Oncotarget

BUFFALO, NY - September 24, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on September 22, 2025, titled “Loss of Trp53 results in a hypoactive T cell phenotype accompanied by reduced pro-inflammatory signaling in a syngeneic orthotopic mouse model of ovarian high-grade serous carcinoma.” In this study, led by first author Jacob Haagsma and corresponding author Trevor G. Shepherd from the Verspeeten Family Cancer Centre and Western University, Canada, researchers investigated how the loss of Trp53 – a critical tumor suppressor gene – affects immune responses in ovarian cancer. The team found that deleting Trp53 led to more aggressive tumor growth and a weaker immune response. These findings help explain why some ovarian tumors may be resistant to immunotherapy and point to new ways to improve treatment. High-grade serous ovarian carcinoma (HGSC) is a deadly cancer that is often diagnosed at a late stage. Immunotherapy, which enhances the body’s immune system to fight cancer, has shown limited effectiveness in treating this type of cancer. To better understand why, the researchers developed a mouse model that closely mimics human HGSC. They injected ovarian epithelial cells, with and without Trp53, into the fallopian tubes, the origin site of most ovarian cancers. “In this study, we developed a syngeneic model reflecting both the site of origin and the genotype of early HGSC disease by deleting Trp53 in mouse oviductal epithelial (OVE) cells.” Mice injected with cells lacking Trp53 developed faster-growing and more invasive tumors, reflecting how the disease typically progresses in humans. These tumors also had fewer active T cells, which are immune cells responsible for attacking cancer. Moreover, the T cells that were present appeared less capable of responding to the tumor, creating an immune environment that allowed cancer to grow uncontrolled. Further analysis revealed that tumor cells without Trp53 had reduced activity in genes related to inflammation. These changes were associated with lower levels of key proteins that normally help immune cells detect and attack tumor cells. When the researchers collected tumor cells from the abdominal fluid of the mice—a condition that simulates advanced-stage disease—they observed even lower immune signaling than before. This suggests that as the tumor spreads, it becomes better at evading the immune system. This study highlights how early genetic mutations can shape the interaction between tumors and the immune system. In particular, the loss of Trp53 appears to trigger a chain of events that weakens immune surveillance and accelerates tumor progression. These findings emphasize the need to consider both genetic mutations and the tumor environment when designing immunotherapies for ovarian cancer. Understanding how genes like Trp53 influence immune behavior may lead to more effective treatments and help identify which patients are most likely to benefit from immunotherapy. DOI - https://doi.org/10.18632/oncotarget.28768 Correspondence to - Trevor G. Shepherd - tshephe6@uwo.ca Abstract video - https://www.youtube.com/watch?v=WFQw0psuC3M Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28768 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Immunotherapy is not usually effective against pancreatic cancer (PC), but a new study published in Oncotarget (Volume 16, 2025) highlights rare cases where it did help. These examples, though uncommon, may offer valuable insights for future treatment. Pancreatic Cancer and Immunotherapy Pancreatic cancer is often diagnosed at an advanced stage, which limits treatment options and contributes to its poor prognosis. While chemotherapy remains the standard treatment, it usually offers only modest benefits in terms of survival. Immunotherapy—an approach that activates the immune system to fight cancer—has been effective in other cancers but has shown limited success in PC. This is largely due to the tumor’s ability to suppress immune responses and create an environment that protects it from attack. Currently, these drugs are only approved for a small subset of patients whose tumors have a specific genetic feature called high microsatellite instability (MSI-high), found in just 1 to 2 percent of cases. The Study: Pancreatic Cancer Immunotherapy Responders The study, titled “Exceptional responders to immunotherapy in pancreatic cancer: A multi-institutional case series of a rare occurrence,” was led by first author Kavin Sugumar and corresponding author Jordan M. Winter, from University Hospitals Seidman Cancer Center. The researchers examined medical records from 14 patients with pancreatic ductal adenocarcinoma (PDAC) who had responded unexpectedly well to immune checkpoint inhibitors—drugs that help reactivate immune cells to attack cancer. The drugs included PD-1 inhibitors such as pembrolizumab and nivolumab, CTLA-4 inhibitors like ipilimumab, and agents targeting tumor-associated macrophages. To find these rare cases, the research team contacted 471 oncologists from 91 major U.S. cancer centers between 2020 and 2021. Full blog - https://www.oncotarget.org/2025/09/11/immunotherapy-response-in-pancreatic-cancer-what-a-new-study-reveals/ Paper DOI - https://doi.org/10.18632/oncotarget.28739 Correspondence to - Jordan M. Winter - jordan.winter@UHHospitals.org Abstract video - https://www.youtube.com/watch?v=VeWTcuVmqgM Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28739 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, pancreatic adenocarcinoma, immunotherapy, exceptional responders, microsatellite instability, survival To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

BUFFALO, NY – August 29, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on August 29, 2025, titled “In vivo manipulation of the protein homeostasis network in rhabdomyosarcoma.” In this study led by first author Kristen Kwong and corresponding author Amit J. Sabnis from the Department of Pediatrics, Division of Oncology, University of California San Francisco, researchers discovered that disrupting the protein quality control system in cancer cells slows tumor growth in rhabdomyosarcoma (RMS), the most common pediatric soft tissue cancer. This finding points to a new strategy for treating high-risk childhood cancers that often resist current therapies. Rhabdomyosarcoma is a rare and aggressive cancer that primarily affects children and adolescents. Standard treatments like chemotherapy and radiation often have limited long-term success in high-risk cases. This study explored a different approach: targeting the cellular machinery that maintains protein quality, known as the proteostasis network. Cancer cells rely heavily on this system to survive stress caused by rapid growth and genetic instability. “To examine whether MAL3-101 or more drug-like proteostasis inhibitors represent a new therapeutic strategy for RMS, we screened proteostasis components that might recapitulate the effects of MAL3-101 in vivo.” The researchers first used a compound called MAL3-101 to disrupt protein control in RMS cells. They then identified which parts of the protein quality system were affected. Based on those findings, they searched for more drug-like compounds that could target the same pathways. They focused on a protein called p97, which plays a critical role in removing damaged or misfolded proteins. When they blocked p97 using a drug called CB-5083, the cancer cells could no longer manage internal stress and began to self-destruct. In both laboratory models and mice implanted with human RMS tumors, the treatment significantly slowed or stopped tumor growth. The drug triggered a stress response in the cells known as the unfolded protein response, which can lead to either recovery or programmed cell death. However, not all tumors responded the same way. Some resisted the treatment by activating a backup system called autophagy, which allows cells to recycle parts of themselves under stress. By comparing tumors that responded well to those that did not, the researchers found that higher autophagy activity could serve as a warning sign for resistance. This insight may help identify which patients are more likely to benefit from therapies that target protein quality control. While the results are promising, the drug’s effectiveness depended on the tumor’s genetic profile and how it handled stress. Combining p97 inhibition with other treatments or blocking alternative survival pathways like autophagy may improve outcomes. The researchers also noted the importance of developing safer and more targeted drugs to reduce side effects. This study opens new possibilities for personalized cancer treatment, particularly for children with aggressive or relapsed RMS. By weakening the systems that cancer cells depend on to survive, rather than only using toxic treatments to kill them, scientists aim to develop more effective and less harmful therapies for young patients. DOI - https://doi.org/10.18632/oncotarget.28764 Correspondence to - Amit J. Sabnis - amit.sabnis@ucsf.edu Video short - https://www.youtube.com/watch?v=YsdffTkXNRQ To learn more about Oncotarget, visit https://www.oncotarget.com. Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Aiden Deacon from the University of Minnesota-Twin Cities, Minneapolis, discusses a research paper he co-authored that was published in Volume 16 of Oncotarget, titled “Dissecting the functional differences and clinical features of R-spondin family members in metastatic prostate cancer.” DOI - https://doi.org/10.18632/oncotarget.28758 Correspondence to - Justin Hwang - jhwang@umn.edu Video interview - https://www.youtube.com/watch?v=OXKhWWU1gnY Abstract This study investigates the R-spondin family of genes (RSPO1/2/3/4), a group of secreted proteins that act as Wnt regulators, and their subsequent role in advanced prostate cancer (PC). When evaluating transcriptomic data from primary and metastatic PC patients, we found that alterations in RSPO2 were more prevalent than in other RSPO family members or Wnt-regulating genes APC and CTNNB1. Further, we found that RSPO2 alterations in PCs were significantly associated with worse disease-free survival. Through our in silico modeling, RSPO2 exhibited strong positive associations with genes regulating epithelial-mesenchymal transition (EMT) and double-negative prostate cancer (DNPC), but had negative correlations with androgen receptor (AR) and AR-associated genes. Furthermore, 3D modeling of RSPO2 revealed structural differences between itself and other RSPOs. In cell lines, RSPO2 overexpression caused up-regulation of EMT pathways, including EMT-regulatory transcription factors ZEB1, ZEB2, and TWIST1. Conversely, this was not observed when CTNNB1 was overexpressed in the same models. These findings highlight that, in PC, RSPO2 functions as a unique member of the R-spondin family by promoting genes and signaling pathways associated with aggressive PC, and RSPO2 amplifications are associated with poor outcomes in PC patients. Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28758 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, RSPO2, prostate cancer, Wnt signaling, genomics, therapeutics About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality. While the development of targeted therapies has improved outcomes for many patients with EGFR-mutated NSCLC, those with rare EGFR variants often face limited treatment options, especially when the disease involves the central nervous system (CNS). A recent research paper, titled “Durable complete response in leptomeningeal disease of EGFR mutated non-small cell lung cancer to amivantamab, an EGFR-MET receptor bispecific antibody, after progressing on osimertinib” published in Volume 16 of Oncotarget, describes a patient with NSCLC harboring two uncommon EGFR mutations—G719A and A289V—who experienced a prolonged and clinically significant response to amivantamab monotherapy, after prior treatments had failed. Full blog - https://www.oncotarget.org/2025/08/26/amivantamab-monotherapy-in-rare-egfr-mutated-advanced-nsclc/ Paper DOI - https://doi.org/10.18632/oncotarget.28730 Correspondence to - Young Kwang Chae - young.chae@northwestern.edu Video short - https://www.youtube.com/watch?v=UEiCz834a8c Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28730 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, amivantamab, monotherapy, rare EGFR mutation, NSCLC, leptomeningeal disease About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Oncotarget is indexed and archived by PubMed/Medline, PubMed Central, Scopus, EMBASE, META (Chan Zuckerberg Initiative) (2018-2022), and Dimensions (Digital Science). To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

BUFFALO, NY – August 19, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on August 19, 2025, titled “The SCD1 inhibitor aramchol interacts with regorafenib to kill GI tumor cells in vitro and in vivo.” In this study, led by first authors Laurence Booth and Michael R. Booth, along with corresponding author Paul Dent from Virginia Commonwealth University, researchers investigated how aramchol, a drug originally developed for liver disease, works with the cancer drug regorafenib in gastrointestinal (GI) tumor cells. They found that the combination is effective, especially in tumor cells with a specific genetic variant. The combined approach offers a potential new strategy for treating liver and colon cancers. Gastrointestinal cancers, such as liver and colon cancer, are serious global health challenges. Regorafenib, already approved for cancer treatment, can have limited impact and frequently causes side effects. Aramchol, a drug developed to treat fatty liver disease, affects how cancer cells process fats and energy. In this study, researchers tested whether combining these two drugs could improve GI cancer treatment, both in cells and mouse models. The results showed that the drug combination killed liver and colorectal cancer cells more effectively than either drug alone. In animal models, mice with human liver tumors had slower tumor growth, without showing signs of weight loss or other toxicity. The researchers also found that aramchol and regorafenib work together to block important survival pathways inside cancer cells. This combination was especially effective in cells with a genetic variant called ATG16L1 T300, which is more common in people of African ancestry. The treatment triggered stress responses in the cancer cells and disrupted key proteins required for survival. It also activated autophagy, a natural recycling process that clears out damaged parts, eventually leading to cancer cell death. “Aramchol interacted with the multi-kinase inhibitors sorafenib, regorafenib or lenvatinib, to kill GI tumor cells, with regorafenib exhibiting the greatest effect.” Aramchol is currently in clinical trials for fatty liver disease and has a well-established safety profile, while regorafenib is already FDA-approved for cancer treatment. Together, their combination could advance fast into clinical testing for patients with GI cancers. However, researchers note that additional studies are needed to support the launch of early-phase clinical trials. Altogether, this study may offer a more effective and less toxic alternative to current treatments for GI cancers. It also highlights the role of genetic variants in shaping treatment response, suggesting that future therapies could be more precisely tailored to each patient’s unique genetic profile. DOI - https://doi.org/10.18632/oncotarget.28762 Correspondence to - Paul Dent - paul.dent@vcuhealth.org Video short - https://www.youtube.com/watch?v=5saAqsqxi-Q Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28762 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, macroautophagy, flux; ER stress, aramchol, regorafenib To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

BUFFALO, NY – August 15, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on August 13, 2025, titled “Clinical and analytical validation of MI Cancer Seek®, a companion diagnostic whole exome and whole transcriptome sequencing-based comprehensive molecular profiling assay.” In this study, first authors Valeriy Domenyuk and Kasey Benson, along with corresponding author David Spetzler from Caris Life Sciences in Irving, Texas, introduce MI Cancer Seek, an FDA-approved test designed to deliver comprehensive tumor profiling. MI Cancer Seek demonstrated strong concordance with other FDA-approved companion diagnostics and serves as a powerful tool to guide treatment decisions in both adult and pediatric cancer patients. Cancer remains one of the most complex and diverse diseases to treat. With many targeted therapies currently FDA-approved, selecting the right one for a specific patient requires detailed genetic insights. MI Cancer Seek addresses this need by analyzing both DNA and RNA from a single tumor sample. The tool identifies key biomarkers linked to FDA-approved treatments for several major cancers, including breast, lung, colon, melanoma, and endometrial cancers. One of the most significant strengths of MI Cancer Seek is its ability to deliver accurate and reliable results from minimal tissue input (50 ng). Even when analyzing formalin-fixed paraffin-embedded samples, which are widely used but often degraded, the test maintained high levels of accuracy. It successfully detected important genetic alterations such as PIK3CA, EGFR, BRAF, and KRAS/NRAS mutations and measured tumor mutational burden (TMB) and microsatellite instability (MSI), both of which are key indicators for immunotherapy response. In clinical comparisons, the test achieved over 97% agreement with other FDA-approved diagnostic tools, confirming its reliability in detecting critical biomarkers. Notably, it showed near-perfect accuracy in identifying MSI status in colorectal and endometrial cancers. The researchers also demonstrated that the test maintains precision across different lab conditions and varying DNA input levels, confirming its robustness for routine clinical use. Beyond its role as a companion diagnostic, MI Cancer Seek incorporates additional features developed under its predecessor, MI Tumor Seek Hybrid. These include detection of homologous recombination deficiency, structural variants, and cancer-related viruses. It also includes advanced tools such as the Genomic Probability Score for identifying the tissue of origin in cancers of unknown primary, as well as a gene signature to guide first-line chemotherapy in colorectal cancer. “One limitation to be considered is the low PPA for ERBB2 CNA detection.” By offering deeper genetic insights from a single, small sample, MI Cancer Seek has the potential to streamline diagnostics, reduce testing costs, and connect patients to effective therapies more quickly. As precision medicine continues to expand, this assay stands out as a comprehensive and efficient solution for meeting the evolving needs of modern oncology. DOI - https://doi.org/10.18632/oncotarget.28761 Correspondence to - David Spetzler - dspetzler@carisls.com Video short - https://www.youtube.com/watch?v=D4hd2FxCYY8 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

BUFFALO, NY - August 13, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on July 29, 2025, titled “PCAIs stimulate MAPK, PI3K/AKT pathways and ROS-Mediated apoptosis in aromatase inhibitor-resistant breast cancer cells while disrupting actin filaments and focal adhesion.” In this study, led by first author Jassy Mary S. Lazarte and corresponding author Nazarius S. Lamango from Florida A&M University College of Pharmacy and Pharmaceutical Sciences, researchers investigated a new class of compounds called polyisoprenylated cysteinyl amide inhibitors (PCAIs) as a potential treatment for aromatase inhibitor (AI) therapy resistant breast cancer. Aromatase inhibitors are a common treatment for estrogen receptor-positive (ER+) breast cancer, but many patients eventually develop resistance, leaving fewer therapeutic options. The study focused on a PCAI compound called NSL-YHJ-2-27, which was tested in long-term letrozole-treated breast cancer cells (LTLT-Ca), an experimental model of AI therapy resistance. NSL-YHJ-2-27 activated two major signaling pathways, MAPK and PI3K/AKT. Although these pathways typically support cancer cell survival, their overstimulation by PCAIs led to increased oxidative stress, damaging the cells and inducing cell death by apoptosis. The compound also reduced levels of RAC1 and CDC42, proteins involved in maintaining cell shape and movement. These alterations resulted in cytoskeletal disruption and reduced structural integrity, making the cancer cells more vulnerable and less capable of spreading. Importantly, the effects of NSL-YHJ-2-27 persisted after the compound was removed, suggesting long-term control over AI resistant cancer cells may be possible. “PCAIs inhibited cell proliferation and colony formation by 95% and 74%, respectively, increased active caspase 7 and BAX 1.5-fold and 56%, respectively. NSL-YHJ-2-27 (10 μM) induced LTLT-Ca spheroid degeneration by 61%.” As a new class of targeted molecules, PCAIs represent an innovative approach distinct from traditional endocrine therapies. Their ability to affect multiple cellular mechanisms simultaneously makes them promising candidates for future drug development. Overall, this study presents a promising new approach for treating AI therapy-resistant breast cancer. By targeting cellular pathways that support survival and mobility, PCAIs like NSL-YHJ-2-27 could provide a novel strategy to manage advanced or resistant forms of the disease. Further research, including in vivo studies and clinical trials, will be essential to confirm these findings and evaluate their therapeutic potential. DOI - https://doi.org/10.18632/oncotarget.28759 Correspondence to - Nazarius S. Lamango - nazarius.lamango@famu.edu Video short - https://www.youtube.com/watch?v=8xQEilloO9Q Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28759 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, PCAIs, ROS, MAPK, PI3K/AKT, LTLT-Ca cells To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Lung cancer, particularly non-small cell lung cancer (NSCLC), is the deadliest cancer worldwide. Cigarette smoking is one of the main causes, but not every smoker develops the disease. This suggests that other biological factors help determine who develops cancer. Researchers from the Division of Pulmonary, Critical Care, Sleep and Occupational Medicine, Indianapolis, and from the Richard L. Roudebush Veterans Affairs Medical Center have now found that cigarette smoke, combined with a weakened DNA repair system, can trigger the early stages of lung cancer, particularly NSCLC. This work, led by first author Nawar Al Nasralla and corresponding author Catherine R. Sears, was recently published in Volume 16 of Oncotarget. Full blog - https://www.oncotarget.org/2025/08/11/cigarette-smoke-and-weak-dna-repair-a-double-hit-behind-lung-cancer-risk/ Paper DOI - https://doi.org/10.18632/oncotarget.28724 Correspondence to - Catherine R. Sears - crufatto@iu.edu Video short - https://www.youtube.com/watch?v=UEiCz834a8c Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28724 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, DNA repair, DNA damage, lung adenocarcinoma, squamous cell carcinoma, Xeroderma Pigmentosum Group C (XPC) To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

BUFFALO, NY – August 11, 2025 – A new #researchpaper was #published in Volume 16 of Oncotarget on July 25, 2025, titled “Dissecting the functional differences and clinical features of R-spondin family members in metastatic prostate cancer.” In this study, researchers led by first author Aiden Deacon and corresponding author Justin Hwang from the University of Minnesota-Twin Cities investigated a group of genes known as the R-spondin family (RSPO1/2/3/4) in advanced prostate cancer (PC). The RSPO gene family regulates Wnt signaling, a pathway involved in cancer progression. Prostate cancer is the most common cancer among men in the United States and becomes especially dangerous when it spreads beyond the prostate. Most patients are treated with hormone therapies that target the androgen receptor; however, many tumors eventually become resistant. The research team analyzed thousands of tumor samples and found that RSPO2 alterations were more common than changes in other R-spondin genes or even some well-known cancer-related genes like CTNNB1 and APC. RSPO2 amplification occurred in over 20% of metastatic prostate cancer. Patients with these alterations showed signs of more aggressive disease, including higher mutation rates and greater tumor complexity. Using laboratory models, the team discovered that RSPO2 increases cancer cell growth and triggers a biological process called epithelial-mesenchymal transition (EMT). EMT is known to promote tumor spread and resistance to standard treatments. Unlike other genes in the same pathway, RSPO2 also appeared to reduce the activity of androgen receptor genes, suggesting it drives a type of prostate cancer that no longer relies on hormones for growth. “In cell lines, RSPO2 overexpression caused up-regulation of EMT pathways, including EMT-regulatory transcription factors ZEB1, ZEB2, and TWIST1.” Importantly, RSPO2 showed structural differences from other R-spondin proteins, which may allow researchers to design drugs that specifically block its activity. Current therapies targeting the Wnt pathway are limited, and there are no approved drugs that inhibit RSPO2. However, this study highlights RSPO2 as a promising therapeutic target, especially for patients who do not respond to existing hormone-based treatments. This research adds critical knowledge about how aggressive prostate cancers develop and persist despite therapy. The identification of RSPO2 as a key driver of disease progression opens new possibilities for treatment strategies aimed at improving outcomes for patients with advanced prostate cancer. DOI - https://doi.org/10.18632/oncotarget.28758 Correspondence to - Justin Hwang - jhwang@umn.edu Video short - https://www.youtube.com/watch?v=iyu5D_c1dbY Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28758 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, RSPO2, prostate cancer, Wnt signaling, genomics, therapeutics To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

Prostate cancer is the second most diagnosed cancer among men worldwide and remains a leading cause of cancer-related death. While early forms of the disease can usually be treated successfully, advanced cases remain a major challenge. Scientists have now discovered a new potential way to slow the growth of advanced, treatment-resistant prostate cancer. These results were recently published in Volume 16 of Oncotarget by researchers from the University of Cincinnati College of Medicine. Understanding Advanced Prostate Cancer Early-stage prostate cancer can often be treated successfully. Most treatments work by lowering testosterone levels or blocking the hormone from activating the androgen receptor (AR), which drives cancer growth. In some patients, however, the disease progresses to castration-resistant prostate cancer (CRPC). Even with drastic reductions in testosterone levels, the tumors continue to grow at this stage. CRPC is much more difficult to treat, and current therapies such as hormone blockers or chemotherapy typically extend life by only a few months. One reason for this resistance is that cancer cells often switch to a different form of the androgen receptor called AR-V7. This variant remains permanently active, even without testosterone, making hormone-based drugs less effective. Because of this, new treatment strategies that work independently of hormone levels are needed. The Study: Targeting a New Weakness in Prostate Cancer Cells In the study titled “Targeting PCNA/AR interaction inhibits AR-mediated signaling in castration resistant prostate cancer cells,” researchers Shan Lu and Zhongyun Dong from the University of Cincinnati College of Medicine investigated a new way to block CRPC growth. Full blog - https://www.oncotarget.org/2025/07/29/a-new-way-to-target-resistant-prostate-cancer-cells/ Paper DOI - https://doi.org/10.18632/oncotarget.28722 Correspondence to - Zhongyun Dong - dongzu@ucmail.uc.edu Video short - https://www.youtube.com/watch?v=fiJWZ_fKxgs Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28722 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, PCNA, androgen receptor, PCNA inhibitors, AR splicing variants, CRPC To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

BUFFALO, NY - July 29, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on July 25, 2025, titled “Comprehensive genomic profiling of over 10,000 advanced solid tumors.” In this study, led by Jean-Paul De La O from Exact Sciences Corporation, researchers analyzed data from over 10,000 solid tumor samples from patients with advanced cancer and found that more than 90 percent contained genetic changes that could guide treatment. This work demonstrates the growing impact of large-scale tumor DNA and RNA testing on patient care. The researchers retrospectively analyzed OncoExTra assay information for 31 types of cancer, including breast, colorectal, prostate, lung, and ovarian cancers. Their analysis revealed that nearly a third of patients had alterations associated with approved drugs for their specific cancer, while another third had changes linked to therapies approved for other cancers. These results show that detailed genetic profiling could expand treatment choices. “Biomarkers associated with on- or off-label FDA-approved therapies were detected in 29.2% and 28.0% of samples, respectively.” Another relevant discovery was that many important mutations occurred at very low levels, which are often missed by simpler tests. By using a broad and highly sensitive approach, the scientists were able to identify these rare mutations. They also reported that 7.5 percent of samples carried gene fusions, unusual genetic events that can drive cancer growth. Such findings can be critical in selecting therapies that specifically target these abnormalities. The study also highlighted the value of RNA sequencing in detecting fusion events that traditional DNA tests might miss. Prostate cancer and certain sarcomas showed particularly high rates of these fusion alterations. This type of information can refine cancer diagnosis and improve therapy planning. In addition, the researchers identified changes in several major cancer-related pathways, including those that control cell growth, DNA repair, and immune system response. Alterations in these pathways can point to newer treatment options, such as immunotherapy or drugs designed to block specific cell signals. Overall, this study shows that comprehensive genomic profiling can guide more personalized cancer care by identifying mutations, gene fusions, and other molecular patterns. Advanced testing methods like the OncoExTra assay reveal treatment opportunities even in advanced cancers, ensuring that subtle but important genetic changes are detected. DOI - https://doi.org/10.18632/oncotarget.28757 Correspondence to - Jean-Paul De La O - jdelao@exactsciences.com Video short - https://www.youtube.com/watch?v=awiRhDfiMTE Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28757 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, solid tumors, comprehensive genomic profiling, matched therapy, gene fusions, limit of detection To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

BUFFALO, NY – July 24, 2025 – A new #casereport was #published in Volume 16 of Oncotarget on July 23, 2025, titled “Extracorporeal blood filtration leading to tumor growth arrest and reduced analgesic requirements in Stage IV poorly differentiated pancreatic adenocarcinoma: A case report.” In this report, Susanna Ulahannan from the University of Oklahoma Health Sciences Center and colleagues describe the use of extracorporeal blood filtration in a patient with metastatic pancreatic cancer. The patient experienced clinical improvement, reduced pain, and no signs of new tumor growth over 12 months of follow-up. Metastatic pancreatic cancer is difficult to treat and is often diagnosed at an advanced stage. In this case, a 51-year-old woman with stage IV poorly differentiated adenocarcinoma chose not to undergo standard chemotherapy. Instead, she received extracorporeal blood filtration with the Seraph® 100 device, which is designed to remove circulating tumor cells (CTCs) from the bloodstream. CTCs are thought to contribute to the spread of cancer to other organs. “Circulating tumor cells (CTC’s) are tumor cells that are shed from the primary tumor and travel via blood or lymphatic system to form micro metastases in distant organs under a suitable environment.“ The patient received between nine and twelve treatments over the course of a year. These treatments were performed both abroad, where the device is approved for this use, and under a clinical protocol in the United States. Medical imaging showed that her disease remained stable, with no new metastases detected. She also reported improvements in appetite, energy levels, and pain control. Her opioid use was reduced by 90%. Blood samples confirmed a drop in CTC levels after treatment. This observation supports the idea that removing CTCs might help limit cancer progression in some patients. However, given that this is a single case report, larger clinical studies are needed to evaluate the effectiveness of this approach. The mechanism behind the patient’s pain relief is not fully understood. Authors suggest that it may be related to the reduction of tumor cells or inflammatory molecules in the blood. Researchers noted that pro-inflammatory cytokines, known to influence pain, could also have been affected by the filtration process. This is the first documented case of stable disease and reduced symptoms following CTC filtration in advanced pancreatic cancer. While these findings should not be generalized, they highlight an approach outside standard protocols that should be further explored in clinical research. Future studies will be needed to determine whether this method can contribute to symptom management or disease control in other patients with metastatic pancreatic cancer. DOI - https://doi.org/10.18632/oncotarget.28756 Correspondence to - Susanna Ulahannan - susanna-ulahannan@ouhsc.edu Video short - https://www.youtube.com/watch?v=dro6iUGDrVQ Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28756 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, extracorporeal blood filtration, circulating tumor cells, metastatic pancreatic cancer, seraph 100, OncoBind To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

BUFFALO, NY – July 22, 2025 – A new #research paper was #published in Volume 16 of Oncotarget on July 21, 2025, titled “Statins exhibit anti-tumor potential by modulating Wnt/β-catenin signaling in colorectal cancer.” In this work, led by first author Sneha Tripathi from the Indian Institute of Science Education and Research and corresponding author Sanjeev Galande from the Center of Excellence in Epigenetics at Shiv Nadar University, researchers discovered that statins, widely used to lower cholesterol, may also suppress colorectal cancer growth. This finding highlights a potential new role for these common drugs in cancer prevention and therapy. Colorectal cancer is one of the leading causes of cancer-related deaths worldwide, and new strategies are urgently needed to improve treatment results. Statins, originally developed to lower cholesterol levels, have gained attention for their possible anti-cancer properties. The study investigated how statins affect the Wnt/β-catenin signaling pathway, a critical driver in colorectal cancer development and progression. The researchers discovered that statins disrupt the Wnt/β-catenin signaling pathway, leading to lower levels of tumor-promoting proteins and to cancer-suppressing cellular behaviors. Experiments in both colorectal cell cultures and mouse models confirmed that statins reduced tumor growth without causing noticeable side effects. This study further revealed that statins downregulate SATB1, a protein linked to aggressive tumor behavior, while increasing SATB2, a protein with tumor-suppressing effects. These changes made the cancer cells less able to grow and spread. “This reciprocal regulation shifts cellular phenotypes between epithelial and mesenchymal states in 3D spheroid models.” Overall, the findings suggest that statins could be repurposed to complement existing colorectal cancer treatments or even be used in preventive strategies for high-risk individuals. By targeting the molecular machinery that drives colorectal tumor development, statins offer a promising, accessible, and well-understood option for further research in cancer therapy. This research opens the door to larger clinical studies to explore how best to integrate statins into cancer care. If successful, this approach could provide a cost-effective strategy for reducing the global burden of colorectal cancer, which remains a significant health challenge. DOI - https://doi.org/10.18632/oncotarget.28755 Correspondence to - Sanjeev Galande - sanjeev.galande@snu.edu.in Video short - https://www.youtube.com/watch?v=A95ICULaH3Y Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28755 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, colorectal cancer, statins, SATB1, Wnt/β-catenin signaling, tumor-suppressive phenotype To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM

BUFFALO, NY - July 18, 2025 – A new #editorial was #published in Volume 16 of Oncotarget on July 16, 2025, titled “microRNAs in soft tissue sarcoma: State of the art and barriers to translation.” In this article, Elizaveta K. Titerina, Alessandro La Ferlita, and Joal D. Beane from Ohio State University discuss the role of microRNAs in soft tissue sarcomas (STS), a rare and diverse group of cancers that begin in connective tissues, like bone or fat. The authors explain how these small molecules regulate cancer-related processes and highlight their potential as non-invasive biomarkers for diagnosis and monitoring. They also outline the main challenges that need to be addressed before microRNA-based strategies can be used in clinical settings. Soft tissue sarcomas include over 50 subtypes, making precise diagnosis and effective treatment difficult. The editorial describes how microRNAs influence cancer growth, spread, and response to therapies. Because microRNAs are stable in body fluids like blood and saliva, they could be used for early detection and to help guide treatment decisions. Such as, certain groups of microRNAs are linked to how patients respond to specific drugs, showing their potential as tools for precision medicine. “For example, miR-17-92 and miR-106b-25 clusters have been associated with sensitivity or resistance to eribulin in STS.” The authors also explain that microRNAs could help distinguish between tumor types that are often difficult to differentiate, such as benign lipomas and malignant liposarcomas. Recognizing these differences is crucial for guiding treatment decisions. Specific patterns of microRNA expression in blood samples may enable clinicians to make quicker and more reliable diagnoses without the need for invasive procedures. Beyond their diagnostic role, microRNAs are also being explored as therapeutic tools, but applying microRNA-based therapies to patients remains challenging. These molecules can act as either cancer promoters or suppressors, depending on the environment, which complicates the development of safe and targeted treatments. However, new delivery methods such as lipid nanoparticles show promise in improving precision and safety. Overall, microRNAs are emerging as an important focus in STS research, offering new possibilities for advancing diagnosis, prognosis, and treatment. As researchers continue to address the current challenges, these small molecules could become valuable tools in improving cancer care. DOI - https://doi.org/10.18632/oncotarget.28754 Correspondence to - Joal D. Beane, joal.beane@osumc.edu Video short - https://www.youtube.com/watch?v=MlLGA8BObPQ Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28754 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, soft tissue sarcoma, liposarcoma, microRNA, small non-coding RNA, cancer biomarkers To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: Facebook - https://www.facebook.com/Oncotarget/ X - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Spotify - https://open.spotify.com/show/0gRwT6BqYWJzxzmjPJwtVh MEDIA@IMPACTJOURNALS.COM