Aberrant splicing helps predict therapeutic responses in patients with metastatic renal cell carcinoma
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Zen Logsdon
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LOS ANGELES and PHOENIX — Researchers at City of Hope® and TGen (part of City of Hope) have identified a significant correlation between a tumor’s “splicing burden” and its clinical response to treatment for metastatic renal cell carcinoma (mRCC).
City of Hope is one of the largest and most advanced cancer research and treatment organizations in the United States, with its National Medical Center ranked among the nation’s top cancer centers by U.S. News & World Report.
In a study published today in the Journal for ImmunoTherapy of Cancer, researchers demonstrated that patients whose tumor tissue exhibits a high frequency of aberrant gene splicing are more likely to respond to therapy compared to those with fewer aberrant splicing events. These findings suggest that errors present within a tumor’s transcriptomic landscape may provide a much-needed predictive framework for personalizing treatment for patients with metastatic kidney cancer.
While the natural process of splicing prepares mature mRNA for protein production, it often goes awry in malignant cells. These aberrant splicing events were previously known to drive cancer progression, but their role as a predictive tool in mRCC treatment remained largely untapped.
“The role of aberrant splicing in mRCC was underexplored until this study,” says Patrick Pirrotte, Ph.D., associate professor in TGen’s Early Detection and Prevention Division, director of the Integrated Mass Spectrometry Shared Resource at TGen and City of Hope, and senior author of the paper. “The more precisely we understand these splicing disruptions, the more directly we can inform therapeutic strategies that restore function for mRCC patients.”
The research team performed RNA sequencing on tumor specimens from 101 mRCC patients. By analyzing the transcriptome, they sought to fill a critical gap in current diagnostics.
“There aren’t many prognostic or predictive biomarkers in the kidney cancer space,” said Benjamin Mercier, B.S., a clinical research coordinator at City of Hope and first author on the study. “Our objective was to determine if we can identify predictive biomarkers from the transcriptome of these tumors.”
The data revealed hundreds of distinct splicing events that differentiated “responders,” individuals whose treatment demonstrated clinical benefit through obvious tumor shrinkage or stable disease for at least six months, from “non-responders.” Specifically, 13 unique splicing events were highly prevalent in those who successfully responded to immunotherapies and tyrosine kinase inhibitors. The results suggest that these mistakes help trigger the immune system by creating new or malformed proteins that flag the cancer cell so the body knows to attack it.
“And that is extremely important when you are trying to use or activate the immune system,” Pirrotte explains. “The tumor cells can only be recognized if they’re producing a signature that makes them different from normal cells.” Tumors with a high splicing burden showed signs of robust adaptive immune activation, suggesting the body may already be “primed” to attack the cancer if given the right therapeutic nudge.
For clinicians, these findings represent more than just molecular data; they could someday provide biomarkers to guide personalized therapy options for patients.
“By understanding how abnormal gene-splicing affects treatment, we’re opening the door to innovative therapies that reshape patient outcomes and redefine what effective cancer treatment can look like,” says Sumanta Pal, M.D., co-director of the Kidney Cancer Program at City of Hope and a senior author on the study.
This work adds to a growing body of evidence from Pirrotte and his colleagues suggesting that splicing events could serve as universal biomarkers across various malignancies, including ovarian cancer and sarcomatoid renal cell carcinoma. By decoding the chaos of the cancer transcriptome, researchers are moving closer to a future where aberrant splicing can be reliably harnessed to guide the next generation of cancer care.
The National Institutes of Health/ National Cancer Institute (P30CA033572, T32CA085183) funded this research.
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About City of Hope
City of Hope's mission is to make hope a reality for all touched by cancer and diabetes. Founded in 1913, City of Hope has grown into one of the largest and most advanced cancer research and treatment organizations in the United States, and one of the leading research centers for diabetes and other life-threatening illnesses. City of Hope research has been the basis for numerous breakthrough cancer medicines, as well as human synthetic insulin and monoclonal antibodies. With an independent, National Cancer Institute-designated comprehensive cancer center that is ranked among the nation’s top cancer centers by U.S. News & World Report at its core, City of Hope’s uniquely integrated model spans cancer care, research and development, academics and training, and a broad philanthropy program that powers its work. City of Hope’s growing national system includes its Los Angeles campus, a network of clinical care locations across Southern California, a new cancer center in Orange County, California, and cancer treatment centers and outpatient facilities in the Atlanta, Chicago and Phoenix areas. City of Hope’s affiliated group of organizations includes Translational Genomics Research Institute and AccessHopeTM. For more information about City of Hope, follow us on Facebook, X, YouTube, Instagram and LinkedIn.
About TGen, part of City of Hope
Translational Genomics Research Institute (TGen) is a Phoenix, Arizona-based nonprofit organization dedicated to conducting groundbreaking research with life-changing results. TGen is part of City of Hope, a world-renowned independent research and treatment center for cancer, diabetes and other life-threatening diseases. This precision medicine affiliation enables both institutes to complement each other in research and patient care, with City of Hope providing a significant clinical setting to advance scientific discoveries made by TGen. TGen is focused on helping patients with neurological disorders, cancer, diabetes, and infectious diseases through cutting-edge translational research (the process of rapidly moving research toward patient benefit). TGen physicians and scientists work to unravel the genetic components of both common and complex rare diseases in adults and children. Working with collaborators in the scientific and medical communities worldwide, TGen makes a substantial contribution to helping patients through efficiency and effectiveness of the translational process. Follow on Facebook, Instagram, LinkedIn and Bluesky.