A new research perspective was published in Oncotarget's Volume 14 on May 10, 2023, entitled, “HER3- A key survival pathway and an emerging therapeutic target in metastatic colorectal cancer and pancreatic ductal adenocarcinoma.”

Colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC) are highly metastatic cancers with poor survival rates. The tumor microenvironment has been shown to play a critical role in cancer progression and response to therapies. Endothelial cells (ECs) are a key component of the tumor microenvironment and promote cancer cell survival by secreting soluble factors that activate cancer-promoting signaling pathways. 

In this new perspective, researchers Omkar Desai and Rui Wang from Case Western Reserve University and University Hospitals Cleveland Medical Center discuss their studies and others that have identified HER3 as a key mediator of liver EC-induced chemoresistance and cancer cell growth in metastatic CRC and PDAC. 

“In complement to our studies, prior preclinical studies have shown that HER3-targeted therapies with antibodies and inhibitors have been effective in blocking tumor growth in several types of cancers [22, 23], specifically breast cancer [24], head and neck squamous cell carcinoma (HNSCC) [25], PDAC [25], and non-small cell lung cancer (NSCLC) [26]. However, translating the preclinical findings to clinical studies has shown limited impact on patient outcomes.”

In this article, the researchers discuss that HER3-targeted therapies may be effective in treating patients with HER3-expressing CRC and PDAC, and highlight the importance of applying HER3 expression as a predictive biomarker for patient response to HER3-targeted therapies. They also discuss the challenges encountered in past clinical trials of HER3-targeted therapies, including the role of NRG1 gene fusions, alternative HER3 activation mechanisms, and adaptive resistance mechanisms. Finally, the team concludes by suggesting the future directions of HER3-targeted therapies, including novel approaches to overcome chemoresistance and promote cancer cell death.

“In summary, we discovered that the surrounding liver EC microenvironment plays a key role in activating HER3 and promoting cell survival in mCRC and mPDAC, and potentially other types of cancer that metastasize to the liver.”

DOI - https://doi.org/10.18632/oncotarget.28421

Correspondence to - Rui Wang -  rxw517@case.edu

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Keywords - HER3, colorectal, pancreatic cancer, metastasis, microenvironment

About Oncotarget

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. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

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Oncotarget

HER3: Survival Pathway and Therapeutic Target in Metastatic Colorectal and Pancreatic Cancer

A conversation with science writer Philip Ball about his new illustrated history of alchemy

Elixirs, Experiments, and the Birth of Modern Science

In this episode, Joseph Ho discusses his book, Developing Mission: Photography, Filmmaking, and American Missionaries in Modern China with Chloë Starr. The conversation ranges from camera technology in the interwar years to the documentation of disease in mission hospitals and circulation of missionary films documenting Japanese war crimes. If the creation of new types of images (such as baptism photographs) changes how we see the self and other, the cultural exchange of transnational images also played a role in Sino-US relations.

Joseph W. Ho, Developing Mission: Photography, Filmmaking, and American Missionaries in Modern China

BUFFALO, NY - September 24, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on September 22, 2025, titled “Loss of Trp53 results in a hypoactive T cell phenotype accompanied by reduced pro-inflammatory signaling in a syngeneic orthotopic mouse model of ovarian high-grade serous carcinoma.”

In this study, led by first author Jacob Haagsma and corresponding author Trevor G. Shepherd from the Verspeeten Family Cancer Centre and Western University, Canada, researchers investigated how the loss of Trp53 – a critical tumor suppressor gene – affects immune responses in ovarian cancer. The team found that deleting Trp53 led to more aggressive tumor growth and a weaker immune response. These findings help explain why some ovarian tumors may be resistant to immunotherapy and point to new ways to improve treatment.

High-grade serous ovarian carcinoma (HGSC) is a deadly cancer that is often diagnosed at a late stage. Immunotherapy, which enhances the body’s immune system to fight cancer, has shown limited effectiveness in treating this type of cancer. To better understand why, the researchers developed a mouse model that closely mimics human HGSC. They injected ovarian epithelial cells, with and without Trp53, into the fallopian tubes, the origin site of most ovarian cancers.

“In this study, we developed a syngeneic model reflecting both the site of origin and the genotype of early HGSC disease by deleting Trp53 in mouse oviductal epithelial (OVE) cells.”

Mice injected with cells lacking Trp53 developed faster-growing and more invasive tumors, reflecting how the disease typically progresses in humans. These tumors also had fewer active T cells, which are immune cells responsible for attacking cancer. Moreover, the T cells that were present appeared less capable of responding to the tumor, creating an immune environment that allowed cancer to grow uncontrolled.

Further analysis revealed that tumor cells without Trp53 had reduced activity in genes related to inflammation. These changes were associated with lower levels of key proteins that normally help immune cells detect and attack tumor cells. When the researchers collected tumor cells from the abdominal fluid of the mice—a condition that simulates advanced-stage disease—they observed even lower immune signaling than before. This suggests that as the tumor spreads, it becomes better at evading the immune system.

This study highlights how early genetic mutations can shape the interaction between tumors and the immune system. In particular, the loss of Trp53 appears to trigger a chain of events that weakens immune surveillance and accelerates tumor progression. These findings emphasize the need to consider both genetic mutations and the tumor environment when designing immunotherapies for ovarian cancer. Understanding how genes like Trp53 influence immune behavior may lead to more effective treatments and help identify which patients are most likely to benefit from immunotherapy.

DOI - https://doi.org/10.18632/oncotarget.28768

Correspondence to - Trevor G. Shepherd - tshephe6@uwo.ca

Abstract video - https://www.youtube.com/watch?v=WFQw0psuC3M

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Loss of Trp53 Gene Promotes Tumor Growth and Immune Suppression in Ovarian Cancer

BUFFALO, NY — September 24, 2025 — A new #research paper was #published in Volume 17, Issue 8 of Aging-US on August 7, 2025, titled, “What is the clinical evidence to support off-label rapamycin therapy in healthy adults?”

In this study, led by Jacob M. Hands from The George Washington University School of Medicine and Health Sciences, researchers analyzed current research to determine whether low-dose rapamycin can extend healthspan or delay aging in healthy adults. While studies in animals have shown promising results, this review found no clear clinical evidence that the same benefits apply to humans. The findings point to the urgent need for larger, better-designed human trials before recommending rapamycin for off-label use to prevent aging.

Rapamycin, originally developed as a drug to suppress the immune system, has gained interest as a possible anti-aging therapy. It works by blocking a key cellular pathway called mTOR, which plays a role in growth and metabolism. In animal studies, blocking this pathway has extended lifespan. However, the translation of these results to humans remains uncertain. The current study examined clinical trials and observational studies involving healthy adults who took low doses of rapamycin or similar drugs.

“This paper has reviewed trials of low-dose mTOR inhibition therapy in human subjects.”

Some trials showed encouraging signs. For example, older adults treated with low-dose mTOR inhibitors showed stronger immune responses and fewer respiratory infections. Other studies suggested possible improvements in subjective well-being and physical performance, such as walking speed and strength. Still, none of the trials directly showed that rapamycin extends life or clearly slows the aging process. 

One small study using a biological aging model (PhenoAge) suggested that users might have reduced their biological age by nearly four years, but the estimate was based on average values, not individual patient data.

There are also concerns about side effects. While short-term use seems safe, some studies reported increases in blood lipids and markers of inflammation. Research on muscle health produced contradictory findings—some studies suggest rapamycin might reduce the body’s ability to build muscle. The impact on mental health is also unclear, with a few participants reporting increased anxiety during treatment.

The researchers emphasize that rapamycin’s role in human aging is still uncertain. Off-label use is growing among longevity clinics and individuals seeking anti-aging solutions, but there is no standard dose, and long-term safety is unknown. The authors advise that off-label use should be approached with caution, including careful monitoring and full disclosure about the limited evidence.

Overall, while animal studies have demonstrated promising effects, human trials have not yet shown that rapamycin can safely or effectively slow aging or extend lifespan. More rigorous and well-controlled studies are necessary before the drug can be considered a reliable option for healthy adults interested in longevity interventions.

DOI - https://doi.org/10.18632/aging.206300

Corresponding author - Jacob M. Hands - jacobhands@gwu.edu

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

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Aging-US

Rapamycin Shows Limited Evidence for Longevity Benefits in Healthy Adults

Colorectal cancer is one of the most common—and deadliest—cancers worldwide. Once it spreads and reaches the metastatic stage, treatment becomes far more difficult. Tumors can also behave very differently from one patient to another, especially after multiple rounds of therapy. Precision oncology is helping to overcome these challenges by enabling clinicians to analyze each tumor’s unique genetic profile and tailor treatment accordingly.

This approach was recently highlighted in a case study published in Volume 16 of Oncotarget. The report detailed how a 62-year-old man with advanced colorectal cancer received a highly personalized treatment plan, developed by an international panel of experts, after completing all standard treatment options.

Full blog - https://www.oncotarget.org/2025/09/24/precision-oncology-in-metastatic-colorectal-cancer-a-real-world-case-study/

Paper DOI - https://doi.org/10.18632/oncotarget.28744

Correspondence to - Shai Magidi - shai.magidi@winconsortium.org

Abstract video - https://www.youtube.com/watch?v=uWDtWNgpK7A

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Keywords - cancer, precision oncology, molecular tumor board, colorectal carcinoma, cancer management

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Precision Oncology in Metastatic Colorectal Cancer: A Real-World Case Study

In this episode of the Longevity & Aging Series, Girish Harinath from AgelessRx joins host Dr. Evgeniy Galimov to discuss a research paper he co-authored in Volume 17, Issue 4 of Aging-US, titled “Influence of rapamycin on safety and healthspan metrics after one year: PEARL trial results.”

DOI - https://doi.org/10.18632/aging.206235

Corresponding author - Stefanie L. Morgan - stefanie@agelessrx.com

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Abstract

Design: This 48-week decentralized, double-blinded, randomized, placebo-controlled trial (NCT04488601) evaluated the long-term safety of intermittent low-dose rapamycin in a healthy, normative-aging human cohort. Participants received placebo, 5 mg or 10 mg compounded rapamycin weekly. The primary outcome measure was visceral adiposity (by DXA scan), secondary outcomes were blood biomarkers, and lean tissue and bone mineral content (by DXA scan). Established surveys were utilized to evaluate health and well-being. Safety was assessed through adverse events and blood biomarker monitoring.

Results: Adverse and serious adverse events were similar across all groups. Visceral adiposity did not change significantly (ηp2 = 0.001, p = 0.942), and changes in blood biomarkers remained within normal ranges. Lean tissue mass (ηp2 = 0.202, p = 0.013) and self-reported pain (ηp2 = 0.168, p = 0.015) improved significantly for women using 10 mg rapamycin. Self-reported emotional well-being (ηp2 = 0.108, p = 0.023) and general health (ηp2 = 0.166, p = 0.004) also improved for those using 5 mg rapamycin. No other significant effects were observed.

Conclusions: Low-dose, intermittent rapamycin administration over 48 weeks is relatively safe in healthy, normative-aging adults, and was associated with significant improvements in lean tissue mass and pain in women. Future work will evaluate benefits of a broader range of rapamycin doses on healthspan metrics for longevity, and will aim to more comprehensively establish efficacy.

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Keywords - aging, rapamycin, geroscience, longevity, healthspan

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Longevity & Aging Series (S3, E6): Girish Harinath

Poet and priest Spencer Reece joins Leader’s Way host Brandon Nappi for a moving conversation about the power of poetry as an act of remembrance, as a response to violence, and as a culture maker and culture keeper. Listen to Father Reece offer spontaneous recitation and remind us of the ways poetry can bring us closer to the Divine.   

Host: Brandon Nappi

Guest: Spencer Reece

Production: Goodchild Media

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65: Poetry Holds Us Together with Spencer Reece

BUFFALO, NY — October 1, 2025 — A new #research paper #featured as the #cover of  Volume 17, Issue 9 of Aging-US was published on August 21, 2025, titled “Sex-specific longitudinal reversal of aging in old frail mice.” 

The study, led by first author Cameron Kato and corresponding author and Aging-US Editorial Board Member Irina M. Conboy from the University of California, Berkeley, reports that a combination of oxytocin and an Alk5 inhibitor (OT+A5i) significantly extended both lifespan and healthspan in frail, elderly, male mice. These rejuvenating effects were not seen in female mice, highlighting key biological differences between the sexes in their response to aging therapies.

The researchers tested a dual-drug approach targeting two biological pathways that change with age. Oxytocin, a hormone that declines with aging and supports tissue repair, was combined with an Alk5 inhibitor that blocks the TGF-beta pathway. TGF-beta becomes overactive with age and contributes to chronic inflammation and tissue damage. In this study, frail mice at 25 months of age—roughly equivalent to 75 human years—were treated regularly with the OT+A5i combination.

Male mice receiving the therapy lived over 70% longer than untreated controls and showed significant improvements in physical endurance, agility, and memory. According to hazard ratio analysis, the treated males were nearly three times less likely to die at any given time than untreated males. 

“Treatment of old frail male mice with OT+A5i resulted in a remarkable 73% life extension from that time, and a 14% increase in the overall median lifespan.”

The therapy also reduced “biological noise” in circulating blood proteins—an established marker of aging—bringing those levels back to a more youthful state. Short-term benefits, were seen in both sexes, however, after four months of continuous treatment, only the male mice showed sustained improvement in systemic protein balance. Female mice did not experience significant gains in lifespan or healthspan, though middle-aged females did show improved fertility after treatment.

These results underscore the importance of understanding sex-specific biology when developing treatments for aging. While the reasons for these differences remain unclear, the findings provide a new model for studying and designing longevity therapies.

Oxytocin is already FDA-approved, and Alk5 inhibitors are currently in clinical trials, suggesting that this approach could be translated to humans. With strong results in aged and frail male animals, OT+A5i appears to be a promising candidate for improving late-life health and survival.

DOI - https://doi.org/10.18632/aging.206304

Corresponding author - Irina M. Conboy - irina@generationlab.co

Abstract video - https://www.youtube.com/watch?v=bpWxDd7hHhM

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Keywords - aging, lifespan, healthspan, Alk5 inhibitor, oxytocin, sex-specific differences

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Sex-Specific Effects Found in New Anti-Aging Therapy for Elderly Mice

BUFFALO, NY - October 1, 2025 – Oncotarget is proud to announce that its Editor-in-Chief, Wafik S. El-Deiry, MD, PhD, FACP, will chair the WIN Symposium as the Oncology Track of the Advancing Precision Medicine (APM) Annual Conference held October 3–4, 2025, at the Pennsylvania Convention Center in Philadelphia.

The WIN Consortium annual symposium featured as the Oncology Track of the APM Annual Conference 2025 unites global leaders in oncology, translational science, and precision medicine. This year’s program features keynote lectures, multi-track sessions– WIN Symposium, Multi-Omics Integration and Precision Medicine Outside of Oncology– and networking opportunities designed to accelerate the translation of research into clinical practice.

Highlights include:

--A keynote at opening of the WIN Symposium in Philadelphia by William G. Kaelin, Jr., MD — 2019 Nobel Laureate.

--Other luminaries in Oncology are speaking, including AACR President Lillian Siu, MD and AACR President-Elect Keith Flaherty, MD along with internationally recognized leaders in precision oncology.

--A world-class precision oncology molecular tumor board and oral presentations from the most competitive abstracts are part of the program.

--Multi-omics and disease-specific tracks spanning oncology, neurology, cardiovascular disease, rare disease, and infectious disease.

--Opportunities for collaboration among scientists, clinicians, industry innovators, and policymakers.

Registration is still open. Attendance is free for students, academic/government/non-profit participants, healthcare providers, and investors. The event provides CME credits. For full program details, visit the APM Annual Conference website.

About WIN Consortium:

WIN Consortium is a non-profit association headquartered in France. WIN was the first consortium that assembled all stakeholders of cancer care, from academia, industry, and patient advocates to work together across the globe. The WIN network assembles 34 world-class academic medical centers, industries, research organizations and patient advocates spanning 18 countries and 5 continents, aligned to launch trials to bolster Precision Oncology across the world. It was also the first organization to launch a N-of-One study using transcriptomics in addition to genomics to inform therapeutic choice in the WINTHER study.

WIN is the organizer of the WIN symposia in Precision Oncology.

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Wafik S. El-Deiry Chairs 2025 WIN Symposium in Collaboration with APM in Philadelphia

As life expectancy increases, there is growing interest not only in extending lifespan but also in improving the quality of those additional years. To address the physical and cognitive decline that often accompanies aging, researchers have explored a variety of strategies. Many of these focus on a single biological factor, such as reducing inflammation or stimulating stem cell activity. However, aging is a complex process involving multiple, interconnected changes in the body.

Recognizing this, researchers at the University of California, Berkeley proposed a more comprehensive approach: targeting multiple aging-related pathways simultaneously. Their study, titled “Sex-specific longitudinal reversal of aging in old frail mice,” was recently featured on the cover of Aging-US (Volume 17, Issue 9).

Full blog - https://aging-us.org/2025/10/new-anti-aging-combo-boosts-lifespan-in-old-male-mice/

Paper DOI - https://doi.org/10.18632/aging.206304

Corresponding author - Irina M. Conboy - irina@generationlab.co

Abstract video - https://www.youtube.com/watch?v=bpWxDd7hHhM

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Keywords - aging, lifespan, healthspan, Alk5 inhibitor, oxytocin, sex-specific differences

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New Anti-Aging Combo Boosts Lifespan in Old Male Mice

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.

Read about the Oncotarget Scientific Integrity Process: https://www.oncotarget.com/scientific_integrity/

HER3: Survival Pathway and Therapeutic Target in Metastatic Colorectal and Pancreatic Cancer

Oncotarget Podcast