new #research paper was #published in Oncotarget, Volume 16, on April 24, 2025, titled “PD-L1 and FOXP3 expression in high-grade squamous intraepithelial lesions of the anogenital region."

Researchers Humberto Carvalho Carneiro, Rodrigo de Andrade Natal, José Vassallo and Fernando Augusto Soares from the Instituto D’Or de Pesquisa e Ensino and Rede D’Or studied early tissue changes caused by human papillomavirus (HPV) in the anal, vulvar, and penile regions. They found that high-grade pre-cancer lesions triggered stronger immune responses and showed higher levels of two immune-related markers, PD-L1 and FOXP3. These findings are important because they help explain how some HPV-related lesions progress to cancer while others heal on their own.

High-risk HPV is known to cause several types of anogenital cancers. Before these cancers appear, the virus often leads to abnormal tissue changes known as high-grade squamous intraepithelial lesions. Many of these lesions disappear without treatment, but some become cancer—especially in people with weakened immune systems. This study explored how immune activity may play a role in this progression.

The researchers examined tissue from 157 patients—95 males and 55 females—with either high-grade or low-grade HPV-related lesions. They found that T-regulatory cells, marked by the FOXP3 protein, were more common in high-grade lesions. These immune cells are known to suppress immune responses, which can allow infected or abnormal cells to grow. The team also found higher expression of PD-L1, a protein that helps cells evade immune detection, particularly in inflammatory immune cells.

"Dense inflammatory infiltrates and high counts of FOXP3+ cells were significantly more frequent in patients with HSILs than in those with LSILsHR (p = 0.04 and 0.02, respectively). HSILs also exhibited higher PD-L1 expression (padj < 0.01 and < 0.01 for the SP142 and 22C3 clones, respectively), based on the Poisson generalized linear model.”

These findings suggest that HPV may begin avoiding the immune system early in infection, even before cancer develops. The combination of high FOXP3 and PD-L1 levels may create a protective environment for infected cells, making them harder for the body to eliminate. This immune evasion may allow the lesions to remain and, over time, become cancerous.

The study also compared patients with and without HIV to assess whether immune health influenced the results. While those with compromised immune systems had more extensive lesions, PD-L1 and FOXP3 expression was also found in patients with healthy immune systems. This evidence shows that immune evasion by HPV can happen regardless of a person’s immune status.

Understanding how PD-L1 and FOXP3 function in early HPV-related lesions may help clinicians predict which lesions are more likely to become cancer. These insights could lead to new strategies for monitoring, treating, or preventing HPV-related precancerous lesions and cancer in the anogenital region. The study highlights how early immune system changes can play a key role in the development of HPV-related cancers.

DOI - https://doi.org/10.18632/oncotarget.28715

Correspondence to - Humberto Carvalho Carneiro - humberto.carneiro@rededor.com.br

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Early Immune Evasion Found in HPV-Related Pre-Cancer Lesions of the Anogenital Region

BUFFALO, NY - May 9, 2025 – A new #research paper was #published in Oncotarget, Volume 16, on May 8, 2025, titled “METTL3 promotes oral squamous cell carcinoma by regulating miR-146a-5p/SMAD4 axis."

In this study, researchers Jayasree Peroth Jayaprakash, Pragati Karemore, and Piyush Khandelia from the Birla Institute of Technology and Science, India, discovered that a molecule called METTL3 contributes to the development and spread of oral squamous cell carcinoma (OSCC). The study shows that METTL3 increases the levels of a small RNA molecule called miR-146a-5p, which blocks SMAD4, a key tumor-suppressing gene. These findings help explain why oral cancers are difficult to treat and may offer a new target for more effective therapies.

Oral squamous cell carcinoma is a common and aggressive cancer affecting the mouth and throat. It has a high death rate, mainly due to late detection, treatment resistance, and the cancer’s ability to invade nearby tissues. In this study, the researchers focused on METTL3, an enzyme that adds chemical tags known as m6A marks to RNA, which change how genetic information is used by cells. They found that METTL3 is unusually active in OSCC cells, causing an increase in miR-146a-5p. This molecule, in turn, blocks the function of SMAD4, which helps control how cells grow and die in our bodies.

“METTL3, the primary m6A RNA methyltransferase, is significantly upregulated in OSCC cells leading to increased global m6A levels.”

When METTL3 was reduced or chemically blocked, miR-146a-5p levels dropped and SMAD4 levels increased. This shift slowed the growth of cancer cells, increased their death, and made them less likely to spread. When researchers reintroduced miR-146a-5p or lowered SMAD4 levels again, the cancer-promoting behavior returned. These results show that the METTL3–miR-146a-5p–SMAD4 pathway plays a key role in OSCC.

The findings open up new possibilities for treatment. Drugs that block METTL3 or miR-146a-5p or that restore SMAD4 could slow or stop tumor growth. One such drug, STM2457, which targets METTL3, has already shown promise in lab studies. As research progresses, targeting this molecular pathway may offer a new strategy in treating OSCC.

This discovery improves our understanding of how OSCC develops and avoids the body’s defenses. By interfering with this newly discovered pathway, future treatments may become more successful, improving survival rates and quality of life for people with this disease.

DOI - https://doi.org/10.18632/oncotarget.28717

Correspondence to - Piyush Khandelia - piyush.khandelia@hyderabad.bits-pilani.ac.in

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METTL3 Drives Oral Cancer by Blocking Tumor-Suppressing Gene

BUFFALO, NY - May 14, 2025 – A new #review paper was #published in Volume 16 of Oncotarget on May 9, 2025, titled “Relationship between ABO blood group antigens and Rh factor with breast cancer: A systematic review and meta-analysis."

A comprehensive study, led by first authors Rahaf Alchazal from Yarmouk University and Khaled J. Zaitoun from Johns Hopkins University School of Medicine and Jordan University of Science and Technology, examined the potential link between blood type and breast cancer. The research team conducted a systematic review and meta-analysis of 29 previously published studies, involving more than 13,000 breast cancer patients and over 717,000 controls. 

“Researchers searched for studies on breast cancer patients and ABO blood groups across four major databases: PubMed, Scopus, Web of Science, and Google.“

Breast cancer is the most common cancer among women worldwide. Identifying risk factors is vital for early detection and prevention. While many studies have explored lifestyle and genetic causes, this analysis focused on the ABO blood group system. By pooling global data, the researchers found that blood type A was the most common among breast cancer patients and was significantly associated with an 18% increased risk compared to type O.

The study did not find a significant association between breast cancer and blood types B, AB, or Rh factor. Although the results do not prove causation, they point to a biological pattern worth further investigation. Blood group antigens are proteins found on the surface of cells, including breast tissue. These molecules may influence how cancer develops and spreads by interacting with the immune system or affecting cell behavior.

This meta-analysis is the most extensive review to date on this topic, based on studies conducted across Asia, Europe, Africa, and the Americas. While previous research found unclear conclusions, this large-scale evaluation provides stronger evidence for a possible connection between blood type A and breast cancer risk.

Researchers note that regional differences, genetic diversity, and study quality may affect individual results. Nevertheless, the overall trend supports considering blood type A as a potential risk marker. This insight could help shape screening guidelines, encouraging earlier or more frequent checkups for women with this blood type.

Further research is needed to understand why blood type A may play a role in cancer development. Future studies may explore genetic mechanisms, immune responses, and other biological pathways. These efforts could lead the way for more personalized cancer prevention and care strategies.

DOI - https://doi.org/10.18632/oncotarget.28718

Correspondence to - Khaled J. Zaitoun - kzaitou1@jh.edu

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Keywords - cancer, breast cancer, cancer risk factors, blood group antigens, tumor

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Blood Type A Identified as Potential Breast Cancer Risk Factor

BUFFALO, NY – May 19, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on May 9, 2025, titled “Analytical validation of a circulating tumor DNA assay using PhasED-Seq technology for detecting residual disease in B-cell malignancies.”

In this study, a team from Foresight Diagnostics led by first author Nina Klimova and corresponding author Laura Hyland validated a new DNA-based blood test designed to detect minimal residual disease (MRD) in patients with B-cell cancers. This assay uses a highly sensitive method called Phased Variant Enrichment and Detection Sequencing (PhasED-Seq) to find tiny fragments of tumor DNA in the blood. Its ultra-sensitive detection capabilities offer a powerful tool for early cancer detection, monitoring treatment response, and predicting cancer reappearance.

B-cell lymphomas, such as diffuse large B-cell lymphoma (DLBCL), are among the most prevalent blood cancers. Although many patients respond to initial treatment, up to 40% relapse. Standard monitoring methods such as imaging scans often miss low levels of cancer cells, creating a need for more precise tools. This study introduces a non-invasive blood test that improves the detection of MRD, a critical factor in guiding follow-up care and early intervention.

The test works by tracking unique groups of mutations known as phased variants in tumor DNA. These mutations are more specific to cancer and allow for highly accurate identification of tumor fragments in the bloodstream. The PhasED-Seq-based MRD assay was tested on three types of samples. First, blood plasma from healthy individuals was used to confirm the test does not give false positives. Second, researchers created controlled samples by mixing tumor DNA from lymphoma patients with healthy DNA to measure how sensitive and precise the test is. Finally, blood samples from patients with B-cell lymphoma were used to compare the new test to an existing method.

Across all sample types, the PhasED-Seq-based MRD assay demonstrated exceptional performance—capable of detecting fewer than one cancer DNA molecule per million normal DNA fragments. It also demonstrated a very low false positive rate and over 96% reproducibility across different laboratory conditions. Compared to an existing method, the new PhasED-Seq assay showed more than 90% agreement in positive results and nearly 78% agreement in negative results. In cases where the tests disagreed, the new method aligned more closely with actual clinical outcomes, including whether patients relapsed or stayed in remission.

“The background error rate of the PhasED-Seq-based MRD assay was 1.95E-08, or 1.95 mutant molecules in 100 million informative molecules.”

The findings support the use of PhasED-Seq-based MRD assays in routine clinical practice. It could be especially useful for identifying patients who need additional treatment even when imaging results appear normal. This aligns with updated clinical guidelines that encourage the use of blood-based DNA tests to supplement traditional scans in lymphoma care.

This study offers strong evidence that the PhasED-Seq-based MRD assay is a precise, reliable, and clinically relevant tool. By detecting signs of cancer earlier and more accurately, it may help clinicians tailor treatments to individual patients and improve long-term outcomes in B-cell malignancies.

DOI - https://doi.org/10.18632/oncotarget.28719

Correspondence to - Laura Hyland - laura.hyland@foresight-dx.com

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New Ultra-Sensitive DNA Blood Test for Detecting Residual Cancer in B-cell Lymphoma Patients

BUFFALO, NY - May 21, 2025 – A new #review was #published in Volume 16 of Oncotarget on May 19, 2025, titled “Advancements in bladder cancer treatment: The synergy of radiation and immunotherapy."

Researchers from the University of California, Irvine, led by Nazmul Hasan, reviewed recent clinical and scientific advances in combining radiation therapy with immunotherapy for bladder cancer. The article summarizes growing evidence that this combined approach may strengthen the immune response and improve long-term disease control. This strategy is especially important for patients who are not candidates for surgery or who respond poorly to conventional treatments.

Bladder cancer is a serious and frequent condition, particularly affecting older men. Traditional treatments—surgery, chemotherapy, and radiation—can be effective, but they often fail to prevent cancer reappearance in advanced cases. The review explores how combining radiation and immunotherapy could improve outcomes by helping the immune system detect and destroy cancer cells more effectively.

Radiation therapy destroys cancer cells and triggers the release of tumor signals that attract immune cells. Immunotherapy, including drugs like pembrolizumab and nivolumab, helps the immune system work better by blocking proteins that allow cancer to evade detection. Used together, these treatments may produce a stronger, more widespread anti-tumor effect, even at distant sites not directly targeted by radiation.

The review discusses several clinical trials that support this approach. One phase II study reported that combining radiation with the immunotherapy drug durvalumab led to promising survival rates and manageable side effects. Another trial in Australia tested pembrolizumab with radiation and chemotherapy, resulting in high tumor control and extended patient survival. However, the review also points out that other trials showed serious side effects when high doses or multiple immunotherapy drugs were used at once.

"Joshi et al. performed a phase II study to determine the safety and efficacy of combining radiation therapy with durvalumab, a PD-L1 inhibitor, in patients who were ineligible for surgery or cisplatin-based chemotherapy."

While the combination approach is promising, the authors emphasize that more research is needed to refine this treatment strategy. One major challenge is determining which patients are most likely to benefit. Future studies should focus on identifying reliable biomarkers, such as tumor mutation burden or immune activity, to guide personalized treatment plans.

This review highlights the potential of combining radiation and immunotherapy to improve outcomes for bladder cancer patients. With continued research and careful treatment design, this approach could offer new treatment options for those facing aggressive or hard-to-treat forms of the disease.

DOI - https://doi.org/10.18632/oncotarget.28723

Correspondence to - Nazmul Hasan - nhasan1@hs.uci.edu

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Keywords - cancer, bladder cancer, immunotherapy, radiation, microenvironment, abscopal

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Combining Radiation and Immunotherapy Shows Promise for Bladder Cancer

BUFFALO, NY - May 23, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on May 19, 2025, titled “Immune-mediated adverse events following atezolizumab and bevacizumab in a multinational Latin American cohort of unresectable hepatocellular carcinoma."

The study, led by first authors Leonardo Gomes da Fonseca from Hospital das Clínicas, Universidade de São Paulo, Brazil, and Federico Piñero from Hospital Universitario Austral, Argentina, investigated how patients with advanced liver cancer in Latin America respond to a widely used immunotherapy combination. The researchers found that although a minority of patients developed immune-related side effects, these events did not significantly impact overall survival. Their findings highlight the importance of early recognition and careful management of such side effects in real-world clinical settings.

Liver cancer is a leading cause of cancer deaths worldwide, with limited treatment options for patients diagnosed at an advanced stage. Immunotherapy, particularly the combination of atezolizumab and bevacizumab, has become a standard approach. However, these treatments can sometimes trigger the body’s immune system to attack healthy organs, leading to what are called immune-related adverse events, or irAEs. Until now, little data existed on how frequently these events occur in Latin American patients and whether they impact treatment outcomes.

The researchers followed 99 patients from Argentina, Brazil, Chile, and Colombia, most of whom had cirrhosis or underlying liver disease. They received atezolizumab and bevacizumab for a median duration of six months. The researchers reported that only 18% of the patients experienced immune-related side effects, most commonly affecting the liver (hepatitis) and thyroid (thyroiditis). Most of these cases were mild or moderate, and half of them resolved completely within a month. Only eight patients needed treatment with steroids to control the immune response.

Importantly, the occurrence of immune-related side effects did not affect how long patients survived after starting treatment. The median survival was the same—18.5 months—for both those who experienced irAEs and those who did not. This result suggests that while irAEs require careful management, they may not reduce the overall benefits of immunotherapy.

Another significant finding was that patients with higher levels of alpha-fetoprotein (AFP), a protein often elevated in liver cancer, were more likely to experience these side effects. This information could help clinicians identify patients who need closer control during treatment.

“Notably, baseline alpha-fetoprotein (AFP) values ≥400 ng/ml were significantly associated with the development of irAEs.”

The study also points to key differences between clinical trial results and real-world experiences. While clinical trials report higher rates of side effects, this real-world data showed a lower incidence, possibly due to less intensive monitoring or differences in how side effects are documented in everyday practice.

In summary, this study highlights that patients require ongoing vigilance and individualized care when treating liver cancer with immunotherapy. It provides valuable information to healthcare providers in Latin America and other regions with similar patient populations, aiming to improve outcomes while minimizing risks.

DOI - https://doi.org/10.18632/oncotarget.28721

Correspondence to - Federico Piñero - fpinerof@cas.austral.edu.ar

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Immune Side Effects of Liver Cancer Therapy Studied in Latin American Patients

BUFFALO, NY - June 3, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on May 19, 2025, titled “PRDX1 protects ATM from arsenite-induced proteotoxicity and maintains its stability during DNA damage signaling."

In this study, led by first author Reem Ali and corresponding author Dindial Ramotar from Hamad Bin Khalifa University in Qatar, researchers discovered that a protein called PRDX1 helps maintain the stability of ATM, a key protein involved in repairing damaged DNA, especially when cells are under stress from arsenite exposure. The study found that without PRDX1, cells lose their ability to repair DNA and become more sensitive to chemotherapy. This finding suggests that targeting PRDX1 could improve the success of some cancer treatments.

PRDX1 is already known for its role in protecting cells from oxidative damage, but this study shows it also plays a role in the DNA repair process. ATM is an essential protein that detects breaks in DNA and starts the repair process. When PRDX1 is missing, ATM is rapidly lost, especially when cells are exposed to arsenite, a toxic substance found in the environment. Without ATM, the DNA repair system fails, leaving cells more vulnerable to damage.

By using both human cell lines and clinical samples from ovarian cancer patients, the team showed that high levels of PRDX1, along with ATM and MRE11 (another DNA repair protein), were linked to tumors' aggressive features and lower patient survival rates. This pattern suggests that tumors with high PRDX1 may resist chemotherapy by increasing their DNA repair capacity. On the other hand, removing PRDX1 weakened the repair system and made cancer cells more responsive to DNA-damaging platinum drugs.

The study also showed that combining low doses of arsenite with drugs that either block ATM or damage DNA caused a much higher rate of cancer cell death in cells that lacked PRDX1. These results suggest a new treatment approach: lowering PRDX1 levels to make cancer cells more sensitive to DNA-damaging platinum therapies already in use. This highlights PRDX1 not only as a protector of cell function but also as a potential weak point in cancer cells.

“As such, we propose that small molecule inhibitors of PRDX1, or single nucleotide polymorphisms that compromise PRDX1 function, in combination with low doses of arsenite can be exploited to treat chemo-resistant tumours.”

These findings open the door for the use of PRDX1 as a biomarker to predict treatment response and as a promising target for new combination therapies. For patients with ovarian cancer and potentially other tumors, adjusting PRDX1 levels may help overcome drug resistance and improve outcomes.

DOI - https://doi.org/10.18632/oncotarget.28720

Correspondence to: Dindial Ramotar - dramotar@hbku.edu.qa

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Keywords - cancer, redox signaling, homologous recombination, protein interaction, cell cycle, protein modification

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Blocking PRDX1 Protein May Improve Chemotherapy Response in Ovarian Cancer

BUFFALO, NY - June 4, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on May 20, 2025, titled “Targeting PCNA/AR interaction inhibits AR-mediated signaling in castration resistant prostate cancer cells."

In this study, authors Shan Lu and Zhongyun Dong from the University of Cincinnati College of Medicine investigated how interfering with a protein interaction could reduce prostate cancer growth. Their study based on prostate cancer cells shows that blocking the link between PCNA, a protein important for DNA repair, and the androgen receptor (AR), which drives prostate cancer growth, can slow down cancer cell multiplication. This discovery could lead to a new treatment for patients with advanced prostate cancer, particularly those no longer responding to hormone therapy.

Prostate cancer is one of the most common cancers in men. Many patients eventually become resistant to hormone treatment. In this advanced stage, called castration-resistant prostate cancer (CRPC), tumors continue to grow by using either the full-length androgen receptor (AR-FL) or altered versions called AR variants (AR-Vs). This study shows that the interaction between AR and PCNA helps both AR-FL and AR-Vs remain active, supporting cancer cell survival and growth.

The researchers identified a new region in the AR that binds to PCNA. They developed a small peptide, R9-AR-PIP, to mimic this region and block the AR-PCNA connection. They found that this peptide reduced AR’s ability to bind DNA and lowered the levels of key genes involved in cancer cell growth. Importantly, the peptide was effective against both types of AR, including the variant forms that are especially challenging in CRPC.

“We identified a second PIP-box (PIP-box592) in the DNA binding domain of AR and found that dihydrotestosterone enhances the binding of full-length AR (AR-FL) but not a constitutively active variant (AR-V7) to PCNA.”

They also tested a small molecule, PCNA-I1S, which interferes with PCNA’s ability to move to the cell nucleus and interact with AR. This molecule showed similar effects as the peptide, reducing AR activity and stopping cancer cell growth. Together, these findings suggest that targeting PCNA/AR interactions could be a promising strategy to fight CRPC, especially in patients with limited treatment options.

One key result was that both the peptide and the small molecule reduced the levels of cyclin A2, a protein that helps cells divide and is often overexpressed in CRPC. Since this protein is linked to patients' poor outcomes, its reduction could be especially beneficial.

This study improves our understanding of how prostate cancer continues to grow even after hormone treatments fail. By blocking a crucial helper of the androgen receptor, researchers have uncovered a new way to potentially slow or stop the disease. Further studies in animal models are needed, but this approach could lead to more effective treatments for men with advanced prostate cancer.

DOI - https://doi.org/10.18632/oncotarget.28722

Correspondence to - Zhongyun Dong - dongzu@ucmail.uc.edu

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Keywords - cancer, PCNA, androgen receptor, PCNA inhibitors, AR splicing variants, CRPC

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Targeting PCNA-Androgen Receptor Interaction Suppresses Prostate Cancer Cell Growth

BUFFALO, NY – June 9, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on May 20, 2025, titled “Cigarette smoke and decreased DNA repair by Xeroderma Pigmentosum Group C use a double hit mechanism for epithelial cell lung carcinogenesis.”

In this study, led by first author Nawar Al Nasralla and corresponding author Catherine R. Sears, from the Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indianapolis and the Richard L. Roudebush Veterans Affairs Medical Center, researchers investigated how cigarette smoke and reduced DNA repair capacity contribute together to the development of lung cancer. They found that when a critical DNA repair protein called XPC is decreased and lung cells are exposed to cigarette smoke, the combination causes extensive damage and significantly increases cancer risk.

Non-small cell lung cancer (NSCLC) develops through both genetic and environmental factors. This study focused on how cigarette smoke affects the body’s natural ability to repair DNA. The researchers studied the role of XPC, a protein essential for recognizing and repairing harmful DNA changes caused by tobacco smoke. They found that low levels of XPC — commonly seen in lung cancer patients — made lung cells less capable of repairing DNA. This made the cells unstable and more likely to become cancerous. These changes were most pronounced in normal lung cells, suggesting that the earliest stages of disease occur before cancer is even detected.

The findings support a “double hit” model, where both cigarette smoke and reduced DNA repair work together to drive cancer development. In laboratory experiments, normal lung cells with low XPC levels showed more damage and cell death after cigarette smoke exposure. By contrast, lung cancer cells were more resistant to smoke damage, even when XPC was low, indicating that critical changes had likely occurred earlier in the disease process.

“Our study suggests that cigarette smoke exposure leads to decreased XPC mRNA expression, exacerbates total and oxidative DNA damage, hinders NER, and may contribute to lung cancer development.”

The study also showed that DNA repair ability declined significantly in healthy cells after smoke exposure, but this effect was not seen in cancer cells. In addition, the researchers confirmed that XPC gene activity was lower in actual lung tumor tissue compared to nearby healthy lung tissue. This pattern was consistent across both adenocarcinoma and squamous cell carcinoma, the two main types of NSCLC.

These results add to our understanding of how lung cancer begins at the molecular level. By showing how cigarette smoke and reduced DNA repair combine to create genetic instability, the research points toward new strategies for prevention. A better understanding of XPC’s role could help identify high-risk individuals and inform future efforts to stop lung cancer before it begins.

DOI - https://doi.org/10.18632/oncotarget.28724

Correspondence to - Catherine R. Sears - crufatto@iu.edu

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Keywords - cancer, DNA repair, DNA damage, lung adenocarcinoma, squamous cell carcinoma, Xeroderma Pigmentosum Group C (XPC)

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Cigarette Smoke and DNA Repair Deficiency Drive Lung Cancer Development

BUFFALO, NY — June 10, 2025 — The Ride for Roswell, one of the USA’s largest cycling events supporting cancer research, returns to Buffalo on Saturday, June 28, 2025. Hosted annually by Roswell Park Comprehensive Cancer Center, this community-wide event brings together riders, volunteers, and supporters to raise funds for cancer research, celebrate survivors, and honor those lost to the disease. 

Among the returning participants is the Open Access Team, led by team captain Sergei Kurenov. This year, the team is once again proudly sponsored by Impact Journals, the publisher of open access journals Oncotarget, Aging, Genes & Cancer, and Oncoscience.

“For the last 10 years, I have continuously participated in the Ride for Roswell in honor of those who have bravely fought cancer,” said Kurenov. “This journey is deeply personal for me. My father battled cancer, and some of my closest friends have fought through prostate and lung cancer with incredible strength.”

This year, the Open Access Team rides in honor of Dr. Mikhail (Misha) Blagosklonny, a visionary scientist who dedicated his career to advancing cancer and aging research. As the founding Editor-in-Chief of Oncotarget, Aging, and Oncoscience, Dr. Blagosklonny was a pioneer of open-access publishing. His groundbreaking work on mTOR signaling and rapamycin transformed our understanding of cancer biology and healthy lifespan extension.

The 2025 Ride for Roswell features nine route options, ranging from 4 to 100 miles, all beginning at the University at Buffalo North Campus. Riders from across the USA and beyond are invited to participate and make a meaningful impact in the fight against cancer.

This ride is more than just a journey on two wheels—it’s a commitment to building a future where no one has to fear a cancer diagnosis. There is still time to support the Open Open Access Team in the 2025 Ride for Roswell. Whether by donating, joining the team, or sharing their story, every action brings us closer to better treatments, deeper understanding, and, ultimately, a cure.

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About Oncotarget 

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Oncotarget Sponsors Open Access Team in 2025 Ride for Roswell

BUFFALO, NY - June 11, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on May 29, 2025, titled “Durable complete response in leptomeningeal disease of EGFR mutated non-small cell lung cancer to amivantamab, an EGFR-MET receptor bispecific antibody, after progressing on osimertinib.”

A team led by first author Jinah Kim, from the University of Vermont Medical Center, and corresponding author Young Kwang Chae, from the Feinberg School of Medicine, reports a clinical case in which a patient with advanced non-small cell lung cancer (NSCLC) carrying rare EGFR mutations responded remarkably to amivantamab after other treatments had failed. The patient experienced a complete resolution of brain and spinal fluid metastases, suggesting that amivantamab may be a viable option for patients with uncommon genetic profiles and limited therapy options.

Lung cancer remains one of the leading causes of cancer-related deaths worldwide. Patients with NSCLC who have rare mutations in the EGFR gene often face limited treatment options and poor outcomes, especially when the disease spreads to the brain or spinal fluid. This case involved a 67-year-old man diagnosed with NSCLC who had two rare EGFR mutations—G719A and A289V. After disease progression on osimertinib and other therapies, the patient began amivantamab monotherapy.

Within six weeks, his lung tumor shrank by over 30 percent. By six months, imaging confirmed the disappearance of brain metastases and leptomeningeal disease, a serious condition affecting the membranes of the brain and spinal cord. Blood tests showed no detectable cancer-related mutations, and the patient, previously wheelchair-bound, regained the ability to walk and perform daily activities. This response has been sustained for more than 19 months.

 “Treatment produced a durable response over 19 months, including a 32.2% reduction in tumor size at six weeks, and complete resolution of brain metastases and LMD by six months.”

Amivantamab is a bispecific antibody that targets EGFR and MET, two key drivers of tumor growth. While it is approved in combination regimens for common EGFR mutations, its effectiveness as a single agent in rare mutations or in treating brain metastases remains largely unproven. This case challenges the assumption that large antibody drugs cannot cross the blood-brain barrier and suggests that amivantamab may have potential in managing central nervous system involvement. Further research is needed to clarify how the drug achieves these effects and to explore its broader use in patients with rare EGFR mutations and limited treatment options.

This case highlights three key findings: amivantamab may be effective against rare EGFR mutations, can be used as monotherapy, and may overcome the challenges of the blood-brain barrier. Although based on a single patient, the results provide encouraging evidence to support further investigation of amivantamab in treating difficult-to-manage forms of NSCLC.

DOI - https://doi.org/10.18632/oncotarget.28730

Correspondence to - Young Kwang Chae - young.chae@northwestern.edu

Video short - https://www.youtube.com/watch?v=RJX3rmtH7h8

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Keywords - cancer, amivantamab, monotherapy, rare EGFR mutation, NSCLC, leptomeningeal disease

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Rare Non-Small Cell Lung Cancer with Brain Metastases Responds to Amivantamab Monotherapy

BUFFALO, NY - June 13, 2025 – A new #review was #published in Volume 16 of Oncotarget on June 4, 2025, titled “Applying the unattainable triangle in cardio-oncology care: Balancing cost, quality, and time.”

In this review, first author John Hoverson, corresponding author Stella Pak, and colleagues from the University of Texas Health Science Center at San Antonio explore how the “unattainable triangle”—a business concept describing the trade-offs between cost, quality, and time—can help improve healthcare delivery in cardio-oncology. As cancer treatments become more complex and often affect the heart, this model highlights the challenge of providing care that is fast, effective, and affordable.

Cardio-oncology is an emerging field focused on preventing and managing heart problems caused by cancer therapies. The review explains that high-quality cancer care often requires advanced diagnostics and close collaboration between oncologists and cardiologists, which can drive up costs and time demands. Understanding how to balance these pressures is essential for delivering better outcomes for patients.

Many cancer survivors face long-term cardiovascular complications due to their treatment. Early monitoring and intervention can reduce these risks. However, these improvements often come with financial burdens, especially when key tests are not covered by insurance. Meanwhile, both patients and clinicians must manage the burden of tight appointment schedules, long clinic visits, and increasing demands on their time.

To improve care quality, the authors emphasize the need for interdisciplinary teamwork and ongoing education. Surveys show that many clinicians are still unfamiliar with cardio-oncology guidelines, which can compromise care. The review also highlights the potential for artificial intelligence and digital tools to streamline care delivery, reduce wait times, and support both patients and providers.

Importantly, the authors point out that improving one area—such as quality—can come at the expense of others, like cost or time. They encourage healthcare systems to take a balanced approach, setting clear goals and using integrated care models that consider all three elements of the triangle together.

“While a perfect model for managing the unattainable triangle may be simply that, ‘unattainable’, investments in research, patient-centered care, data-driven decision-making, and financial alignment with payers will be crucial to the long-term success of both patient outcomes and the organization’s profitability.”

While achieving perfect balance may be difficult, the review suggests that using the unattainable triangle as a guiding framework can help hospitals and clinicians make smarter, more sustainable decisions. As cardio-oncology continues to expand in response to the growing number of cancer survivors with cardiovascular needs, this approach could help improve patient outcomes and strengthen healthcare systems.

DOI - https://doi.org/10.18632/oncotarget.28738

Correspondence to - Stella Pak - stellacpak@outlook.com

Video short - https://www.youtube.com/watch?v=65-5eUuVyyk

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Keywords - cancer, cardio-oncology, quality improvement, cardiology, oncology

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Balancing Time, Cost, and Quality in Cardio-Oncology Care

BUFFALO, NY - June 17, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on June 10, 2025, titled “Exceptional responders to immunotherapy in pancreatic cancer: A multi-institutional case series of a rare occurrence.”

The study, led by first author Kavin Sugumar and corresponding author Jordan M. Winter, from University Hospitals Seidman Cancer Center, reports on a rare group of pancreatic cancer (PC) patients who responded remarkably well to immunotherapy, a treatment typically considered ineffective for this cancer type. The analysis, which includes data from 14 patients across multiple U.S. institutions, identifies outcomes that could help refine treatment strategies for one of the most aggressive and deadly forms of cancer.

“Between 2020–21, 471 oncologists from 91 major cancer centers in the United States were contacted.”

Pancreatic cancer has among the lowest survival rates and few effective therapies. While immunotherapy has transformed the treatment landscape for several other cancers, it generally offers little benefit for pancreatic cancer. However, this study highlights a small but important group of patients who experienced significant and sustained responses to immune-based treatment without chemotherapy. Most had advanced or metastatic disease and had already progressed after standard treatments.

Among the 14 patients, 82% had partial tumor shrinkage, and nearly one-third had a notable decrease in tumor markers. The median progression-free survival was 12 months, and most patients were still alive at follow-up, with survival rates of 80% at one year and 70% at two years. These outcomes contrast sharply with standard therapies, which often provide only a few months of benefit for similar patients.

Interestingly, while some patients had high microsatellite instability (MSI-high)—a known marker for immunotherapy success—more than half did not, suggesting other biological mechanisms may be involved. This result highlights the need for new biomarkers to be discovered to predict treatment response in future studies.

This case series is the largest focused exclusively on exceptional immunotherapy responders in pancreatic cancer. By excluding patients who received chemotherapy, the study isolates the effects of immune-based drugs, including PD-1 inhibitors such as pembrolizumab and nivolumab, CTLA-4 inhibitors like ipilimumab, and agents targeting macrophages.

While the sample size is small, the findings challenge the assumption that immunotherapy is ineffective for nearly all pancreatic cancer patients. The study suggests that, under certain biological conditions, this treatment can be remarkably successful. Further research is needed to understand the underlying mechanisms.

This work supports the need to reconsider how clinical trials are designed for pancreatic cancer and who is eligible for immunotherapy. Broader criteria and more personalized molecular profiling could help uncover hidden opportunities for treatment in this highly lethal cancer.

DOI - https://doi.org/10.18632/oncotarget.28739

Correspondence to - Jordan M. Winter - jordan.winter@UHHospitals.org

Video short - https://www.youtube.com/watch?v=VeWTcuVmqgM

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Rare Pancreatic Cancer Patients Show Strong Response to Immunotherapy

BUFFALO, NY – June 20, 2025 – A new #review was #published in Volume 16 of Oncotarget on June 10, 2025, titled “Beyond DNA damage response: Immunomodulatory attributes of CHEK2 in solid tumors.”

In this paper, led by first author Helen Qian and corresponding author Crismita Dmello from Northwestern University Feinberg School of Medicine, researchers compiled growing evidence that the CHEK2 gene, long known for its role in repairing DNA damage, may also influence how tumors respond to immunotherapy. Their analysis suggests that problems in CHEK2 function might make cancer cells more vulnerable to immune system attacks, highlighting a new opportunity to improve treatment outcomes in solid tumors.

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment; however, they are effective in only a subset of patients. This review suggests that tumors with reduced CHEK2 activity may accumulate more mutations that produce signals the immune system can recognize. These signals, known as neoantigens, help immune cells identify and destroy cancer cells more effectively. The review connects this process not only to CHEK2’s established role in the DNA damage response but also to a newly proposed function in shaping the immune environment of tumors.

CHEK2 normally helps maintain genomic stability by enabling precise DNA repair. When this function is lost, cells rely on more error-prone repair methods, leading to additional mutations. These mutations can increase tumor mutational burden, which has been linked to better outcomes with immunotherapy. Beyond DNA repair, the review highlights a second mechanism: activation of the cGAS-STING pathway. This pathway detects fragments of damaged DNA and triggers inflammation that attracts immune cells to the tumor.

The authors highlight studies where CHEK2-deficient tumors responded better to PD-1 inhibitors, a common type of immune checkpoint inhibitor. In both lab models and early-stage clinical settings, CHEK2 loss was associated with increased infiltration of CD8+ T cells—immune cells essential for attacking cancer cells. In cancers such as glioblastoma and renal cell carcinoma, which are typically resistant to immunotherapy, reduced CHEK2 expression was linked with more favorable immune activity and higher expression of interferon-related genes.

The compiled evidence points to CHEK2 as a potential biomarker for identifying patients likely to respond to immunotherapy. In addition, combining CHEK2 inhibitors with existing immunotherapies may enhance anti-tumor effects, particularly in cancers with limited treatment options. The review notes that some clinical trials using the CHEK1/2 inhibitor prexasertib alongside immune checkpoint therapies have already shown promising early results.

“The initial results from this Phase I clinical trial support the immunomodulatory role of CHEK2 expression and even suggest CHEK2 potentiates immunosuppression.”

Although more research is needed to confirm these mechanisms and improve treatment approaches, this review underscores the expanding role of DNA repair genes like CHEK2—not only in maintaining genome integrity but also in helping the immune system fight cancer.

DOI - https://doi.org/10.18632/oncotarget.28740

Correspondence to - Crismita Dmello - stellacpak@outlook.com

Video short - https://www.youtube.com/watch?v=C26pEBc0itk

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CHEK2 Identified as a Potential Target to Improve Immunotherapy in Solid Tumors

Prostate cancer is the second most diagnosed cancer among men worldwide and remains a leading cause of cancer-related death. While early forms of the disease can usually be treated successfully, advanced cases remain a major challenge. Scientists have now discovered a new potential way to slow the growth of advanced, treatment-resistant prostate cancer. These results were recently published in Volume 16 of Oncotarget by researchers from the University of Cincinnati College of Medicine.

Understanding Advanced Prostate Cancer

Early-stage prostate cancer can often be treated successfully. Most treatments work by lowering testosterone levels or blocking the hormone from activating the androgen receptor (AR), which drives cancer growth.

In some patients, however, the disease progresses to castration-resistant prostate cancer (CRPC). Even with drastic reductions in testosterone levels, the tumors continue to grow at this stage. CRPC is much more difficult to treat, and current therapies such as hormone blockers or chemotherapy typically extend life by only a few months.

One reason for this resistance is that cancer cells often switch to a different form of the androgen receptor called AR-V7. This variant remains permanently active, even without testosterone, making hormone-based drugs less effective. Because of this, new treatment strategies that work independently of hormone levels are needed.

The Study: Targeting a New Weakness in Prostate Cancer Cells

In the study titled “Targeting PCNA/AR interaction inhibits AR-mediated signaling in castration resistant prostate cancer cells,” researchers Shan Lu and Zhongyun Dong from the University of Cincinnati College of Medicine investigated a new way to block CRPC growth.

Full blog - https://www.oncotarget.org/2025/07/29/a-new-way-to-target-resistant-prostate-cancer-cells/

Paper DOI - https://doi.org/10.18632/oncotarget.28722

Correspondence to - Zhongyun Dong - dongzu@ucmail.uc.edu

Video short - https://www.youtube.com/watch?v=fiJWZ_fKxgs

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Keywords - cancer, PCNA, androgen receptor, PCNA inhibitors, AR splicing variants, CRPC

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A New Way to Target Resistant Prostate Cancer Cells

BUFFALO, NY – August 11, 2025 – A new #researchpaper was #published in Volume 16 of Oncotarget on July 25, 2025, titled “Dissecting the functional differences and clinical features of R-spondin family members in metastatic prostate cancer.”

In this study, researchers led by first author Aiden Deacon and corresponding author Justin Hwang from the University of Minnesota-Twin Cities investigated a group of genes known as the R-spondin family (RSPO1/2/3/4) in advanced prostate cancer (PC). The RSPO gene family regulates Wnt signaling, a pathway involved in cancer progression.

Prostate cancer is the most common cancer among men in the United States and becomes especially dangerous when it spreads beyond the prostate. Most patients are treated with hormone therapies that target the androgen receptor; however, many tumors eventually become resistant.

The research team analyzed thousands of tumor samples and found that RSPO2 alterations were more common than changes in other R-spondin genes or even some well-known cancer-related genes like CTNNB1 and APC. RSPO2 amplification occurred in over 20% of metastatic prostate cancer. Patients with these alterations showed signs of more aggressive disease, including higher mutation rates and greater tumor complexity.

Using laboratory models, the team discovered that RSPO2 increases cancer cell growth and triggers a biological process called epithelial-mesenchymal transition (EMT). EMT is known to promote tumor spread and resistance to standard treatments. Unlike other genes in the same pathway, RSPO2 also appeared to reduce the activity of androgen receptor genes, suggesting it drives a type of prostate cancer that no longer relies on hormones for growth.

“In cell lines, RSPO2 overexpression caused up-regulation of EMT pathways, including EMT-regulatory transcription factors ZEB1, ZEB2, and TWIST1.”

Importantly, RSPO2 showed structural differences from other R-spondin proteins, which may allow researchers to design drugs that specifically block its activity. Current therapies targeting the Wnt pathway are limited, and there are no approved drugs that inhibit RSPO2. However, this study highlights RSPO2 as a promising therapeutic target, especially for patients who do not respond to existing hormone-based treatments.

This research adds critical knowledge about how aggressive prostate cancers develop and persist despite therapy. The identification of RSPO2 as a key driver of disease progression opens new possibilities for treatment strategies aimed at improving outcomes for patients with advanced prostate cancer.

DOI - https://doi.org/10.18632/oncotarget.28758

Correspondence to - Justin Hwang - jhwang@umn.edu

Video short - https://www.youtube.com/watch?v=iyu5D_c1dbY

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Keywords - cancer, RSPO2, prostate cancer, Wnt signaling, genomics, therapeutics

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New Gene Linked to Aggressive, Treatment-Resistant Prostate Cancer

Lung cancer, particularly non-small cell lung cancer (NSCLC), is the deadliest cancer worldwide. Cigarette smoking is one of the main causes, but not every smoker develops the disease. This suggests that other biological factors help determine who develops cancer.

Researchers from the Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indianapolis, and from the Richard L. Roudebush Veterans Affairs Medical Center have now found that cigarette smoke, combined with a weakened DNA repair system, can trigger the early stages of lung cancer, particularly NSCLC. This work, led by first author Nawar Al Nasralla and corresponding author Catherine R. Sears, was recently published in Volume 16 of Oncotarget.

Full blog - https://www.oncotarget.org/2025/08/11/cigarette-smoke-and-weak-dna-repair-a-double-hit-behind-lung-cancer-risk/

Paper DOI - https://doi.org/10.18632/oncotarget.28724

Correspondence to - Catherine R. Sears - crufatto@iu.edu

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Keywords - cancer, DNA repair, DNA damage, lung adenocarcinoma, squamous cell carcinoma, Xeroderma Pigmentosum Group C (XPC)

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Cigarette Smoke and Weak DNA Repair: A Double Hit Behind Lung Cancer Risk

BUFFALO, NY - August 13, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on July 29, 2025, titled “PCAIs stimulate MAPK, PI3K/AKT pathways and ROS-Mediated apoptosis in aromatase inhibitor-resistant breast cancer cells while disrupting actin filaments and focal adhesion.”

In this study, led by first author Jassy Mary S. Lazarte and corresponding author Nazarius S. Lamango from Florida A&M University College of Pharmacy and Pharmaceutical Sciences, researchers investigated a new class of compounds called polyisoprenylated cysteinyl amide inhibitors (PCAIs) as a potential treatment for aromatase inhibitor (AI) therapy resistant breast cancer. Aromatase inhibitors are a common treatment for estrogen receptor-positive (ER+) breast cancer, but many patients eventually develop resistance, leaving fewer therapeutic options.

The study focused on a PCAI compound called NSL-YHJ-2-27, which was tested in long-term letrozole-treated breast cancer cells (LTLT-Ca), an experimental model of AI therapy resistance. NSL-YHJ-2-27 activated two major signaling pathways, MAPK and PI3K/AKT. Although these pathways typically support cancer cell survival, their overstimulation by PCAIs led to increased oxidative stress, damaging the cells and inducing cell death by apoptosis. The compound also reduced levels of RAC1 and CDC42, proteins involved in maintaining cell shape and movement. These alterations resulted in cytoskeletal disruption and reduced structural integrity, making the cancer cells more vulnerable and less capable of spreading. Importantly, the effects of NSL-YHJ-2-27 persisted after the compound was removed, suggesting long-term control over AI resistant cancer cells may be possible.

“PCAIs inhibited cell proliferation and colony formation by 95% and 74%, respectively, increased active caspase 7 and BAX 1.5-fold and 56%, respectively. NSL-YHJ-2-27 (10 μM) induced LTLT-Ca spheroid degeneration by 61%.”

As a new class of targeted molecules, PCAIs represent an innovative approach distinct from traditional endocrine therapies. Their ability to affect multiple cellular mechanisms simultaneously makes them promising candidates for future drug development.

Overall, this study presents a promising new approach for treating AI therapy-resistant breast cancer. By targeting cellular pathways that support survival and mobility, PCAIs like NSL-YHJ-2-27 could provide a novel strategy to manage advanced or resistant forms of the disease. Further research, including in vivo studies and clinical trials, will be essential to confirm these findings and evaluate their therapeutic potential.

DOI - https://doi.org/10.18632/oncotarget.28759

Correspondence to - Nazarius S. Lamango - nazarius.lamango@famu.edu

Video short - https://www.youtube.com/watch?v=8xQEilloO9Q

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Keywords - cancer, PCAIs, ROS, MAPK, PI3K/AKT, LTLT-Ca cells

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New Compound Disrupts Survival Pathways in Aromatase Inhibitor-Resistant Breast Cancer Cells

BUFFALO, NY – August 15, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on August 13, 2025, titled “Clinical and analytical validation of MI Cancer Seek®, a companion diagnostic whole exome and whole transcriptome sequencing-based comprehensive molecular profiling assay.”

In this study, first authors Valeriy Domenyuk and Kasey Benson, along with corresponding author David Spetzler from Caris Life Sciences in Irving, Texas, introduce MI Cancer Seek, an FDA-approved test designed to deliver comprehensive tumor profiling. MI Cancer Seek demonstrated strong concordance with other FDA-approved companion diagnostics and serves as a powerful tool to guide treatment decisions in both adult and pediatric cancer patients.

Cancer remains one of the most complex and diverse diseases to treat. With many targeted therapies currently FDA-approved, selecting the right one for a specific patient requires detailed genetic insights. MI Cancer Seek addresses this need by analyzing both DNA and RNA from a single tumor sample. The tool identifies key biomarkers linked to FDA-approved treatments for several major cancers, including breast, lung, colon, melanoma, and endometrial cancers.

One of the most significant strengths of MI Cancer Seek is its ability to deliver accurate and reliable results from minimal tissue input (50 ng). Even when analyzing formalin-fixed paraffin-embedded samples, which are widely used but often degraded, the test maintained high levels of accuracy. It successfully detected important genetic alterations such as PIK3CA, EGFR, BRAF, and KRAS/NRAS mutations and measured tumor mutational burden (TMB) and microsatellite instability (MSI), both of which are key indicators for immunotherapy response.

In clinical comparisons, the test achieved over 97% agreement with other FDA-approved diagnostic tools, confirming its reliability in detecting critical biomarkers. Notably, it showed near-perfect accuracy in identifying MSI status in colorectal and endometrial cancers. The researchers also demonstrated that the test maintains precision across different lab conditions and varying DNA input levels, confirming its robustness for routine clinical use.

Beyond its role as a companion diagnostic, MI Cancer Seek incorporates additional features developed under its predecessor, MI Tumor Seek Hybrid. These include detection of homologous recombination deficiency, structural variants, and cancer-related viruses. It also includes advanced tools such as the Genomic Probability Score for identifying the tissue of origin in cancers of unknown primary, as well as a gene signature to guide first-line chemotherapy in colorectal cancer.

“One limitation to be considered is the low PPA for ERBB2 CNA detection.”

By offering deeper genetic insights from a single, small sample, MI Cancer Seek has the potential to streamline diagnostics, reduce testing costs, and connect patients to effective therapies more quickly. As precision medicine continues to expand, this assay stands out as a comprehensive and efficient solution for meeting the evolving needs of modern oncology.

DOI - https://doi.org/10.18632/oncotarget.28761

Correspondence to - David Spetzler - dspetzler@carisls.com

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FDA-Approved MI Cancer Seek Test Enhances Tumor Profiling for Precision Oncology

BUFFALO, NY – August 19, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on August 19, 2025, titled “The SCD1 inhibitor aramchol interacts with regorafenib to kill GI tumor cells in vitro and in vivo.”

In this study, led by first authors Laurence Booth and Michael R. Booth, along with corresponding author Paul Dent from Virginia Commonwealth University, researchers investigated how aramchol, a drug originally developed for liver disease, works with the cancer drug regorafenib in gastrointestinal (GI) tumor cells. They found that the combination is effective, especially in tumor cells with a specific genetic variant. The combined approach offers a potential new strategy for treating liver and colon cancers.

Gastrointestinal cancers, such as liver and colon cancer, are serious global health challenges. Regorafenib, already approved for cancer treatment, can have limited impact and frequently causes side effects. Aramchol, a drug developed to treat fatty liver disease, affects how cancer cells process fats and energy. In this study, researchers tested whether combining these two drugs could improve GI cancer treatment, both in cells and mouse models.

The results showed that the drug combination killed liver and colorectal cancer cells more effectively than either drug alone. In animal models, mice with human liver tumors had slower tumor growth, without showing signs of weight loss or other toxicity. 

The researchers also found that aramchol and regorafenib work together to block important survival pathways inside cancer cells. This combination was especially effective in cells with a genetic variant called ATG16L1 T300, which is more common in people of African ancestry. The treatment triggered stress responses in the cancer cells and disrupted key proteins required for survival. It also activated autophagy, a natural recycling process that clears out damaged parts, eventually leading to cancer cell death.

“Aramchol interacted with the multi-kinase inhibitors sorafenib, regorafenib or lenvatinib, to kill GI tumor cells, with regorafenib exhibiting the greatest effect.”

Aramchol is currently in clinical trials for fatty liver disease and has a well-established safety profile, while regorafenib is already FDA-approved for cancer treatment. Together, their combination could advance fast into clinical testing for patients with GI cancers. However, researchers note that additional studies are needed to support the launch of early-phase clinical trials.

Altogether, this study may offer a more effective and less toxic alternative to current treatments for GI cancers. It also highlights the role of genetic variants in shaping treatment response, suggesting that future therapies could be more precisely tailored to each patient’s unique genetic profile.

DOI - https://doi.org/10.18632/oncotarget.28762

Correspondence to - Paul Dent - paul.dent@vcuhealth.org

Video short - https://www.youtube.com/watch?v=5saAqsqxi-Q

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Keywords - cancer, macroautophagy, flux; ER stress, aramchol, regorafenib

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Aramchol Boosts Regorafenib Effectiveness in Gastrointestinal Tumors

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality. While the development of targeted therapies has improved outcomes for many patients with EGFR-mutated NSCLC, those with rare EGFR variants often face limited treatment options, especially when the disease involves the central nervous system (CNS).

A recent research paper, titled “Durable complete response in leptomeningeal disease of EGFR mutated non-small cell lung cancer to amivantamab, an EGFR-MET receptor bispecific antibody, after progressing on osimertinib” published in Volume 16 of Oncotarget, describes a patient with NSCLC harboring two uncommon EGFR mutations—G719A and A289V—who experienced a prolonged and clinically significant response to amivantamab monotherapy, after prior treatments had failed.

Full blog - https://www.oncotarget.org/2025/08/26/amivantamab-monotherapy-in-rare-egfr-mutated-advanced-nsclc/

Paper DOI - https://doi.org/10.18632/oncotarget.28730

Correspondence to - Young Kwang Chae - young.chae@northwestern.edu

Video short - https://www.youtube.com/watch?v=UEiCz834a8c

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Keywords - cancer, amivantamab, monotherapy, rare EGFR mutation, NSCLC, leptomeningeal disease

About Oncotarget 

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science).

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Amivantamab Monotherapy in Rare EGFR-Mutated Advanced NSCLC

Aiden Deacon from the University of Minnesota-Twin Cities, Minneapolis, discusses a research paper he co-authored that was published in Volume 16 of Oncotarget, titled “Dissecting the functional differences and clinical features of R-spondin family members in metastatic prostate cancer.”

DOI - https://doi.org/10.18632/oncotarget.28758

Correspondence to - Justin Hwang - jhwang@umn.edu

Video interview - https://www.youtube.com/watch?v=OXKhWWU1gnY

Abstract

This study investigates the R-spondin family of genes (RSPO1/2/3/4), a group of secreted proteins that act as Wnt regulators, and their subsequent role in advanced prostate cancer (PC). When evaluating transcriptomic data from primary and metastatic PC patients, we found that alterations in RSPO2 were more prevalent than in other RSPO family members or Wnt-regulating genes APC and CTNNB1. Further, we found that RSPO2 alterations in PCs were significantly associated with worse disease-free survival. Through our in silico modeling, RSPO2 exhibited strong positive associations with genes regulating epithelial-mesenchymal transition (EMT) and double-negative prostate cancer (DNPC), but had negative correlations with androgen receptor (AR) and AR-associated genes. Furthermore, 3D modeling of RSPO2 revealed structural differences between itself and other RSPOs. In cell lines, RSPO2 overexpression caused up-regulation of EMT pathways, including EMT-regulatory transcription factors ZEB1, ZEB2, and TWIST1. Conversely, this was not observed when CTNNB1 was overexpressed in the same models. These findings highlight that, in PC, RSPO2 functions as a unique member of the R-spondin family by promoting genes and signaling pathways associated with aggressive PC, and RSPO2 amplifications are associated with poor outcomes in PC patients.

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Keywords - cancer, RSPO2, prostate cancer, Wnt signaling, genomics, therapeutics

About Oncotarget 

Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science.

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Oncotarget author interview: Aiden Deacon

Behind the Study: R-spondin Family Roles in Metastatic Prostate Cancer

BUFFALO, NY – August 29, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on August 29, 2025, titled “In vivo manipulation of the protein homeostasis network in rhabdomyosarcoma.”

In this study led by first author Kristen Kwong and corresponding author Amit J. Sabnis from the Department of Pediatrics, Division of Oncology, University of California San Francisco, researchers discovered that disrupting the protein quality control system in cancer cells slows tumor growth in rhabdomyosarcoma (RMS), the most common pediatric soft tissue cancer. This finding points to a new strategy for treating high-risk childhood cancers that often resist current therapies.

Rhabdomyosarcoma is a rare and aggressive cancer that primarily affects children and adolescents. Standard treatments like chemotherapy and radiation often have limited long-term success in high-risk cases. This study explored a different approach: targeting the cellular machinery that maintains protein quality, known as the proteostasis network. Cancer cells rely heavily on this system to survive stress caused by rapid growth and genetic instability.

“To examine whether MAL3-101 or more drug-like proteostasis inhibitors represent a new therapeutic strategy for RMS, we screened proteostasis components that might recapitulate the effects of MAL3-101 in vivo.”

The researchers first used a compound called MAL3-101 to disrupt protein control in RMS cells. They then identified which parts of the protein quality system were affected. Based on those findings, they searched for more drug-like compounds that could target the same pathways. 

They focused on a protein called p97, which plays a critical role in removing damaged or misfolded proteins. When they blocked p97 using a drug called CB-5083, the cancer cells could no longer manage internal stress and began to self-destruct. In both laboratory models and mice implanted with human RMS tumors, the treatment significantly slowed or stopped tumor growth. The drug triggered a stress response in the cells known as the unfolded protein response, which can lead to either recovery or programmed cell death.

However, not all tumors responded the same way. Some resisted the treatment by activating a backup system called autophagy, which allows cells to recycle parts of themselves under stress. By comparing tumors that responded well to those that did not, the researchers found that higher autophagy activity could serve as a warning sign for resistance. This insight may help identify which patients are more likely to benefit from therapies that target protein quality control.

While the results are promising, the drug’s effectiveness depended on the tumor’s genetic profile and how it handled stress. Combining p97 inhibition with other treatments or blocking alternative survival pathways like autophagy may improve outcomes. The researchers also noted the importance of developing safer and more targeted drugs to reduce side effects.

This study opens new possibilities for personalized cancer treatment, particularly for children with aggressive or relapsed RMS. By weakening the systems that cancer cells depend on to survive, rather than only using toxic treatments to kill them, scientists aim to develop more effective and less harmful therapies for young patients.

DOI - https://doi.org/10.18632/oncotarget.28764

Correspondence to - Amit J. Sabnis - amit.sabnis@ucsf.edu

Video short - https://www.youtube.com/watch?v=YsdffTkXNRQ

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Blocking Protein Control Pathway Slows Rhabdomyosarcoma Growth in Mice

Immunotherapy is not usually effective against pancreatic cancer (PC), but a new study published in Oncotarget (Volume 16, 2025) highlights rare cases where it did help. These examples, though uncommon, may offer valuable insights for future treatment.

Pancreatic Cancer and Immunotherapy

Pancreatic cancer is often diagnosed at an advanced stage, which limits treatment options and contributes to its poor prognosis. While chemotherapy remains the standard treatment, it usually offers only modest benefits in terms of survival. Immunotherapy—an approach that activates the immune system to fight cancer—has been effective in other cancers but has shown limited success in PC.

This is largely due to the tumor’s ability to suppress immune responses and create an environment that protects it from attack. Currently, these drugs are only approved for a small subset of patients whose tumors have a specific genetic feature called high microsatellite instability (MSI-high), found in just 1 to 2 percent of cases.

The Study: Pancreatic Cancer Immunotherapy Responders

The study, titled “Exceptional responders to immunotherapy in pancreatic cancer: A multi-institutional case series of a rare occurrence,” was led by first author Kavin Sugumar and corresponding author Jordan M. Winter, from University Hospitals Seidman Cancer Center. 

The researchers examined medical records from 14 patients with pancreatic ductal adenocarcinoma (PDAC) who had responded unexpectedly well to immune checkpoint inhibitors—drugs that help reactivate immune cells to attack cancer. The drugs included PD-1 inhibitors such as pembrolizumab and nivolumab, CTLA-4 inhibitors like ipilimumab, and agents targeting tumor-associated macrophages. To find these rare cases, the research team contacted 471 oncologists from 91 major U.S. cancer centers between 2020 and 2021.

Full blog - https://www.oncotarget.org/2025/09/11/immunotherapy-response-in-pancreatic-cancer-what-a-new-study-reveals/

Paper DOI - https://doi.org/10.18632/oncotarget.28739

Correspondence to - Jordan M. Winter - jordan.winter@UHHospitals.org

Abstract video - https://www.youtube.com/watch?v=VeWTcuVmqgM

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Keywords - cancer, pancreatic adenocarcinoma, immunotherapy, exceptional responders, microsatellite instability, survival

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Immunotherapy Response in Pancreatic Cancer: What a New Study Reveals

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We, the scientists, should change the situation and change the policies of Indexes such as Clarivate's Web of Science, and Medline, and make indexes work for us. Otherwise, why should all of these organizations exist?

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Librarians Against Scientists: Oncotarget lesson

Hundreds of scientific studies, reviews, and analyses are being published from around the world at any given time. This can make reading the latest research literature a time consuming task—depending, of course, on the quantity of papers one hopes to consume. As a tool to help alleviate this important undertaking, many researchers have taken to listening to one of the top open-access podcasts of 2020 and 2021: The Oncotarget Podcast.

After a paper is published, it is added to an enhanced post-publication service provided by Oncotarget, in an effort to help authors reach a wider audience. This podcast series is another way to widely distribute the research that is published with free access by Oncotarget. Oncotarget Podcast episodes regularly include audio readings, press releases, and interviews with authors about their latest and trending papers published by Oncotarget. Player.fm (https://player.fm/podcasts/open-access) rated the Oncotarget Podcast on their lists of Best Open Access Podcasts of 2020 and 2021.

Oncotarget, and Impact Journals as a whole, is constantly expanding the definition of open-access to include a wide variety of accessibility-based audio and visual media to support researchers and readers with disabilities. Creators of the Oncotarget Podcast hope that offering audible renderings of literature from Oncotarget.com, and of blog posts from Oncotarget.org and Oncotarget.net, will be helpful for the vision impaired community.

Stay up-to-date with all of the latest oncology-focused research literature published by Oncotarget by subscribing to the Oncotarget Podcast, which can be found on Soundcloud, Apple, Stitcher, and Blubrry podcast streaming services.

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Oncotarget is a bi-weekly, peer-reviewed, open access biomedical journal covering research on all aspects of oncology.

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Oncotarget Podcast Episodes: The Latest in Oncology-Focused Research

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form and then quickly released to Pubmed.

Oncotarget is now indexed by MEDLINE, PubMed and PMC/PubMed.

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