SU2C Scientific Research Teams
SU2C Colorectal Cancer Dream Team: Targeting Genomic, Metabolic and Immunological Vulnerabilities of Colorectal Cancer
Luis A. Diaz Jr., MD
Head, Division of Solid Tumor Oncology, Memorial Sloan Kettering Cancer Center
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Lewis C. Cantley, PhD
Director of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine and NewYork-Presbyterian Hospital
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Charles S. Fuchs, MD
Director of the Yale Cancer Center; Physician-in-Chief at Smilow Cancer Hospital at Yale New Haven Health
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Zhenghe Wang, PhD
Professor of Genetics and Genome Science, School of Medicine, Case Western Reserve University Co-leader, GI Cancer Genetics program (GICG), Case Comprehensive Cancer Center
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“Though a combination of new avenues in immunotherapy, targeted therapeutics, metabolomics, and precision prevention, we believe we can find new ways to fight colorectal cancer and bring new hope to patients.” Luis A. Diaz, MD
Colorectal cancer is among the leading causes of cancer-related death in the United States, with 50,260 deaths from the disease anticipated to occur in 2017. Patients can be effectively treated when the tumor is detected and removed early; however, most patients are diagnosed when the disease has spread outside the colon or rectum. Five-year relative survival rates are particularly poor for patients with metastatic disease, and novel therapies are urgently needed to fight this deadly disease.
To tackle this problem, this SU2C-Colorectal Cancer Dream Team has assembled renowned experts in the field of colorectal cancer research, spanning all aspects of translational science and medicine. This team will focus on three complementary areas of research that have the potential to impact all stages of colorectal cancer, from the pre-malignant lesion to patients suffering from metastatic disease. The emphasis of the first two areas of research is on the potential of immunotherapy and targeted therapy to revolutionize the treatment of colorectal cancer, while the last area of study will evaluate strategies to target different colorectal cancer subtypes specifically.
Over the past decade, targeted therapy and immunotherapy have revolutionized the treatment of many cancer types. However, these approaches have yet to make a substantial impact for colorectal cancer. The key factors underlying the limited efficacy of targeted and immunotherapies in colorectal cancer have recently been elucidated, creating an unprecedented opportunity to effectively optimize and integrate these two powerful therapeutic approaches to develop novel treatments for colorectal cancer patients. This Dream Team will first determine the molecular determinants of resistance to immunotherapies. With this information, they will devise new strategies to overcome the resistance. Similarly, they will determine the molecular adaptations responsible for the resistance of colorectal cancer cells to targeted therapies, and formulate novel approaches to counteract the resistance. This will include developing new therapies involving combinations of drugs, both targeted agents and immune agents.
Another important discovery of the past decade is that genomic abnormalities can be used to define distinct subgroups of cancer. Mutations in the KRAS, BRAF, and PIK3CA genes, for instance are collectively found in more than 60% of colorectal cancers. While mutations in those genes cause colorectal cancer development by promoting uninhibited growth, evading immune surveillance, and spreading to other organs in the body, they also bring vulnerabilities to cancer cells that can be exploited for design of novel therapies. Scientists in this team discovered that two major subgroups of colorectal cancer—those with a mutation in the KRAS/BRAF gene, and those with a mutation in the PIK3CA gene—are susceptible to high dose of vitamin C combined with depletion of a nutrient called glutamine. Drugs developed to target these vulnerabilities were efficient to slow down or cure colorectal cancers of the two subgroups in animal studies. This team will now use state-of-the-art technologies to evaluate if those on promising findings can be transposed to patients with similar genomic abnormalities
By leveraging the potential synergy between their different therapeutic avenues, the Dream Team believes that more frequent and durable treatment responses for patients will emerge, enhancing the lives of people suffering from this terrible disease.