Delineate Tumor-Immune Contexture That Shapes ccRCC Metastatic Progression and Response to Immunotherapy
Abstract
Objective and Rationale: Renal adenocarcinomas are molecularly and clinically distinct, with clear cell and papillary type accounting for 90% of the cases. Despite increased early detection of primary tumor, approximately 25% of patients are presented with metastatic disease and more than one-third of the patients who undergo nephrectomy with curative intent experience local or distal relapse. Around 78% of metastases occur within 5 years and 11% occur after more than 10 years of initial diagnosis. Despite early detection and increased efforts to treat metastatic disease, we have limited understanding of why some invasive ccRCC tumors metastasize and some do not -- and why immunotherapies are effective in some metastatic patients and not all. Innovation: By implanting PDXs in humanized mice models we have developed a novel approach to define the immune contexture and activity status in tumors that metastasize versus that don’t and in tumors that respond to immunotherapy versus that do not. Applicability of Research: If successful, in the short term the insights gained from these studies will identify patients likely to develop metastatic disease and predict response to immunotherapy. Moreover, the gene expression data obtained from tumors will be the basis for testing several novel hypothesis such as the features associated with metastatic tumors and immunotherapy response. Insights gained from non-metastatic and therapy-resistant ccRCC tumors is invaluable to identify mediators that resist metastatic progression and immunotherapy. Strategies designed to modulate activity of these mediators will result in long-term cures. The application aligns well with the FY22 KCRP focus area on conducting basic biology research to better understand etiology and cancer progression, metastatic disease, refractory disease and therapeutic resistance, genetic and environmental risk factors, and the prevention of kidney cancer. The findings from this project has broad implications on how we approach clinical management of not only metastatic ccRCC patients but also other cancers in Service Members, their Families, Veterans and the American public.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310867
Entities
People
- Srinivas Malladi
Organizations
- United States Army
- University of Texas Southwestern Medical Center