Developing Mechanism-Based Therapeutic Strategies for Aggressive Rare Kidney Cancer
Abstract
Background: Renal cell carcinoma (RCC) comprises a heterogeneous group of diseases varying in their clinical course, histologic features, and responsiveness to current systemic therapies. Over the last decade, the most common type of kidney cancer, clear cell renal cell carcinoma (RCC), has evolved from a chemotherapy-resistant disease with very limited treatment options to a model cancer due to the clinical success of molecularly targeted therapies. This therapeutic transformation largely stems from an improved understanding of kidney cancer biology and pathogenesis. In contrast, rare kidney cancers have a serious basic research and clinical treatment disparity. Among the rare types of RCC, one of the most challenging groups are RCCs with histology not fitting into any of the established subtypes, an unclassified category in the current World Health Organization classification (uRCC). These are aggressive cancers without standard pharmacological treatment, leaving these patients and their families without options. We have conducted a genomic analysis of a unique cohort of 62 uRCC tumors and discovered subsets of tumors with distinct molecular features. Particularly, we identified a novel subset of tumors characterized by NF2 (22q12) mutations and/or 22q loss, a feature that has not been previously recognized as a frequent molecular event in any established subtypes of RCC. We have generated a preclinical mouse model of uRCC for the investigation of molecular pathogenesis and therapeutic interventions. We will use this mouse model to test the therapeutic effects of immunotherapy in combination with targeted therapy. To investigate whether uRCC patients will benefit from immunotherapy we plan to employ a novel single-cell proteomic platform to interrogate the cancer-immune interface for translational clinical correlative studies. We believe our integrated approaches will transform the therapeutic landscape of uRCC. Areas of Emphasis: Rare Kidney Cancers; Chromatin and Gene Regulation; Therapeutic Development; Microenvironment and Immunology; New Disease Model Systems Innovation: We have established an invaluable experimental model of unclassified kidney cancer for the study of mechanisms and treatment of this rare type of kidney cancer. An innovative approach involving a novel single-cell proteomic platform to interrogate the cancer-immune interface in combination with advanced sequencing techniques will be performed to establish the molecular and immune networks of uRCC with the goal of identifying new therapeutic targets. To this end, our preliminary studies have uncovered several mechanism-based targeted therapies, paving the way for new potential clinical trials. Furthermore, a novel mouse model of uRCC will be generated to help elucidate the molecular mechanisms underlying kidney cancer development and facilitate the assessment of immunotherapy. Impact: This proposal is both mechanism-driven and highly translational in nature, which will have broad impact across basic and translational kidney cancer research and can be easily translated into clinics. Our investigation of the molecular pathogenesis of uRCC will advance the knowledge of this disease and will have significant impact now and in the future. In the short term, our preclinical studies testing immunotherapy and various therapy combinations can be translated into clinical trials and benefit patients immediately. In the long term, our creation of a uRCC kidney cancer model will offer a physiological preclinical model for future therapeutic interventions including immunotherapy, thus accelerating new drug development. Our characterization of the tumor-immune microenvironment interactions in human uRCC tumors will provide critical molecular insights for prognostication and intervention of uRCC.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110897
Entities
People
- Emily Cheng
Organizations
- Sloan-Kettering Institute
- United States Army