City of Hope
City of Hope
Physician-scientists are using one of the world’s most comprehensive genomic analysis tools to determine whether targeted therapy or immunotherapy has the best chance of working for each individual patient
DUARTE, Calif. — Experts at City of Hope and the Translational Genomics Research Institute (TGen) are using one of the world’s most comprehensive genomic analysis tools to map out personalized treatment plans for metastatic kidney cancer patients.
While the physician-scientists are at the beginning of this long journey, they believe they’re on the right path. They recently published a study in the Journal of Immunotherapy of Cancer that suggests mutations in the TERT gene predicts that a patient may not be receptive to immune checkpoint inhibitors such as nivolumab or pembrolizumab.
“The hope is to one day identify patients who will benefit from immunotherapy and those who will not. Eventually we may be able to distinguish which patient is better suited for other treatments, like targeted therapy,” said Sumanta Pal, M.D., one of the study’s senior authors and co-director of the Kidney Cancer Program at City of Hope, a world-renowned independent research and treatment center for cancer, diabetes and other life-threatening diseases. Examples of targeted therapy include vascular endothelial growth factor (VEGF) tyrosine kinase inhibitors like cabozantinib.
Nearly 74,000 new cases of kidney cancer will be diagnosed this year, and about 14,800 people will die from the disease, according to the American Cancer Society. Ironically, experts know patients who have certain genetic mutations are more susceptible to specific drugs, but most doctors are not genetically sequencing each kidney cancer patient’s tumors, Pal said.
“It’s a paradox: We don’t use targeted therapy in a targeted fashion,” he added. “At City of Hope, we have begun to provide comprehensive genome and exome sequencing for all patients with Stage 4 cancer, regardless of their cancer site.”
City of Hope is on pace to be the only major cancer center in the United States to genetically profile the tumors of every single patient, regardless of cancer type. The goal is to enable patients to receive effective targeted therapies or to enroll people in innovative clinical trials as early as possible so that they can fight their disease.
In the study, Pal and his colleagues sent samples of 91 patients’ tumors to TGen’s clinical laboratory, Ashion Analytics, so that the specimens could be sequenced by GEM ExTra a leading-edge tool that features tumor-normal whole exome sequencing and tumor whole transcriptome sequencing. These are molecular-level analyses of each patient’s entire protein-coding DNA and RNA.
“The goal was to identify genomic alterations that correlated with therapy response,” said Sara Byron, Ph.D., assistant professor in TGen’s Integrated Cancer Genomics Division and co-senior author of the study. “We wanted to use this ‘real-world evidence’ to explore potential molecular and genomic features associated with response.” (Ashion Analytics recently announced that Medicare has approved coverage of GEM ExTra, potentially providing 44 million more patients access to this test, which aims to match patients with the best available treatments for their disease.)
Kidney cancer treatment regimens involving either targeted therapy or immunotherapy have burgeoned since 2015. Because new treatments sprouted so rapidly, scientists have not yet discovered the ideal strategy to sequence regimens for optimal outcomes. Moreover, the current way treatment risk is assessed tends to be subjective with ingrained bias, the study reported. City of Hope and TGen are working to develop objective laboratory-based biomarkers for kidney cancer.
Only patients whose genomic profiling was performed prior to systemic treatment were included in the study. Patients received either targeted therapy known as VEGF tyrosine kinase inhibitors (sunitinib, cabozantib, lenvatinib/everolimus) or immunotherapy (nivolumab, ipilimumab, pembrolizumab). They were divided into those who received no clinical benefit, meaning their disease progressed, or those who received clinical benefit, meaning the disease shrunk or stabilized for more than six months. Some 19,396 genes and nucleic sequences were analyzed to tease out a therapeutic treatment plan that would have best suited each patient based on their specific tumor mutations. More research in larger sample sizes are needed, but the scientists are off to a good start.
“Stage 4 cancer is often considered incurable, but that doesn’t always have to be the case,” Pal said. “By sequencing all protein-coding DNA, that is by sequencing the whole exome, we may be able to identify new therapeutic targets, and that’s a very exciting prospect.”
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About City of Hope
City of Hope is an independent biomedical research and treatment center for cancer, diabetes and other life-threatening diseases. Founded in 1913, City of Hope is a leader in bone marrow transplantation and immunotherapy such as CAR T cell therapy. City of Hope’s translational research and personalized treatment protocols advance care throughout the world. Human synthetic insulin and numerous breakthrough cancer drugs are based on technology developed at the institution. A National Cancer Institute-designated comprehensive cancer center and a founding member of the National Comprehensive Cancer Network, City of Hope is the highest ranked cancer hospital in the West, according to U.S. News & World Report’s Best Hospitals: Specialty Ranking. Its main campus is located near Los Angeles, with additional locations throughout Southern California. For more information about City of Hope, follow us on Facebook, Twitter, YouTube or Instagram.
About TGen, an affiliate 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 affiliated with City of Hope, a world-renowned independent research and treatment center for cancer, diabetes and other life-threatening diseases: CityofHope.org. 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 help our patients through efficiency and effectiveness of the translational process. For more information, visit: tgen.org. Follow TGen on Facebook, LinkedIn and Twitter @TGen.