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Oncotarget

Announcement: Impact Journals at AACR Annual Meeting 2022

BUFFALO, NY- January 3, 2024 – A new #editorial paper was #published in Oncotarget's Volume 14 on December 20, 2023, entitled, “Therapeutically harnessing cancer stem cell-derived exosomes.”

In this editorial, researcher Yong Teng from Emory University discusses cancer stem cell-derived exosomes. Cancer stem cells (CSCs), a small population of cancer cells capable of self-renewal, are thought to serve as a central hub for tumor initiation, growth, metastasis, and recurrence. The potential for using CSCs in the diagnosis and treatment of cancer is gaining recognition. Exosomes are formed when multivesicular endosomes or multivesicular bodies fuse with the outer membrane of the cell, releasing various components such as DNA, RNA, lipids, metabolites, and cytosolic and cell surface proteins. 

“Over the past decade, our understanding of the characteristics and function of cancer-associated exosomes has expanded rapidly.”

As the major messengers, exosomes present in the tumor microenvironment (TME) play a critical role in maintaining the delicate balance between CSCs and non-CSCs. Given the importance of CSCs, it is reasonable to believe that CSC-derived exosomes (CSC-Exos) are essential for communication between CSCs and other cells in the TME. Accumulating evidence has demonstrated that CSC-Exos contribute significantly to almost all fundamental aspects of cancer, including maintaining a continuous cycle of self-renewal within the TME, exerting control over neighboring or distant cells, enabling cancer cells to evade immune surveillance, and promoting immune tolerance. 

“A deeper understanding of the characteristics and functions of CSC-Exos has the potential to lay the foundation for the development of novel clinical tools for diagnosis and prognosis, as well as therapies aimed at preventing tumor progression and recurrence.”

DOI - https://doi.org/10.18632/oncotarget.28542

Correspondence to - Yong Teng - yong.teng@emory.edu

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Keywords - cancer, cancer stem cells, exosomes, the tumor microenvironment, therapeutic target, anticancer strategy

About Oncotarget 

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Therapeutically Harnessing Cancer Stem Cell-derived Exosomes

BUFFALO, NY- January 8, 2024 – A new #review paper was #published in Oncotarget's Volume 14 on December 22, 2023, entitled, “Transformation-associated recombination (TAR) cloning and its applications for gene function; genome architecture and evolution; biotechnology and biomedicine.”

Transformation-associated recombination (TAR) cloning represents a unique tool to selectively and efficiently recover a given chromosomal segment up to several hundred kb in length from complex genomes (such as animals and plants) and simple genomes (such as bacteria and viruses). The technique exploits a high level of homologous recombination in the yeast Sacharomyces cerevisiae. 

“TAR cloning has become a valuable procedure for the selective and efficient isolation and manipulation of large DNA molecules. [...] The ability to isolate individual gene alleles will help to clarify whether a particular allele is associated with predisposition to different diseases, including cancer.”

In this new review, researchers Natalay Kouprina and Vladimir Larionov from the National Cancer Institute's Developmental Therapeutics Branch summarized multiple applications of the pioneering TAR cloning technique, developed previously for complex genomes, for functional, evolutionary, and structural studies, and extended the modified TAR versions to isolate biosynthetic gene clusters (BGCs) from microbes, which are the major source of pharmacological agents and industrial compounds, and to engineer synthetic viruses with novel properties to design a new generation of vaccines. TAR cloning was adapted as a reliable method for the assembly of synthetic microbe genomes for fundamental research. 

“In this review, we also discuss how the TAR cloning in combination with HAC (human artificial chromosome)- and CRISPR-based technologies may contribute to the future.”

DOI - https://doi.org/10.18632/oncotarget.28546

Correspondence to - Natalay Kouprina - kouprinn@mail.nih.gov

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Keywords - cancer, transformation-associated recombination, TAR, microbes, biomedicine, biotechnology

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Transformation-associated Recombination (TAR) Cloning and Its Applications

BUFFALO, NY- January 10, 2024 – A new #editorial paper was #published in Oncotarget's Volume 14 on December 22, 2023, entitled, “One more step toward treatment of PARP inhibitor-resistant ovarian cancers.”

Over 80% of ovarian cancer cases experience recurrence, resulting in roughly 12,000 annual deaths in the United States. While targeted therapies like poly (ADPribose) polymerase inhibitors (PARPis) have received FDA approval for both initial and recurrent treatments, extending median progression-free survival for individuals with homologous recombination repair (HRR) deficiency, the emergence of PARPi resistance remains a common challenge among patients. Consequently, addressing resistance to PARPi treatment in ovarian cancer has become a pressing therapeutic dilemma, necessitating innovative strategies. 

In this editorial, researchers Upasana Ray, Prabhu Thirusangu and Viji Shridhar from Mayo Clinic School of Medicine and Science responded to this unmet need with their current study, which unveiled promising findings related to the Pixatimod (PG545) drug, a sulfated small molecule compound. Engineered with a core structure mimicking heparan sulfate, this compound targets heparanase and heparin binding growth factor (HB-GF) signaling. 

“Our present study has revealed a previously unknown effect of PG545 in ovarian cancer cells, inducing DNA damage. The investigation unveiled that PG545 induces both single- and double-strand breaks in DNA while also promoting the autophagic degradation of RAD51, a critical DNA repair protein, thereby impeding the homologous recombination repair (HRR) pathway in cancer cells.”

DOI - https://doi.org/10.18632/oncotarget.28545

Correspondence to - Viji Shridhar - Shridhar.Vijayalakshmi@mayo.edu

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Keywords - cancer, ovarian cancer, PARP inhibitors, PG545, DNA damage, cell death

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One More Step Toward Treatment of PARP Inhibitor-resistant Ovarian Cancers

BUFFALO, NY- January 16, 2024 – A new #editorial paper was #published in Oncotarget's Volume 14 on December 1, 2023, entitled, “Reductive carboxylation of glutamine as a potential target in acute myeloid leukemia.”

In this new editorial, researchers Alessia Roma, Lawrence D. Goodridge and Paul A. Spagnuolo from the University of Guelph discuss acute myeloid leukemia (AML) — an aggressive cancer of the blood and bone marrow defined by poor patient outcomes and sub-optimal therapeutics. 

Recent advancements in our understanding of AML biology bring optimism to improving patient outcomes for this devastating disease. For example, the discovery and validation of metabolic vulnerabilities that are distinct to AML open new strategies for novel drug development. In fact, since 2017, a third of newly approved AML therapeutics have targeted metabolic abnormalities. Thus, further identification and elucidation of metabolic vulnerabilities in AML could lead to novel therapies aimed at improving patient outcomes. 

“One approach is to weaken tumor cell survival mechanisms. In this regard, exploring reductive carboxylation as a possible drug target could provide new avenues for optimizing existing treatments aimed at improving AML patient outcomes.”

DOI -  https://doi.org/10.18632/oncotarget.28474

Correspondence to - Paul A. Spagnuolo - paul.spagnuolo@uoguelph.ca

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Keywords - cancer, acute myeloid leukemia, aml, reductive carboxylation, metabolism, mitochondria, complex I

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Reductive Carboxylation of Glutamine as a Potential Target in AML

BUFFALO, NY- January 17, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on January 16, 2024, entitled, “ATR inhibition using gartisertib enhances cell death and synergises with temozolomide and radiation in patient-derived glioblastoma cell lines.”

Glioblastoma cells can restrict the DNA-damaging effects of temozolomide (TMZ) and radiation therapy (RT) using the DNA damage response (DDR) mechanism which activates cell cycle arrest and DNA repair pathways. Ataxia-telangiectasia and Rad3-Related protein (ATR) plays a pivotal role in the recognition of DNA damage induced by chemotherapy and radiation causing downstream DDR activation. 

In this new study, researchers Mathew Lozinski, Nikola A. Bowden, Moira C. Graves, Michael Fay, Bryan W. Day, Brett W. Stringer, and Paul A. Tooney from University of Newcastle, Hunter Medical Research Institute, GenesisCare, QIMR Berghofer Medical Research Institute, and Griffith University investigated the activity of the ATR inhibitor gartisertib alone, and in combination with TMZ and/or RT, in multiple patient-derived glioblastoma cell lines. 

“Using a panel of 12 patient-derived glioblastoma cell lines, we investigated the chemo- and radio-sensitizing effect of gartisertib, a potent and selective inhibitor of ATR [26] that was explored in a phase 1 clinical trial for patients with advanced solid tumors (NCT02278250).”

The team showed that gartisertib alone potently reduced the cell viability of glioblastoma cell lines, where sensitivity was associated with the frequency of DDR mutations and higher expression of the G2 cell cycle pathway. ATR inhibition significantly enhanced cell death in combination with TMZ and RT and was shown to have higher synergy than TMZ+RT treatment. MGMT promoter unmethylated and TMZ+RT resistant glioblastoma cells were also more sensitive to gartisertib. Analysis of gene expression from gartisertib treated glioblastoma cells identified the upregulation of innate immune-related pathways. 

“Overall, this study identifies ATR inhibition as a strategy to enhance the DNA-damaging ability of glioblastoma standard treatment, while providing preliminary evidence that ATR inhibition induces an innate immune gene signature that warrants further investigation.”

DOI - https://doi.org/10.18632/oncotarget.28551

Correspondence to - Paul A. Tooney - paul.tooney@newcastle.edu.au

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Keywords - cancer, glioblastoma, DNA damage response, ataxia-telangiectasia and rad3-related protein, radiation therapy, temozolomide

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ATR Inhibition Using Gartisertib in Patient-derived Glioblastoma Cell Lines

BUFFALO, NY- January 22, 2024 – A new #research perspective was #published in Oncotarget's Volume 15 on January 16, 2024, entitled, “Bone marrow adipocytes provide early sign for progression from MGUS to multiple myeloma.”

Multiple Myeloma (MM) is the second most common hematological malignancy and is characterized by clonal expansion of malignant plasma cells in the bone marrow. In spite of recent advances in the field of MM, the disease has remained incurable. MM is preceded by a premalignant state known as monoclonal gammopathy of undetermined significance (MGUS), with a risk of progression to MM of 1% per year. Establishing a scalable approach that refines the identification of MGUS patients at high risk of progression to MM can transform the clinical management of the disease, improve the patient’s quality of life, and will have significant socioeconomic implications. 

In this new perspective, researchers Bilal M. El-Masri, Benedeta Leka, Fatima Mustapha, Michael Tveden Gundesen, Maja Hinge, Thomas Lund, Thomas L. Andersen, Marta Diaz-delCastillo, and Abbas Jafari from the Danish Spatial Imaging Consortium, University of Southern Denmark, University of Copenhagen, University of Aarhus, Odense University Hospital, and Lillebaelt Hospital provide evidence that changes in the bone marrow adipose tissue (BMAT) provide an early sign for progression from MGUS to MM. 

“We employed AI-assisted histological analysis of unstained bone marrow biopsies from MGUS subjects with or without progression to MM within 10 years (n = 24, n = 17 respectively).” 

Although the BMAT fraction was not different between the two groups, bone marrow adipocyte (BMAd) density was decreased in MGUS patients who developed MM, compared to non-progressing MGUS patients. Importantly, the distribution profile for BMAd size and roundness was significantly different between the two groups, indicating a shift toward increased BMAd size and roundness in MGUS patients who developed MM. These early changes in the BMAT could serve as valuable early indicators for the transition from MGUS to MM, potentially enabling timely interventions and personalized treatment strategies. 

“[...] the AI-based approach for histological characterization of unstained bone marrow biopsies is cost-effective and fast, rendering its clinical implementation feasible.”

DOI - https://doi.org/10.18632/oncotarget.28548

Correspondence to - Abbas Jafari - ajafari@sund.ku.dk, Marta Diaz-delCastillo - marta@forens.au.dk, and Thomas L. Andersen - thomas.levin.andersen@rsyd.dk

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Keywords - cancer, multiple myeloma, MGUS, bone marrow adipocyte

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Bone Marrow Adipocytes Provide Early Sign of Progression from MGUS to Multiple Myeloma

BUFFALO, NY- January 24, 2024 – A new #case report was #published in Oncotarget's Volume 15 on January 16, 2024, entitled, “Lazarus effect in a patient initially empirically treated with osimertinib for EGFR L858R mutant non-small cell lung cancer with leptomeningeal disease: a case report.”

Osimertinib has been shown to be effective for patients with non-small cell lung cancer (NSCLC) with activating EGFR mutations. These patients are also at risk for leptomeningeal disease (LMD). LMD is characterized by central nervous system metastases with spread to the cerebrospinal fluid or leptomeninges. In patients with NSCLC with EGFR activating mutations, there is an increased occurrence of LMD, which occurs in 9% of patients.

In this new report, researchers Shreya Bhatia, Manuel G. Cortez, Spencer Lessans, and Wade T. Iams from Vanderbilt-Ingram Cancer Center present a patient of East Asian descent whose initial presentation included severe, progressive leptomeningeal carcinomatosis and a small lung mass, with limited tissue available for molecular testing. She responded to empiric, urgent initiation of osimertinib, repeat tissue sampling revealed an EGFR L858R mutation, and she has experienced durable disease improvement for 18 months on osimertinib monotherapy.

“Our case demonstrates the nuances of decision-making in starting osimertinib in urgent clinical settings. Given our patient’s progressively worsening functional status and spread of disease to her CNS upon presentation, there was a need to begin treatment imminently. Time constraints, financial constraints, and lack of sufficient tissue for analysis ultimately led to the empiric use of osimertinib. Through the urgent initiation of appropriate anti-cancer therapy, she experienced both a life saving improvement in functional status and improvement in her LUL primary tumor one month into treatment.”

DOI - https://doi.org/10.18632/oncotarget.28550

Correspondence to - Wade T. Iams - wade.t.iams@vumc.org

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Keywords - cancer, EGFR mutation, leptomeningeal disease, non-small cell lung cancer, osimertinib

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Lazarus Effect in Patient Treated with Osimertinib for NSCLC with Leptomeningeal Disease

BUFFALO, NY- January 29, 2024 – A new #research perspective was #published in Oncotarget's Volume 15 on January 24, 2024, entitled, “Genetic alterations in thyroid cancer mediating both resistance to BRAF inhibition and anaplastic transformation.”

In this new paper, researchers Mark Lee and Luc GT Morris from New York Presbyterian Hospital and Memorial Sloan Kettering Cancer Center discuss thyroid cancer. A subset of thyroid cancers present at advanced stage or with dedifferentiated histology and have limited response to standard therapy. Tumors harboring the BRAF V600E mutation may be treated with BRAF inhibitors; however, tumor response is often short-lived due to multiple compensatory resistance mechanisms. 

“One mode of resistance is the transition to an alternative cell state, which on rare occasions can correspond to tumor dedifferentiation.” 

DNA sequencing and RNA expression profiling show that thyroid tumors that dedifferentiate after BRAF inhibition are enriched in known genetic alterations that mediate resistance to BRAF blockade, and may also drive tumor dedifferentiation, including mutations in the PI3K/AKT/MTOR (PIK3CA, MTOR), MAP/ERK (MET, NF2, NRAS, RASA1), SWI/SNF chromatin remodeling complex (ARID2, PBRM1), and JAK/STAT pathways (JAK1). Given these findings, recent investigations have evaluated the efficacy of dual-target therapies; however, continued lack of long-term tumor control illustrates the complex and multifactorial nature of these compensatory mechanisms. Transition to an immune-suppressed state is another correlate of BRAF inhibitor resistance and tumor dedifferentiation, suggesting a possible role for concurrent targeted therapy with immunotherapy. 

“Investigations into combined targeted and immunotherapy are ongoing, but early results with checkpoint inhibitors, viral therapies, and CAR T-cells suggest enhanced anti-tumor immune activity with these combinations.”

DOI - https://doi.org/10.18632/oncotarget.28544

Correspondence to - Luc GT Morris - morrisl@mskcc.org

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Keywords - cancer, thyroid cancer, drug resistance, anaplastic transformation, BRAF inhibitors, PIK3CA

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Gene Alterations in Thyroid Cancer Mediate Resistance to BRAF Inhibition & Anaplastic Transformation

BUFFALO, NY- January 31, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on January 24, 2024, entitled, “BCAS1 defines a heterogeneous cell population in diffuse gliomas.”

Oligodendrocyte precursor markers have become of great interest to identify new diagnostic and therapeutic targets for diffuse gliomas, since state-of-the-art studies point towards immature oligodendrocytes as a possible source of gliomagenesis. Brain enriched myelin associated protein 1 (BCAS1) is a novel marker of immature oligodendrocytes and was proposed to contribute to tumorigenesis in non-central nervous system tumors. However, the role of BCAS1 in diffuse glioma is still underexplored. 

In this new study, researchers Raquel Morales-Gallel, María José Ulloa-Navas, Patricia García-Tárraga, Ricardo Prat-Acín, Gaspar Reynés, Pedro Pérez-Borredá, Luis Rubio, Vivian Capilla-González, Jaime Ferrer-Lozano, and José Manuel García-Verdugo from the University of Valencia-CIBERNED, Mayo Clinic, Hospital Universitari i Politècnic La Fe, University of Pablo de Olavide, and University of Seville-CSIC analyzed the expression of BCAS1 in different tumor samples from patients with diffuse gliomas (17 oligodendrogliomas; 8 astrocytomas; 60 glioblastomas) and uncovered the molecular and ultrastructural features of BCAS1+ cells by immunostaining and electron microscopy. 

“Our results show that BCAS1+ cells exhibit stellate or spherical morphology with similar ultrastructural features.”

Stellate and spherical cells were detected as isolated cells in all studied gliomas. Nevertheless, only stellate cells were found to be proliferative and formed tightly packed nodules with a highly proliferative rate in oligodendrogliomas. Their findings provide a comprehensive characterization of the BCAS1+ cell population within diffuse gliomas. The observed proliferative capacity and distribution of BCAS1+ stellate cells, particularly in oligodendrogliomas, highlight BCAS1 as an interesting marker, warranting further investigation into its role in tumor malignancy.

“In conclusion, this insight will shed light on the establishment of BCAS1 as a clinically relevant molecule, serving not only as a diagnostic or prognostic marker but also as a novel therapeutic target for the development of cutting-edge treatments.”

DOI - https://doi.org/10.18632/oncotarget.28553

Correspondence to - José Manuel García-Verdugo - j.manuel.garcia@uv.es

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Keywords - cancer, brain tumor, diffuse glioma, oligodendroglioma, glioblastoma, BCAS1

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BCAS1 Defines a Heterogeneous Cell Population in Diffuse Glioma Patients

BUFFALO, NY- February 5, 2024 – A new #editorial paper was #published in Oncotarget's Volume 15 on January 24, 2024, entitled, “The fate of drug discovery in academia; dumping in the publication landfill?”

In this new editorial, researchers Uzma Saqib, Isaac S. Demaree, Alexander G. Obukhov, Mirza S. Baig, Amiram Ariel, and Krishnan Hajela, from Devi Ahilya Vishwavidyalaya, Indore, discuss drug discovery—a tedious process that is time consuming in both divulging whether a molecule is efficacious and specific in hitting the target and also in confirming that the potential drug does not cause severe adverse effects. Many drug candidates fail crossing multiple checkpoints of this long journey; they lag in one or several aspects and never move beyond the research bench to contribute to public health. These setbacks make the process of drug discovery very time consuming, expensive, and tedious. 

“This viewpoint is focused on delineating how and why the multi-million [dollar] research efforts in the field of drug discovery often fail to reach its full potential.”

There is no shortage of studies focusing on drug discovery. They are published on a daily basis describing the efforts encompassing conventional and/or modern drug discovery technology, including structure-based drug design (SBDD), virtual screening, high-throughput screening (HTS), Artificial Intelligence (AI), and cell-based screening approaches (Figure 1). However, many drug development strategies are rather fuzzy in their advancement. 

Thus, there is a large gap between drug “discovery” and “development.” This part could be attributed to the lack of synergy between Academia and Industry at multiple levels. A significant part of this failure results from the lack of streamlining of drug development process. 

“In the current perspective, we discussed why many therapeutic molecules never make it to clinical studies despite being proven efficacious pre-clinically. Additionally, we discussed the possible solutions to overcome this défaut of the drug development process.”

DOI - https://doi.org/10.18632/oncotarget.28552

Correspondence to - Krishnan Hajela - hajelak@gmail.com

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Keywords - cancer, drug discovery and development, clinical trials, academia-industry collaboration, translational research, drug database

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Drug Discovery in Academia; Dumping in the Publication Landfill?

BUFFALO, NY- February 7, 2024 – A new #research perspective was #published in Oncotarget's Volume 15 on February 5, 2024, entitled, “Preclinical and clinical evaluation of the Janus Kinase inhibitor ruxolitinib in multiple myeloma.”

In this new paper, researchers Ashley Del Dosso, Elizabeth Tadevosyan, and James R. Berenson from ONCOtherapeutics, Berenson Cancer Center, and Institute for Myeloma and Bone Cancer Research discussed multiple myeloma (MM) — the most common primary malignancy of the bone marrow. No established curative treatment is currently available for patients diagnosed with MM. 

In recent years, new and more effective drugs have become available for the treatment of this B-cell malignancy. These new drugs have often been evaluated together and in combination with older agents. However, even these novel combinations eventually become ineffective; and, thus, novel therapeutic approaches are necessary to help overcome resistance to these treatments. 

Recently, the Janus Kinase (JAK) family of tyrosine kinases, specifically JAK1 and JAK2, has been shown to have a role in the pathogenesis of MM. Preclinical studies have demonstrated a role for JAK signaling in direct and indirect growth of MM and downregulation of anti-tumor immune responses in these patients. Also, inhibition of JAK proteins enhances the anti-MM effects of other drugs used to treat MM. These findings have been confirmed in clinical studies which have further demonstrated the safety and efficacy of JAK inhibition as a means to overcome resistance to currently available anti-MM therapies. Additional studies will provide further support for this promising new therapeutic approach for treating patients with MM.

“The following sections of this article will be focused on studies of RUX [Ruxolitinib] in the preclinical [21–24] and clinical settings [18–20] focused on the treatment of relapsed/refractory (RR) MM.”

DOI - https://doi.org/10.18632/oncotarget.28547

Correspondence to - James R. Berenson - jberenson@berensoncancercenter.com

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Keywords - cancer, multiple myeloma, ruxolitinib, JAK/STAT, cytokine, clinical trial

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Evaluation of Ruxolitinib, a Janus Kinase Inhibitor, in Multiple Myeloma

BUFFALO, NY- February 12, 2024 – A new research paper was published in Oncotarget's Volume 15 on February 5, 2024, entitled, “Differential expression of Mad2 gene is consequential to the patterns of histone H3 post-translational modifications in its promoter region in human esophageal cancer samples.”

Raw areca nut (AN) consumption increases esophageal squamous cell carcinoma (ESCC) due to overexpression of securin (pituitary tumor transforming gene1), causing chromosomal instability. Mitotic arrest deficient protein 2 (Mad2), a crucial spindle assembly checkpoint protein, is at risk of aneuploidy and tumor development when overexpressed or underexpressed. In this new study, researchers Chongtham Sovachandra Singh, Nabamita Boruah, Atanu Banerjee, Sillarine Kurkalang, Pooja Swargiary, Hughbert Dakhar, and Anupam Chatterjee from The Assam Royal Global University, University of Pennsylvania, LN Mithila University, University of Chicago Medicine, Nazareth Hospital, Laitumkhrah, and North-Eastern Hill University evaluated Mad2 status in human ESCC with AN consumption habits, revealing unclear molecular mechanisms. 

Human ESCC samples (n = 99) were used for loss of heterozygosity analysis at 4q25-28, while 32 samples were used for expression analysis of Mad2, E2F1 genes, and Rb-phosphorylation. Blood samples were used for metaphase preparation. The Mad2 deregulation was assessed using chromatin immunoprecipitation-qPCR assay in the core promoter region, establishing its association with the pRb-E2F1 circuit for the first time. 

“The study revealed overexpression and underexpression of Mad2, premature anaphase, and chromosome missegregation in all the samples.” 

LOH pattern identified a deletion in D4S2975 in 40% of ESCC samples. The study reveals the deregulation of pRb-E2F1 circuit in all samples. 4q27 disruption could be a factor for Mad2 underexpression in AN-induced esophageal carcinogenesis, while overexpression may be due to the deregulation of the Rb-E2F1 circuit and consequently elevation of H3K4me3 and H3K9ac. 

“Mad2 expression levels with chromosomal abnormalities can be a clinical biomarker, but further research is needed to understand pRb’s role in Mad2 down-regulation.”

DOI - https://doi.org/10.18632/oncotarget.28554

Correspondence to - Anupam Chatterjee - achatterjee@rgu.ac, chatterjeeanupam@hotmail.com

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Keywords - cancer, Mad2 gene, histone methylation, histone acetylation, Rb-phosphorylation; esophageal cancer

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Differential Expression of Mad2 Gene in Human Esophageal Cancer

BUFFALO, NY- February 14, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on February 5, 2024, entitled, “Genetic and therapeutic landscapes in cohort of pancreatic adenocarcinomas: next-generation sequencing and machine learning for full tumor exome analysis.”

About 7% of all cancer deaths are caused by pancreatic cancer (PCa). PCa is known for its lowest survival rates among all oncological diseases and heterogenic molecular profile. Enormous amount of genetic changes, including somatic mutations, exceeds the limits of routine clinical genetic laboratory tests and further stagnates the development of personalized treatments. 

In this new study, researchers P.A. Shatalov, N.A. Falaleeva, E.A. Bykova, D.O. Korostin, V.A. Belova, A.A. Zabolotneva, A.P. Shinkarkina, A. Yu Gorbachev, M.B. Potievskiy, V.S. Surkova, Zh V. Khailova, N.A. Kulemin, Denis Baranovskii, A.A. Kostin, A.D. Kaprin, and P.V. Shegai from the Ministry of Health of the Russian Federation, Pirogov Russian National Research Medical University, Federal Medical-Biological Agency, Moscow, and the Peoples Friendship University of Russia (RUDN University) aimed to build a mutational landscape of PCa in the Russian population based on full exome next-generation sequencing (NGS) of the limited group of patients. 

“Applying a machine learning model on full exome individual data, we received personalized recommendations for targeted treatment options for each clinical case and summarized them in the unique therapeutic landscape.”

DOI - https://doi.org/10.18632/oncotarget.28512

Correspondence to - Denis Baranovskii - doc.baranovsky@gmail.com

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Keywords - cancer, pancreatic cancer, tumor mutation burden, somatic mutations, artificial intelligence, machine learning

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Genetic and Therapeutic Landscapes in Cohort of Pancreatic Cancer Using NGS and Machine Learning

BUFFALO, NY- February 19, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on February 5, 2024, entitled, “Neurotrophic-tyrosine receptor kinase gene fusion in papillary thyroid cancer: A clinicogenomic biobank and record linkage study from Finland.”

Selective tropomyosin receptor kinase (TRK) inhibitors are approved targeted therapies for patients with solid tumors harboring a neurotrophic tyrosine receptor kinase (NTRK) gene fusion. Country-specific estimates of NTRK gene fusion frequency, and knowledge on the characteristics of affected patients, are limited.

In this new study, researchers Wei Zhang, Arndt A. Schmitz, Roosa E. Kallionpää, Merja Perälä, Niina Pitkänen, Mikko Tukiainen, Erika Alanne, Korinna Jöhrens, Renate Schulze-Rath, Bahman Farahmand, and Jihong Zong from Bayer HealthCare Pharmaceuticals Inc., University of Turku, Turku University Hospital, Technical University Dresden, and Western Finland Cancer Centre identified patients with histologically-confirmed papillary thyroid cancer (PTC) from Finland’s Auria Biobank. 

“The study objectives were to determine the frequency of NTRK gene fusion in patients with PTC in Finland, and to describe co-occurring genetic alternations, clinical characteristics, disease progression, and treatment pathways in NTRK gene fusion positive patients.”

TRK protein expression was determined by pan-TRK immunohistochemistry. Immuno-stained tumor samples were scored by a certified pathologist. Gene fusions and other co-occurring gene alterations were identified by next generation sequencing. Patient characteristics and vital status were determined from linked hospital electronic health records (EHRs). 

Patients were followed from 1 year before PTC diagnosis until death. 6/389 (1.5%) PTC patients had an NTRK gene fusion (all NTRK3); mean age 43.8 years (and none had comorbidities) at PTC diagnosis. Gene fusion partners were EML4 (n = 3), ETV6 (n = 2), and RBPMS (n = 1). Of 3/6 patients with complete EHRs, all received radioactive iodine ablation only and were alive at end of follow-up (median observation, 9.12 years). 

“In conclusion, NTRK gene fusion is infrequent in patients with PTC. Linkage of biobank samples to EHRs is feasible in describing the characteristics and outcomes of patients with PTC and potentially other cancer types.”

DOI - https://doi.org/10.18632/oncotarget.28555

Correspondence to - Jihong Zong - jihong.zong@bayer.com

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Keywords - cancer, NTRK gene fusion, papillary thyroid cancer, clinicogenomic, epidemiology, biobank

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NTRK Gene Fusion in Thyroid Cancer: A Clinicogenomic Biobank and Record Linkage Study From Finland

BUFFALO, NY- February 21, 2024 – A new research #perspective was #published in Oncotarget's Volume 15 on February 8, 2024, entitled, “Combining causal and correlative approaches to discover biomarkers of response to paclitaxel.”

As discussed in this new paper, researchers Alberto Moscona-Nissan, Karl J. Habashy, Victor A. Arrieta, Adam M. Sonabend, and Crismita Dmello from Universidad Panamericana School of Medicine, Northwestern University and Universidad Nacional Autónoma de México recently discovered a putative paclitaxel response predictive biomarker for glioblastoma and breast cancer using the whole genome CRISPR knockout screen. The biomarker candidate was validated in two independent breast cancer patient cohorts that received taxane treatment. 

“To further evaluate the potential application of this biomarker in the clinic for patients with glioblastoma, a prospective validation in cohorts of patients with glioblastoma is essential and will be performed as part of our ongoing phase II clinical trial (NCT04528680).”

The validation of novel biomarkers of susceptibility to therapy is critical to elucidate the efficacy signal of therapeutic agents. This is especially important in the context of glioblastoma, where therapeutic benefit is variable and unpredictable, leading to negative trials, yet the outcome of subset of patients has outperformed expectations.

“Precision and personalized medicine can lead to a transition from a stochastic treatment response into predictable scenarios. Further identification of predictive biomarkers, validation, and study of combinations as predictive models is critical to generate a greater impact that can be translated to the bedside of patients.”

DOI - https://doi.org/10.18632/oncotarget.28549

Correspondence to - Crismita Dmello - crismita.dmello@northwestern.edu, and Adam M. Sonabend - adam.sonabend@northwestern.edu

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Keywords - cancer, glioblastoma, predictive biomarker, CRISPR screen, paclitaxel

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Combining Causal and Correlative Approaches to Discover Response Biomarkers to Paclitaxel

BUFFALO, NY- February 26, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on February 8, 2024, entitled, “GZ17-6.02 interacts with bexarotene to kill mycosis fungoides cells.”

In this new study, researchers Michael R. Booth, Laurence Booth, Jane L. Roberts, Cameron West, and Paul Dent from Virginia Commonwealth University and Genzada Pharmaceuticals investigated the therapeutic agent GZ17-6.02, composed of curcumin, harmine and isovanillin.

“Combined with our curcumin findings, we believe that isovanillin can complex with curcumin and harmine to create an entity with unique biology when compared to the three individual agents.”

GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525) with an RP2D of 375 mg PO BID. The biology of GZ17-6.02 in malignant T cells and in particular those derived from mycosis fungoides (MF) patients, has not previously been studied. The researchers found that GZ17-6.02 alone and in combination with standard-of-care agents was effective in killing MF cells. 

“All three components are necessary for optimal killing of MF cells.” 

GZ17-6.02 activated ATM, the AMPK, NFκB and PERK and inactivated ERK1/2, AKT, ULK1, mTORC1, eIF2α, and reduced the expression of BCL-XL and MCL1. GZ17-6.02 increased ATG13 S318 phosphorylation and the expression of Beclin1, ATG5, BAK and BIM. GZ17-6.02 in a dose-dependent fashion enhanced autophagosome formation and autophagic flux, and tumor cell killing. 

Signaling by ATM and AMPK were both required for efficient killing but not for the dose-response effect whereas ER stress (eIF2α) and macroautophagy (Beclin1, ATG5) were required for both efficient killing and the dose-response. Knock down of the death receptor CD95 reduced killing by ~20% and interacted with autophagy inhibition to further reduce killing, collectively, by ~70%. Inhibition of autophagy and knock down of death-mediators downstream of the mitochondrion, AIF and caspase 3, almost abolished tumor cell killing. Hence in MF cells, the team wrote that GZ17-6.02 is a multi-factorial killer, utilizing ER stress, macroautophagy, death receptor signaling and directly causing mitochondrial dysfunction.”

 “We discovered that GZ17-6.02 containing harmine, isovanillin and curcumin caused more tumor cell killing than any of the agents individually or in pairs, and that it could interact in an additive fashion with standard of care MF drugs such as bexarotene and vorinostat to cause additional tumor cell death.”

DOI - https://doi.org/10.18632/oncotarget.28557

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

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Keywords - cancer, autophagy, ER stress, GZ17-6.02, bexarotene, vorinostat

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GZ17-6.02 With Bexarotene Kills Mycosis Fungoides Cells

BUFFALO, NY- February 28, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on February 22, 2024, entitled, “Prevalence and spectrum of germline BRCA1 and BRCA2 in a cohort of ovarian cancer patients from the Salento peninsula (Southern Italy): a matter of preventive health.”

In this new exploratory and descriptive study, researchers Elisabetta De Matteis, Maria Rosaria Tumolo, Paolo Tarantino, Mariangela Ciccarese, Tiziana Grassi, Francesco Bagordo, Maria Rita De Giorgio, Emanuele Rizzo, and Graziana Ronzino from Vito Fazzi Hospital, University of Salento, Strategic Regional Agency for Health and Social of Puglia, and University of Bari Aldo Moro aimed to characterize the deleterious BRCA1 and BRCA2 variants evaluated by genetic testing in a group of Ovarian cancer patients living in the Salento peninsula (Southern Italy).

From June 2014 to July 2023, patients with histologically confirmed high-grade serous carcinoma, fallopian tube, or primary peritoneal cancer who were referred to Lecce Familial Cancer Clinic were considered. BRCA-mutation genetic testing was performed on these patients. Socio-demographic data and cancer epidemiology were assessed, and Next Generation Sequencing and Sanger DNA sequencing were performed.

The median age at the diagnosis of 332 ovarian cancer patients collected was 57 years. The pedigree analyses showed that 28.6% had familial cases and 39.7% had sporadic cases. Of the 319 patients submitted to genetic testing, 29.8% were carriers of BRCA1/2 mutation, 75.8% at BRCA1 and 24.2% at BRCA2 gene. Of the 21 BRCA1 mutations, the variant c.5266dupC was the most frequent alteration (28.4%). With respect to BRCA2, 13 mutations were found and the variant c.9676delT was the most frequently recorded (6.3%).

“This study reveals that the prevalence of germline mutations in the BRCA1 and BRCA2 genes was higher than reported by other studies. A broader understanding of the prevalence and role of BRCA mutations in development, response to treatment, and prognosis represents an exciting and developing area of ovarian cancer treatment and prevention.”

DOI - https://doi.org/10.18632/oncotarget.28561

Correspondence to - Maria Rosaria Tumolo - mariarosaria.tumolo@unisalento.it

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Keywords - cancer, ovarian cancer, BRCA1, BRCA2, mutation

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BRCA1 and BRCA2 in a Cohort of Ovarian Cancer Patients From the Salento Peninsula

BUFFALO, NY- March 4, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on February 22, 2024, entitled, “Sacituzumab govitecan plus platinum-based chemotherapy mediates significant antitumor effects in triple-negative breast, urinary bladder, and small-cell lung carcinomas.”

Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an anti-Trop-2-directed antibody conjugated with the topoisomerase I inhibitory drug, SN-38, via a proprietary hydrolysable linker. SG has received United States Food and Drug Administration (FDA) approval to treat metastatic triple-negative breast cancer (TNBC), unresectable locally advanced or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer, and accelerated approval for metastatic urothelial cancer (mUC).

In this new study, researchers Thomas M. Cardillo, Maria B. Zalath, Roberto Arrojo, Robert M. Sharkey, Serengulam V. Govindan, Chien-Hsing Chang, and David M. Goldenberg from Gilead Sciences and the Center for Molecular Medicine and Immunology investigated the utility of combining SG with platinum-based chemotherapeutics in TNBC, urinary bladder carcinoma (UBC), and small-cell lung carcinoma (SCLC). 

“Given recent FDA approval of SG in mTNBC and accelerated approval in mUC [metastatic urothelial cancer], as well as its demonstrated clinical activity in SCLC [11], we investigated the possibility of expanding use of SG through combinations with currently utilized chemotherapeutics for these disease indications.”

SG plus carboplatin or cisplatin produced additive growth-inhibitory effects in vitro that trended towards synergy. Immunoblot analysis of cell lysates suggests perturbation of the cell-cycle and a shift towards pro-apoptotic signaling evidenced by an increased Bax to Bcl-2 ratio and down-regulation of two anti-apoptotic proteins, Mcl-1 and survivin. Significant antitumor effects were observed with SG plus carboplatin in mice bearing TNBC or SCLC tumors compared to all controls (P < 0.0062 and P < 0.0017, respectively) and with SG plus cisplatin in UBC and SCLC tumor-bearing animals (P < 0.0362 and P < 0.0001, respectively). These combinations were well tolerated by the animals. 

“Combining SG with platinum-based chemotherapeutics demonstrates the benefit in these indications and warrants further clinical investigation.”

DOI - https://doi.org/10.18632/oncotarget.28559

Correspondence to - Thomas M. Cardillo - Thomas.Cardillo1@Gilead.com

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Keywords - cancer, sacituzumab govitecan, Trop-2, SN-38, carboplatin, cisplatin

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Sacituzumab Govitecan Plus Platinum-based Chemotherapy in Breast, Bladder, and Lung Carcinomas

BUFFALO, NY- March 6, 2024 – A new #researchpaper was #published in Oncotarget's Volume 15 on March 5, 2024, entitled, “GZ17-6.02 interacts with proteasome inhibitors to kill multiple myeloma cells.”

In this new study, researchers Laurence Booth, Jane L. Roberts, Cameron West, and Paul Dent from Virginia Commonwealth University and Genzada Pharmaceuticals investigated GZ17-6.02, a synthetically manufactured compound containing isovanillin, harmine and curcumin, in multiple myeloma cells. GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525) with a recommended phase 2 dose (RP2D) of 375 mg PO BID. GZ17-6.02 was more efficacious as a single agent at killing multiple myeloma cells than had previously been observed in solid tumor cell types. 

“GZ17-6.02 interacted with proteasome inhibitors in a greater than additive fashion to kill myeloma cells and alone it killed inhibitor-resistant cells to a similar extent.”

The drug combination of GZ17-6.02 and bortezomib activated ATM, the AMPK and PERK and inactivated ULK1, mTORC1, eIF2α, NFκB and the Hippo pathway. The combination increased ATG13 S318 phosphorylation and the expression of Beclin1, ATG5, BAK and BIM, and reduced the levels of BCL-XL and MCL1. GZ17-6.02 interacted with bortezomib to enhance autophagosome formation and autophagic flux, and knock down of ATM, AMPKα, ULK1, Beclin1 or ATG5 significantly reduced both autophagy and tumor cell killing. Knock down of BAK and BIM significantly reduced tumor cell killing. 

The expression of HDACs1/2/3 was significantly reduced beyond that previously observed in solid tumor cells and required autophagy. This was associated with increased acetylation and methylation of histone H3. Combined knock down of HDACs1/2/3 caused activation of ATM and the AMPK and caused inactivation of ULK1, mTORC1, NFκB and the Hippo pathway. HDAC knock down also enhanced ATG13 phosphorylation, increased BAK levels and reduced those of BCL-XL. 

“Collectively, our present studies support performing additional in vivo studies with multiple myeloma cells.”

DOI - https://doi.org/10.18632/oncotarget.28558

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

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Keywords - cancer, autophagy, ER stress, GZ17-6.02, bortezomib, proteasome inhibitor

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GZ17-6.02 With Proteasome Inhibitors Kills Multiple Myeloma Cells

BUFFALO, NY- March 11, 2024 – Impact Journals publishes #scholarly journals in the #biomedical sciences with a focus on all areas of cancer and aging research. Oncotarget is one of the most prominent journals published by Impact Journals. 

Impact Journals will be participating as an exhibitor at the American Association for Cancer Research (AACR) Annual Meeting 2024 from April 5-10 at the San Diego Convention Center in San Diego, California. This year, the AACR meeting theme is “Inspiring Science • Fueling Progress • Revolutionizing Care.”

Visit booth number 4159 at the AACR Annual Meeting 2024 to connect with members of the Oncotarget team.

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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 at AACR Annual Meeting 2024

BUFFALO, NY- March 18, 2024 – A new #researchpaper was #published in Oncotarget's Volume 15 on March 14, 2024, entitled, “G-quadruplex landscape and its regulation revealed by a new antibody capture method.”

In this new study, researchers Subhamoy Datta, Manthan Patel, Chakkarai Sathyaseelan, Chandrama Ghosh, Akanksha Mudgal, Divyesh Patel, Thenmalarchelvi Rathinavelan, and Umashankar Singh from the Indian Institute of Technology Gandhinagar, Indian Institute of Technology Hyderabad, Queen Mary University of London, Bar-Ilan University, Medical University of Lublin, and the University of Helsinki discuss a secondary structure of DNA that has attracted wide interest, G-quadruplexes or G4s.

“Our understanding of DNA G-quadruplexes (G4s) from in vitro studies has been complemented by genome-wide G4 landscapes from cultured cells.”

Conventionally, the formation of G4s is accepted to depend on G-repeats such that they form tetrads. However, genome-wide G4s characterized through high-throughput sequencing suggest that these structures form at a large number of regions with no such canonical G4-forming signatures. Many G4-binding proteins have been described with no evidence for any protein that binds to and stabilizes G4s. 

“It remains unknown what fraction of G4s formed in human cells are protein-bound.” 

The G4-chromatin immunoprecipitation (G4-ChIP) method hitherto employed to describe G4 landscapes preferentially reports G4s that get crosslinked to proteins in their proximity. The current understanding of the G4 landscape is biased against representation of G4s which escape crosslinking as they are not stabilized by protein-binding and presumably transient. The researchers reported a protocol that captures G4s from the cells efficiently without any bias as well as eliminates the detection of G4s formed artifactually on crosslinked sheared chromatin post-fixation. They discovered that G4s form sparingly at SINEs (short interspersed nuclear elements). An application of this method shows that depletion of a repeat-binding protein CGGBP1 enhances net G4 capture at CGGBP1-dependent CTCF-binding sites and regions of sharp interstrand G/C-skew transitions. 

“The AbC G4-ChIP presents a powerful technique to decipher the cellular G4 landscape and its regulation and it has the potential to be adapted for discovering any DNA secondary structures genome-wide against which reliable antibodies are available.”

DOI - https://doi.org/10.18632/oncotarget.28564

Correspondence to - Umashankar Singh - usingh@iitgn.ac.in

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Keywords - cancer, DNA G-quadruplexes, G4-ChIP, CGGBP1, CTCF, G/C-skew

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A New Antibody Capture Method Reveals G-quadruplex Landscape and its Regulation

BUFFALO, NY- March 19, 2024 – A new #research perspective was #published by Mikhail V. Blagosklonny M.D., Ph.D., from Roswell Park Comprehensive Cancer Center in Oncotarget's Volume 15 on March 15, 2024, entitled, “From osimertinib to preemptive combinations.”

“Here, I suggest that while first-line osimertinib extends median progression-free survival (PFS) in EGFR-mutant lung cancer compared to first-generation TKIs, it reduces individual PFS in 15–20% of patients compared to first-generation TKIs. Since detecting a single resistant cell before treatment is usually impossible, osimertinib must be used in all patients as a first-line treatment, raising median PFS overall but harming some. 

The simplest remedy is a preemptive combination (PC) of osimertinib and gefitinib. A comprehensive PC (osimertinib, afatinib/gefitinib, and capmatinib) could dramatically increase PFS for 80% of patients compared to osimertinib alone, without harming anyone. This article also explores PCs for MET-driven lung cancer.”

DOI - https://doi.org/10.18632/oncotarget.28569

Correspondence to - Mikhail V. Blagosklonny - Blagosklonny@oncotarget.com, Blagosklonny@rapalogs.com

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Keywords - cancer, lung cancer, NSCLC, EGFR, resistance, afatinib, gefitinib, capmatinib

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“From Osimertinib to Preemptive Combinations” by Dr. Blagosklonny

BUFFALO, NY- March 20, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on March 14, 2024, entitled, “Analytical validation of NeXT Personal®, an ultra-sensitive personalized circulating tumor DNA assay.”

In this new study, researchers Josette Northcott, Gabor Bartha, Jason Harris, Conan Li, Fabio C.P. Navarro, Rachel Marty Pyke, Manqing Hong, Qi Zhang, Shuyuan Ma, Tina X. Chen, Janet Lai, Nitin Udar, Juan-Sebastian Saldivar, Erin Ayash, Joshua Anderson, Jiang Li, Tiange Cui, Tu Le, Ruthie Chow, Randy Jerel Velasco, Chris Mallo, Rose Santiago, Robert C. Bruce, Laurie J. Goodman, Yi Chen, Dan Norton, Richard O. Chen, and John M. Lyle from Personalis, Inc. describe the analytical validation of NeXT Personal®, an ultra-sensitive, tumor-informed circulating tumor DNA (ctDNA) assay for detecting residual disease, monitoring therapy response, and detecting recurrence in patients diagnosed with solid tumor cancers. 

“NeXT Personal uses whole genome sequencing of tumor and matched normal samples combined with advanced analytics to accurately identify up to ~1,800 somatic variants specific to the patient’s tumor.” 

A personalized panel is created, targeting these variants and then used to sequence cell-free DNA extracted from patient plasma samples for ultra-sensitive detection of ctDNA. The NeXT Personal analytical validation is based on panels designed from tumor and matched normal samples from two cell lines, and from 123 patients across nine cancer types. Analytical measurements demonstrated a detection threshold of 1.67 parts per million (PPM) with a limit of detection at 95% (LOD95) of 3.45 PPM. NeXT Personal showed linearity over a range of 0.8 to 300,000 PPM (Pearson correlation coefficient = 0.9998). Precision varied from a coefficient of variation of 12.8% to 3.6% over a range of 25 to 25,000 PPM. The assay targets 99.9% specificity, with this validation study measuring 100% specificity and in silico methods giving a confidence interval of 99.92 to 100%.

“In summary, this study demonstrates NeXT Personal as an ultra-sensitive, highly quantitative and robust ctDNA assay that can be used to detect residual disease, monitor treatment response, and detect recurrence in patients.”

DOI - https://doi.org/10.18632/oncotarget.28565

Correspondence to - John M. Lyle - john.lyle@personalis.com 

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Keywords - cancer, circulating tumor DNA, whole genome sequencing, molecular residual disease, tumor-informed assay, analytical validation

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Analytical Validation of an Ultra-sensitive Personalized Circulating Tumor DNA Assay: NeXT Personal®

BUFFALO, NY- March 25, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on March 14, 2024, entitled, “ABT199/venetoclax synergism with thiotepa enhances the cytotoxicity of fludarabine, cladribine and busulfan in AML cells.”

ABT199/venetoclax, an inhibitor of the pro-survival BCL-2 protein, has improved AML treatment. Its efficacy in hematopoietic stem cell transplantation (HSCT), when combined with other chemotherapeutic drugs, has not been thoroughly investigated. In this new study, researchers Benigno C. Valdez, Bin Yuan, David Murray, Jeremy L. Ramdial, Uday Popat, Yago Nieto, and Borje S. Andersson from The University of Texas MD Anderson Cancer Center and the University of Alberta demonstrate the synergistic cytotoxicity of ABT199/venetoclax with the DNA alkylator thiotepa (Thio) in AML cells. 

“The results may provide relevant information for the design of clinical trials using these drugs to circumvent recognized drug-resistance mechanisms when used as part of pre-transplant conditioning regimens for AML patients undergoing allogenic HSCT.”

Cleavage of Caspase 3, PARP1 and HSP90, as well as increased Annexin V positivity, suggest potent activation of apoptosis by this two-drug combination; increased levels of γ-H2AX, P-CHK1 (S317), P-CHK2 (S19) and P-SMC1 (S957) indicate an enhanced DNA damage response. Likewise, the increased level of P-SAPK/JNK (T183/Y185) and decreased P-PI3Kp85 (Y458) suggest enhanced activation of stress signaling pathways. These molecular readouts were synergistically enhanced when ABT199/venetoclax and Thio were combined with fludarabine, cladribine and busulfan. 

The five-drug combination decreased the levels of BCL-2, BCL-xL and MCL-1, suggesting its potential clinical relevance in overcoming ABT199/venetoclax resistance. Moreover, this combination is active against P53-negative and FLT3-ITD-positive cell lines. Enhanced activation of apoptosis was observed in leukemia patient-derived cell samples exposed to the five-drug combination, suggesting a clinical relevance. 

“The results provide a rationale for clinical trials using these two- and five-drug combinations as part of a conditioning regimen for AML patients undergoing HSCT.”

DOI - https://doi.org/10.18632/oncotarget.28563

Correspondence to - Benigno C. Valdez - mbalasik@yahoo.com

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Keywords - cancer, acute myeloid leukemia, aml, pre-transplant regimens, venetoclax, thiotepa, busulfan

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ABT199/Venetoclax Synergism With Thiotepa in Acute Myeloid Leukemia (AML) Cells

BUFFALO, NY- March 27, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on March 19, 2024, entitled, “Durvalumab and tremelimumab before surgery in patients with hormone receptor positive, HER2-negative stage II–III breast cancer.”

In this new study, researchers Haven R. Garber, Sreyashi Basu, Sonali Jindal, Zhong He, Khoi Chu, Akshara Singareeka Raghavendra, Clinton Yam, Lumarie Santiago, Beatriz E. Adrada, Padmanee Sharma, Elizabeth A. Mittendorf, and Jennifer K. Litton from the University of Texas MD Anderson Cancer Center, Brigham and Women’s Hospital, Dana-Farber Brigham Cancer Center, and Harvard Medical School conducted a clinical trial to assess the feasibility of enrolling patients with Stage II or III hormone receptor positive (HR+)/HER2-negative breast cancer to pre-operative dual PD-L1/CTLA-4 checkpoint inhibition administered prior to neoadjuvant chemotherapy (NACT). 

“This feasibility study was conducted to begin testing the hypothesis that dual checkpoint blockade would increase TIL and enhance the response to subsequent NACT in patients with stage II or III HR+/HER2-negative breast cancer.”

Eight eligible patients were treated with upfront durvalumab and tremelimumab for two cycles. Patients then received NACT prior to breast surgery. Seven patients had baseline and interval breast ultrasounds after combination immunotherapy and the responses were mixed: 3/7 patients experienced a ≥30% decrease in tumor volume, 3/7 a ≥30% increase, and 1 patient had stable disease. At the time of breast surgery, 1/8 patients had a pathologic complete response (pCR).

The trial was stopped early after 3 of 8 patients experienced immunotherapy-related toxicity or suspected disease progression that prompted discontinuation or a delay in the administration of NACT. Two patients experienced grade 3 immune-related adverse events (1 with colitis, 1 with endocrinopathy). Analysis of the tumor microenvironment after combination immunotherapy did not show a significant change in immune cell subsets from baseline.

“There was limited benefit for dual checkpoint blockade administered prior to NACT in our study of 8 patients with HR+/HER2-negative breast cancer.”

DOI - https://doi.org/10.18632/oncotarget.28567

Correspondence to - Haven R. Garber - hrgarber@mdanderson.org

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Keywords - cancer, breast cancer, ER positive,  immunotherapy, neoadjuvant chemotherapy, tumor microenvironment

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Durvalumab and Tremelimumab Before Surgery in Patients With HR+/HER2-negative Breast Cancer

BUFFALO, NY- April 10, 2024 – A new #researchpaper was #published in Oncotarget's Volume 15 on April 8, 2024, entitled, “Exploring the role of GHRH antagonist MIA-602 in overcoming Doxorubicin-resistance in acute myeloid leukemia.”

Acute myeloid leukemia (AML) is characterized by the rapid proliferation of mutagenic hematopoietic progenitors in the bone marrow. Conventional therapies include chemotherapy and bone marrow stem cell transplantation; however, they are often associated with poor prognosis. Notably, growth hormone-releasing hormone (GHRH) receptor antagonist MIA-602 has been shown to impede the growth of various human cancer cell lines, including AML. In this new study, researchers Simonetta I. Gaumond, Rama Abdin, Joel Costoya, Andrew V. Schally, and Joaquin J. Jimenez from the University of Miami, Florida Atlantic University and Veterans Affairs Medical Center, Miami examined the impact of MIA-602 as monotherapy and in combination with Doxorubicin on three Doxorubicin-resistant AML cell lines, KG-1A, U-937, and K-562. 

“Given the role of GHRH in multiple cancer types, it is possible that GHRH antagonists may offer an alternative treatment approach for AML as well as drug-resistant AML, which may circumvent the side effects associated with standard chemotherapy.”

The in vitro results revealed a significant reduction in cell viability for all treated wild-type cells. Doxorubicin-resistant clones were similarly susceptible to MIA-602 as the wild-type counterpart. Their in vivo experiment of xenografted nude mice with Doxorubicin-resistant K-562 revealed a reduction in tumor volume with MIA-602 treatment compared to control. 

“Our study demonstrates that these three AML cell lines, and their Doxorubicin-resistant clones, are susceptible to GHRH antagonist MIA-602.”

DOI - https://doi.org/10.18632/oncotarget.28579

Correspondence to - Simonetta I. Gaumond - sxg1204@miami.edu

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Keywords - cancer, leukemia, AML, resistance, growth hormone-releasing hormone, MIA-602

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Exploring the Role of MIA-602 in Overcoming Doxorubicin-resistance in Acute Myeloid Leukemia

BUFFALO, NY- April 16, 2024 – A new #researchpaper was #published in Oncotarget's Volume 15 on April 12, 2024, entitled, “Novel therapeutic bispecific antibodies for B-cell lymphoma targeting IgM and other antigens on the B-cell surface.”

The B-cell receptor regulates B-cell proliferation and apoptosis. Aberrations in BCR signaling are associated with the development and progression of B-cell malignancies, such as mantle cell lymphoma, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia, many of which express the IgM type of BCR on their cellular surface. 

Therefore, IgM is an attractive target for therapeutic antibodies against B-cell malignancies. However, soluble IgM competitively binds to anti-IgM antibodies in the serum, and these antibodies show insufficient cytotoxic activity. Thus, antibody therapy targeting IgM is hindered by the presence of soluble IgM in the blood. In this new study, researchers Takahiro Ohashi, Sayuri Terada, Shinsuke Hiramoto, Yuko Nagata, Hirokazu Suzuki, Hitoshi Miyashita, Tetsuo Sasaki, Yasukatsu Tsukada, and Keiko Fukushima from ZENOAQ (Zenyaku Kogyo Co., Ltd.) used a bispecific antibody to address this problem. 

“In this study, we aimed to produce IgM-dependent bispecific antibodies targeting IgM and the other B-cell antigens such as CD20, CD32b (FcγRIIB), CD79b, and human leukocyte antigen (HLA)-DR using the Cys1m technology [10, 43–45]. Additionally, the correct IgG-like bispecific antibody structures were confirmed and their efficacies in the presence of soluble IgM were analyzed.”

The researchers generated bispecific antibodies bound to IgM and other B-cell antigens such as CD20 and HLA-DR using their own bispecific antibody-producing technology, Cys1m. These bispecific antibodies directly inhibited cell proliferation via cell-cycle arrest and apoptosis in vitro, although large amounts of soluble IgM were present. Additionally, a bispecific antibody bound to IgM and HLA-DR (BTA106) depleted B-cells in cynomolgus monkeys. 

“These data suggest that anti-IgM/B-cell surface antigen-binding specific antibodies are promising therapeutic agents for B-cell malignancies. Moreover, the bispecific antibody modality can potentially overcome problems caused by soluble antigens.”

DOI - https://doi.org/10.18632/oncotarget.28578

Correspondence to - Keiko Fukushima - keiko_fukushima@mail.zenyaku.co.jp

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Keywords - cancer, bispecific antibody, Cys1m, IgM, lymphoma, cynomolgus monkey

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Novel Therapeutic Bispecific Antibodies for B-cell Lymphoma

BUFFALO, NY- April 29, 2024 – Oncotarget is a contributing #sponsor at the 19th International p53 Workshop, organized by the International Center for Genetic Engineering and Biotechnology (ICGEB), which takes place from May 13–16, 2024, in Trieste, Italy.

“Groundbreaking research and cutting-edge advancements in the field of the most studied human gene and most frequently mutated gene in cancer, will take center stage at the 19th International p53 Workshop.” – ICGEB.org

Among the 24 invited speakers at the 19th International p53 Workshop, 18 speakers have published new research on p53 in Oncotarget. These distinguished speakers who have published with Oncotarget include Dr. Andrei Gudkov — one of Oncotarget’s founding Editors-in-Chief. Dr. Gudkov will be speaking in the session on “p53 Inflammation and Immunity” and moderating the session on “Targeting p53 in Human Disease.”

“The event will gather leading scientists, clinicians, and researchers from around the world providing a unique opportunity to delve into the latest discoveries and innovations related to TP53 biology and explore the intricate role of TP53 in cancer and its potential for transformative impact in oncology.” – ICGEB.org

About Oncotarget 

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Oncotarget Sponsors 19th International p53 Workshop in Italy

BUFFALO, NY- May 6, 2024 – A new research paper was published in Oncotarget's Volume 15 on May 3, 2024, 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.”

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 infection has led to worsened outcomes for patients with cancer. SARS-CoV-2 spike protein mediates host cell infection and cell-cell fusion that causes stabilization of tumor suppressor p53 protein. In-silico analysis previously suggested that SARS-CoV-2 spike interacts with p53 directly but this putative interaction has not been demonstrated in cells. In this new study, researchers Shengliang Zhang and Wafik S. El-Deiry from Brown University and Lifespan Health System examined the interaction between SARS-CoV-2 spike, p53 and MDM2 (E3 ligase, which mediates p53 degradation) in cancer cells using an immunoprecipitation assay. 

“We observed that SARS-CoV-2 spike protein interrupts p53-MDM2 protein interaction but did not detect SARS-CoV-2 spike bound with p53 protein in the cancer cells.”

The researchers further observed that SARS-CoV-2 spike suppresses p53 transcriptional activity in cancer cells including after nutlin exposure of wild-type p53-, spike-expressing tumor cells and inhibits chemotherapy-induced p53 gene activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2. The suppressive effect of SARS-CoV-2 spike on p53-dependent gene activation provides a potential molecular mechanism by which SARS-CoV-2 infection may impact tumorigenesis, tumor progression and chemotherapy sensitivity. In fact, cisplatin-treated tumor cells expressing spike were found to have increased cell viability as compared to control cells. 

Further observations on γ-H2AX expression in spike-expressing cells treated with cisplatin may indicate altered DNA damage sensing in the DNA damage response pathway. The preliminary observations reported here warrant further studies to unravel the impact of SARS-CoV-2 and its various encoded proteins including spike on pathways of tumorigenesis and response to cancer therapeutics. More efforts should be directed at studying the effects of the SARS-CoV-2 spike and other viral proteins on host DNA damage sensing, response and repair mechanisms. 

“A goal would be to understand the structural basis for maximal anti-viral immunity while minimizing suppression of host defenses including the p53 DNA damage response and tumor suppression pathway. Such directions are relevant and important including not only in the context of viral infection and mRNA vaccines in general but also for patients with cancer who may be receiving cytotoxic or other cancer treatments.”

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

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

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Transfected SARS-CoV-2 Spike DNA Suppresses Cancer Cell Response to Chemotherapy

BUFFALO, NY- May 15, 2024 – A new #research paper was #published in Oncotarget's Volume 15 on May 14, 2024, entitled, “Cyclin D1 expression in penile cancer.”

In this new study, researchers Wesliany Everton Duarte, Jaqueline Diniz Pinho, Syomara Pereira da Costa Melo, Denner Rodrigo Diniz Duarte, Juliana Martins da Guia Ribeiro do Carmo, André Salim Khayat, José Ribamar Rodrigues Calixto, Marcos Adriano Garcia Campos, Rita da Graça Carvalhal Frazão Correa, Antonio Machado Alencar Júnior, Antônio Augusto Lima Teixeira-Júnior, and Gyl Eanes Barros Silva from Federal University of Maranhão, State University of Maranhão, Federal University of Pará, São Paulo State University, and University of São Paulo analyzed the expression profile of cyclin D1 in patients with PC, and to determine possible correlations with clinical and histopathological features. 

“Regarding PC, however, few studies have assessed the role of cyclin D1, reinforcing the necessity for initiatives that aim to investigate its actual role in the pathophysiology of this disease. As such, the present study aimed to characterize the expression of cyclin D1 in patients with PC, and to determine possible correlations with the clinical and histopathological features of the disease.”

A survey was conducted with 100 patients diagnosed with PC, who were treated at two reference hospitals in São Luís, Maranhão, Brazil, between 2013 and 2017. A review of clinical, epidemiological, and histopathological data was performed, Human Papillomavírus (HPV) DNA was detected using polymerase chain reaction (PCR) and cyclin D1 expression analysis was performed using immunohistochemical techniques. The data revealed that the absence of cyclin D1 expression was significantly associated with HPV-positive histological subtypes (p = 0.001), while its expression was associated with high-grade tumors (p = 0.014), histological subtype (p = 0.001), presence of sarcomatoid transformation (p = 0.04), and perineural invasion (p = 0.023). Patients with cyclin D1 expression exhibited lower disease-free survival compared to the cyclin D1-negative group, although the difference was not statistically significant. 

“The results suggest that cyclin D1 may be a potential biomarker for PC, especially for poorer prognosis.”

DOI - https://doi.org/10.18632/oncotarget.28584

Correspondence to - Gyl Eanes Barros Silva - gyl.silva@ufma.br

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Keywords - cancer, immunohistochemistry, biomarkers, cyclin D1, penile neoplasms

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Expression of Cyclin D1 in Penile Cancer

BUFFALO, NY- May 20, 2024 – A new research paper was published in Oncotarget's Volume 15 on May 16, 2024, entitled, “The anticancer potential of the CLK kinases inhibitors 1C8 and GPS167 revealed by their impact on the epithelial-mesenchymal transition and the antiviral immune response.”

The diheteroarylamide-based compound 1C8 and the aminothiazole carboxamide-related compound GPS167 inhibit the CLK kinases, and affect the proliferation of a broad range of cancer cell lines. A chemogenomic screen previously performed with GPS167 revealed that the depletion of components associated with mitotic spindle assembly altered sensitivity to GPS167.
 
In this new study, researchers Lulzim Shkreta, Johanne Toutant, Aurélie Delannoy, David Durantel, Anna Salvetti, Sophie Ehresmann, Martin Sauvageau, Julien A. Delbrouck, Alice Gravel-Trudeau, Christian Comeau, Caroline Huard, Jasmin Coulombe-Huntington, Mike Tyers, David Grierson, Pierre-Luc Boudreault, and Benoit Chabot from Université de Sherbrooke, Université de Lyon, Institut de recherches cliniques de Montréal, Université de Montréal, and University of British Columbia a similar screen performed with 1C8 also established the impact of components involved in mitotic spindle assembly. 

“Accordingly, transcriptome analyses of cells treated with 1C8 and GPS167 indicated that the expression and RNA splicing of transcripts encoding mitotic spindle assembly components were affected.” 

The functional relevance of the microtubule connection was confirmed by showing that subtoxic concentrations of drugs affecting mitotic spindle assembly increased sensitivity to GPS167. 1C8 and GPS167 impacted the expression and splicing of transcripts in pathways relevant to tumor progression, including MYC targets and the epithelial mesenchymal transition (EMT). Finally, 1C8 and GPS167 altered the expression and alternative splicing of transcripts involved in the antiviral immune response. Consistent with this observation, depleting the double-stranded RNA sensor DHX33 suppressed GPS167-mediated cytotoxicity on HCT116 cells. 

“Our study uncovered molecular mechanisms through which 1C8 and GPS167 affect cancer cell proliferation as well as processes critical for metastasis."

DOI - https://doi.org/10.18632/oncotarget.28585

Correspondence to - Benoit Chabot - benoit.chabot@usherbrooke.ca

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Keywords - cancer, CLK kinases inhibitors, EMT, antiviral immune response, microtubules, metastasis

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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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Anticancer Potential of CLK Kinase Inhibitors 1C8 and GPS167 via EMT and Antiviral Immune Response

BUFFALO, NY- May 22, 2024 – A new research paper was published in Oncotarget's Volume 15 on May 17, 2024, entitled, “GZ17-6.02 kills PDX isolates of uveal melanoma.”

In this new study, researchers Laurence Booth, Jane L. Roberts, Ivan Spasojevic, Kaitlyn C. Baker, Andrew Poklepovic, Cameron West, John M. Kirkwood, and Paul Dent from Virginia Commonwealth University, Duke University School of Medicine, Genzada Pharmaceuticals, Texas Tech University Health Sciences Center, and University of Pittsburgh Cancer Institute defined the biology of GZ17-6.02 in UM cells and in parallel determined its interaction with irreversible ERBB inhibitors (afatinib, neratinib) and with the cytotoxic agent doxorubicin. 

“GZ17-6.02 is a novel compound, containing the synthetically manufactured components: curcumin, harmine and isovanillin and has undergone phase I safety evaluation in cancer patients (NCT03775525).”

GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525). The RP2D is 375 mg PO BID, with an uveal melanoma patient exhibiting a 15% reduction in tumor mass for 5 months at this dose. Studies in this manuscript have defined the biology of GZ17-6.02 in PDX isolates of uveal melanoma cells. 

GZ17-6.02 killed uveal melanoma cells through multiple convergent signals including enhanced ATM-AMPK-mTORC1 activity, inactivation of YAP/TAZ and inactivation of eIF2α. GZ17-6.02 significantly enhanced the expression of BAP1, predictive to reduce metastasis, and reduced the levels of ERBB family RTKs, predicted to reduce growth. GZ17-6.02 interacted with doxorubicin or ERBB family inhibitors to significantly enhance tumor cell killing which was associated with greater levels of autophagosome formation and autophagic flux. 

Knock down of Beclin1, ATG5 or eIF2α were more protective than knock down of ATM, AMPKα, CD95 or FADD, however, over-expression of FLIP-s provided greater protection compared to knock down of CD95 or FADD. Expression of activated forms of mTOR and STAT3 significantly reduced tumor cell killing. GZ17-6.02 reduced the expression of PD-L1 in uveal melanoma cells to a similar extent as observed in cutaneous melanoma cells whereas it was less effective at enhancing the levels of MHCA. The components of GZ17-6.02 were detected in tumors using a syngeneic tumor model. 

“Our data support future testing GZ17-6.02 in uveal melanoma as a single agent, in combination with ERBB family inhibitors, in combination with cytotoxic drugs, or with an anti-PD1 immunotherapy.”

DOI - https://doi.org/10.18632/oncotarget.28586

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

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Keywords - cancer, autophagy, ER stress, GZ17-6.02, doxorubicin, afatinib, neratinib

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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GZ17-6.02 Kills Uveal Melanoma Cells

Upon diagnosing acute myeloid leukemia (AML), the initial step involves assessing a patient’s eligibility for intensive chemotherapy. The standard treatment protocol for newly diagnosed AML encompasses intensive chemotherapy to achieve complete remission, followed by post-remission therapy, which may include additional chemotherapy and/or stem cell transplantation. Complete response rates to this approach range from 60% to 85% in adults aged 60 or younger.

While this approach has proven effective, the risk of relapse within three years of diagnosis remains a significant concern. Numerous factors contribute to the likelihood of relapse, including short duration of remission, genetic derangements, prior allogeneic transplantation, advanced age, and concomitant comorbidities. These negative prognostic factors underscore the need for continuous exploration of novel therapeutic agents, as relapse remains a formidable barrier to treatment success.

In a new study, researchers Simonetta I. Gaumond, Rama Abdin, Joel Costoya, Andrew V. Schally (awarded the Nobel Prize in Physiology or Medicine in 1977), and Joaquin J. Jimenez from the University of Miami, Florida Atlantic University and Veterans Affairs Medical Center, Miami, investigated newly emerging therapies targeting drug resistance in AML. On April 8, 2024, their new research paper was published in Oncotarget’s Volume 15, entitled, “Exploring the role of GHRH antagonist MIA-602 in overcoming Doxorubicin-resistance in acute myeloid leukemia.”

Full blog - https://www.oncotarget.org/2024/05/23/combating-doxorubicin-resistant-acute-myeloid-leukemia/

Paper DOI - https://doi.org/10.18632/oncotarget.28579

Correspondence to - Simonetta I. Gaumond - sxg1204@miami.edu

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Keywords - cancer, leukemia, AML, resistance, growth hormone-releasing hormone, MIA-602

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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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Combating Doxorubicin-Resistant Acute Myeloid Leukemia

BUFFALO, NY- May 28, 2024 – A new review paper was published in Oncotarget's Volume 15 on May 23, 2024, entitled, “The importance of integrated therapies on cancer: Silibinin, an old and new molecule.”

In this new review, researchers Elisa Roca, Giuseppe Colloca, Fiorella Lombardo, Andrea Bellieni, Alessandra Cucinella, Giorgio Madonia, Licia Martinelli, Maria Elisa Damiani, Ilaria Zampieri, and Antonio Santo from Perderzoli Hospital and Fondazione Policlinico Universitario “A. Gemelli” begin their abstract by noting that the efficacy of coadjuvant molecules, in the landscape of cancer treatments, remains a focus of attention for clinical research with the aim of reducing toxicity and achieving better outcomes.

“Most of the pathogenetic processes causing tumour development, neoplastic progression, ageing, and increased toxicity involve inflammation.”

Inflammatory mechanisms can progress through a variety of molecular patterns. As is well known, the ageing process is determined by pathological pathways very similar and often parallel to those that cause cancer development. Among these complex mechanisms, inflammation is currently much studied and is often referred to in the geriatric field as ‘inflammaging’. In this context, treatments active in the management of inflammatory mechanisms could play a role as adjuvants to standard therapies.

Among these emerging molecules, Silibinin has demonstrated its anti-inflammatory properties in different neoplastic types, also in combination with chemotherapeutic agents. Moreover, this molecule could represent a breakthrough in the management of age-related processes. Thus, Silibinin could be a valuable adjuvant to reduce drug-related toxicity and increase therapeutic potential.

“For this reason, the main aim of this review is to collect and analyse data presented in the literature on the use of Silibinin, to better understand the mechanisms of the functioning of this molecule and its possible therapeutic role.”

DOI - https://doi.org/10.18632/oncotarget.28587

Correspondence to - Elisa Roca - elisaroca@gmail.com

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Keywords - cancer, silibinin, anti-inflammatory, inflammation, toxicity, integrated therapy

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The Importance of Integrated Therapies on Cancer: Silibinin, an Old and New Molecule

Dr. Benoit Chabot from Université de Sherbrooke in Quebec, CA, discusses a research paper he co-authored that was published by Oncotarget in Volume 15, entitled, “The anticancer potential of the CLK kinases inhibitors 1C8 and GPS167 revealed by their impact on the epithelial-mesenchymal transition and the antiviral immune response.”

DOI - https://doi.org/10.18632/oncotarget.28585

Correspondence to - Benoit Chabot - benoit.chabot@usherbrooke.ca

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Transcription - https://www.oncotarget.net/2024/05/30/behind-the-study-anticancer-potential-of-clk-kinase-inhibitors-1c8-and-gps167/

Abstract

The diheteroarylamide-based compound 1C8 and the aminothiazole carboxamide-related compound GPS167 inhibit the CLK kinases, and affect the proliferation of a broad range of cancer cell lines. A chemogenomic screen previously performed with GPS167 revealed that the depletion of components associated with mitotic spindle assembly altered sensitivity to GPS167. Here, a similar screen performed with 1C8 also established the impact of components involved in mitotic spindle assembly. Accordingly, transcriptome analyses of cells treated with 1C8 and GPS167 indicated that the expression and RNA splicing of transcripts encoding mitotic spindle assembly components were affected. The functional relevance of the microtubule connection was confirmed by showing that subtoxic concentrations of drugs affecting mitotic spindle assembly increased sensitivity to GPS167. 1C8 and GPS167 impacted the expression and splicing of transcripts in pathways relevant to tumor progression, including MYC targets and the epithelial mesenchymal transition (EMT). Finally, 1C8 and GPS167 altered the expression and alternative splicing of transcripts involved in the antiviral immune response. Consistent with this observation, depleting the double-stranded RNA sensor DHX33 suppressed GPS167-mediated cytotoxicity on HCT116 cells. Our study uncovered molecular mechanisms through which 1C8 and GPS167 affect cancer cell proliferation as well as processes critical for metastasis.

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Keywords - cancer, CLK kinases inhibitors, EMT, antiviral immune response, microtubules, metastasis

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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Behind the Study: Anticancer Potential of CLK Kinase Inhibitors 1C8 and GPS167

BUFFALO, NY- June 4, 2024 – A new research perspective was published in Oncotarget's Volume 15 on June 3, 2024, entitled, “Bruton’s tyrosine kinase inhibitor-related cardiotoxicity: The quest for predictive biomarkers and improved risk stratification.”

In this new perspective, researchers Jai N. Patel, Jai Singh, and Nilanjan Ghosh from Atrium Health discuss Ibrutinib — the first Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment of patients with chronic lymphocytic leukemia (CLL). 

“While producing durable responses and prolonging survival, roughly 20–25% of patients experience dose limiting side effects, mostly consisting of cardiovascular toxicities like severe hypertension and atrial fibrillation.”

While clinical predictors of BTK inhibitor-related cardiotoxicity have been proposed and may aid in risk stratification, there is no routine risk model used in clinical practice today to identify patients at highest risk. A recent study investigating genetic predictors of ibrutinib-related cardiotoxicity found that single nucleotide polymorphisms in KCNQ1 and GATA4 were significantly associated with cardiotoxic events. If replicated in larger studies, these biomarkers may improve risk stratification in combination with clinical factors. 

“A clinicogenomic risk model may aid in identifying patients at highest risk of developing BTK inhibitor-related cardiotoxicity in which further risk mitigation strategies may be explored.”

DOI - https://doi.org/10.18632/oncotarget.28589

Correspondence to - Nilanjan Ghosh - nilanjan.ghosh@atriumhealth.org

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Keywords - cancer, BTK inhibitor, cardiotoxicity, biomarkers, risk, genetics

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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BTK Inhibitor-related Cardiotoxicity: Quest for Predictive Biomarkers, Improved Risk Stratification

BUFFALO, NY- June 5, 2024 – A new research paper was published in Oncotarget's Volume 15 on June 3, 2024, entitled, “Synergistic cytotoxicity of histone deacetylase and poly-ADP ribose polymerase inhibitors and decitabine in pancreatic cancer cells: Implications for novel therapy.”

Histone deacetylase inhibitors (HDACi) can modulate the acetylation status of proteins, influencing the genomic instability exhibited by cancer cells. Poly (ADP ribose) polymerase (PARP) inhibitors (PARPi) have a direct effect on protein poly (ADP-ribosyl)ation, which is important for DNA repair. Decitabine is a nucleoside cytidine analogue, which when phosphorylated gets incorporated into the growing DNA strand, inhibiting methylation and inducing DNA damage by inactivating and trapping DNA methyltransferase on the DNA, thereby activating transcriptionally silenced DNA loci.

In this new study, researchers Benigno C. Valdez, Apostolia M. Tsimberidou, Bin Yuan, Yago Nieto, Mehmet A. Baysal, Abhijit Chakraborty, Clark R. Andersen, and Borje S. Andersson from The University of Texas MD Anderson Cancer Center explored various combinations of HDACi and PARPi +/− decitabine (hypomethylating agent) in pancreatic cancer cell lines BxPC-3 and PL45 (wild-type BRCA1 and BRCA2) and Capan-1 (mutated BRCA2). 

“[...] we explored various combinations of HDACis and PARPis, with or without decitabine, in pancreatic cancer cell lines.”

The combination of HDACi (panobinostat or vorinostat) with PARPi (talazoparib or olaparib) resulted in synergistic cytotoxicity in all cell lines tested. The addition of decitabine further increased the synergistic cytotoxicity noted with HDACi and PARPi, triggering apoptosis (evidenced by increased cleavage of caspase 3 and PARP1). 

The 3-drug combination treatments (vorinostat, talazoparib, and decitabine; vorinostat, olaparib, and decitabine; panobinostat, talazoparib, and decitabine; panobinostat, olaparib, and decitabine) induced more DNA damage (increased phosphorylation of histone 2AX) than the individual drugs and impaired the DNA repair pathways (decreased levels of ATM, BRCA1, and ATRX proteins). The 3-drug combinations also altered the epigenetic regulation of gene expression (NuRD complex subunits, reduced levels). 

“This is the first study to demonstrate synergistic interactions between the aforementioned agents in pancreatic cancer cell lines and provides preclinical data to design individualized therapeutic approaches with the potential to improve pancreatic cancer treatment outcomes.”

DOI - https://doi.org/10.18632/oncotarget.28588

Correspondence to - Apostolia M. Tsimberidou - atsimber@mdanderson.org

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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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Synergistic Cytotoxicity of HDAC and PARP Inhibitors and Decitabine in Pancreatic Cancer Cells

In the relentless battle against non-small cell lung cancer (NSCLC) driven by epidermal growth factor receptor (EGFR) mutations, the development of resistance has long been a formidable obstacle. Historically, first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) like gefitinib, erlotinib, afatinib, and dacomitinib have faced a significant hurdle: the emergence of the T790M point mutation in approximately 50% of patients, rendering the tumor resistant to these therapies.

This resistance stems from a sobering reality – before treatment, a small subset of cancer cells already harbor the T790M mutation, conferring no selective advantage initially. However, once treatment commences, these rare mutated cells proliferate selectively, eventually dominating the tumor population and diminishing the effectiveness of first- and second-generation TKIs.

Full blog - https://www.oncotarget.org/2024/06/06/dr-blagosklonnys-strategy-from-osimertinib-to-preemptive-combinations/

Paper DOI - https://doi.org/10.18632/oncotarget.28569

Correspondence to - Mikhail V. Blagosklonny - Blagosklonny@oncotarget.com, Blagosklonny@rapalogs.com

Video short - https://www.youtube.com/watch?v=UO5BGLIggTE

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Keywords - cancer, lung cancer, NSCLC, EGFR, resistance, afatinib, gefitinib, capmatinib

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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Dr. Blagosklonny’s Strategy: From Osimertinib to Preemptive Combinations

BUFFALO, NY- June 11, 2024 – The Ride for Roswell is one of the nation’s largest cycling events—hosted by Roswell Park Comprehensive Cancer Center—to raise awareness and funds for cancer research and patient care. This charity bike ride, based out of Buffalo, New York, has brought people together for 28 years to celebrate cancer survivors, pay tribute to lives that have been lost, and to work together to support research and find a cure.

THE ORIGIN OF THE RIDE

The Ride for Roswell started in 1989 when Mitch Flynn, owner of the advertising agency Flynn & Friends, met Katherine Gioia. Katherine was a four-year-old patient battling a rare form of cancer. After Katherine’s death (less than a year after her diagnosis), Katherine’s mother, Anne Gioia, and aunt, Donna Gioia, founded the Roswell Park Alliance Foundation in her memory to raise money for cancer research and treatment. On June 29, 1996, Mitch and Alliance Foundation staff launched the first Ride for Roswell.

In the 28 years since then, thanks to over 135,000 riders and thousands of volunteers, the Ride for Roswell has raised over $72 million to fund cancer research. The event has become one of the largest charity rides in the United States.

THIS YEAR

This year, Ride Day is on Saturday, June 22, 2024, and will once again begin at the University at Buffalo North Campus. There are nine routes to choose from, ranging from five to 100 mile distances. All riders are encouraged to check in on the Thursday or Friday before Ride Day.

Learn more about The Ride, check in, and routes: www.rideforroswell.org/routes/

JOIN A TEAM: TEAM OPEN ACCESS

Impact Journals has been a part of this event since 2018 and continues to sponsor captain Sergei Kurenov’s peloton, Team Open Access. Team Open Access was named in honor of all open-source online medical journals, such as Oncotarget, Aging, Genes & Cancer, and Oncoscience. Sergei works at Roswell Park Comprehensive Cancer Center to create, develop, and implement innovative diagnostic and surgical pre-planning software used in cancer treatment. He has been riding in the event since 2016.

“I am proud to [say] that our team is supported again by open source cancer-related scientific journals: Oncotarget and Aging! Both of these journals publish high-impact research papers of general interest and biological significance in all fields of cancer research,” Sergei said.

There is still time to join Team Open Access in the Ride for Roswell. You can also support the team by giving a donation of any size. Any avenue of support you may choose to donate to the Ride for Roswell will make a difference and change lives.

“Finding a cure for cancer is something we are all incredibly passionate about, and we are so thankful and grateful for your support. Together, we can make a difference!” Sergei said. “Thank you so much for your donations, your support, and well wishes!”

Visit the Open Access team page to join or donate today:
give.roswellpark.org/site/TR/Specia…eam&fr_id=1940

For media requests, please contact media@impactjournals.com.

Impact Journals Sponsors 2024 Ride for Roswell

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.

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