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

Video interview - https://www.youtube.com/watch?v=zAnSZ0oycDY

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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Oncotarget

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

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

Elixirs, Experiments, and the Birth of Modern Science

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Aging-US

Rapamycin Shows Limited Evidence for Longevity Benefits in Healthy Adults

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

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

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

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

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

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

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

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

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

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

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

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Abstract

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

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

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

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Keywords - aging, rapamycin, geroscience, longevity, healthspan

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

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

Host: Brandon Nappi

Guest: Spencer Reece

Production: Goodchild Media

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65: Poetry Holds Us Together with Spencer Reece

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Highlights include:

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

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

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

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

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

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

About WIN Consortium:

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

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

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

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

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

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

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

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

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

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

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New Anti-Aging Combo Boosts Lifespan in Old Male Mice

BUFFALO, NY — October 3, 2025 — A new #research perspective was #published in Volume 17, Issue 9 of Aging-US on August 26, 2025, titled “Analysis of the current state of frailty indexes and their implementation for aging intervention studies.” 

In this work, led by first author Oliver G. Frost from  Loughborough University alongside corresponding authors Abdelhadi Rebbaa and Amit Sharma,  from the Lifespan Research Institute, the authors explore growing concerns about the lack of standardization in how frailty is measured in rodent aging studies, which may limit the development of effective interventions targeting age-related decline.

Frailty, a key indicator of deteriorating health in older adults, is increasingly assessed in preclinical models using frailty indexes (FIs). These indexes quantify health deficits, such as reduced mobility, cognitive decline, or physical weakness. However, this perspective highlights that FI methodologies vary significantly across studies, from the selection of parameters to the cut-off thresholds used, resulting in inconsistent outcomes that affects reproducibility and translational value.

The authors reviewed 18 rodent studies and found substantial variation in how frailty is defined and measured. Some FIs rely on clinical observations, such as appearance or beahaviour, while others focus on physical performance metrics like grip strength or locomotion. In several cases, applying different FIs to the same group of animals produced contradictory results, underscoring the importance of harmonized protocols.

To illustrate these issues, the researchers applied an 8-item FI to mice of different ages and found that even young mice were sometimes scored as frail, depending on the scoring method and reference values. This finding emphasizes the need for consistent baselines and controlled environments, especially when comparing across studies. The authors recommend using each animal as its own baseline in longitudinal studies, a strategy that enhances reliability without adding significant cost.

“Sex as a biological variable in FIs is an important consideration, as there is a known difference between male and female frailty onset and progression.” 

The authors also discuss emerging automated tools, such as video-based open-field testing, which can reduce observer bias and improve reproducibility. In the future, broader health indicators, such as cognition, circadian rhythms, social behavior, and body composition, may further enhance frailty assessments.

Overall, this work underscores the urgent need for standardized, transparent, and reproducible methods for evaluating frailty in preclinical aging studies. Improved consistency in frailty scoring will better inform the development of healthspan-extending therapies and enhance the translational relevance of animal models.

DOI - https://doi.org/10.18632/aging.206307

Corresponding authors - Abdelhadi Rebbaa - rebbaa@gmail.com, and Amit Sharma - amit.sharma@sens.org

Abstract video - https://www.youtube.com/watch?v=eha3XA9LyWA

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Keywords - aging, frailty, rodents, frailty index, phenotype

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Standardizing Frailty Indexes to Improve Preclinical Aging Research

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

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

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

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

Oncotarget Podcast