Thursday, December 26, 2024
12/26/2024
Project Summary/Abstract Synthetic lethality screens hold great promise for cancer therapy since they enable the identification of chemical compounds that selectively target tumor cells while sparing normal tissue. This approach presumes that cancer cells harboring a specific mutation will be more sensitive to manipulation of certain pathways than normal cells that lack the mutation. The von Hippel-Lindau (VHL) tumor-suppressor gene is functionally lost in about 90% of Clear Cell Renal Cell Carcinomas (ccRCCs). Because VHL-deficient ccRCCs resist current therapies and frequently metastasize, identifying effective new therapies will be crucial for achieving long- lasting responses. This project’s long-term goal is to therapeutically target VHL-deficient ccRCCs using a synthetic lethality approach, and to move the most promising therapeutics to clinical trials. Here we propose to investigate cyclin-dependent kinase (CDK) inhibitors as synthetic lethality-based therapeutics for targeting ccRCC. We have validated a multi-CDK inhibitor—Dinaciclib—as a therapeutic candidate with potent in vivo activity in a patient-derived xenograft (PDX)-based orthotopic mouse model of ccRCC. Our preliminary data indicate that several specific CDK9 inhibitors (CDK9i)—AZD4573, NVP-2, and KB-0742—mimic Dinaciclib- induced death of VHL-deficient cells in vitro. CDK9 represents a promising therapeutic target since: (1) it is a non-canonical CDK regulating RNA polymerase II-mediated transcription; (2) multiple CDK9i have been developed, with several undergoing clinical trials in cancers other than ccRCC. Accordingly, our goal is to evaluate AZD4573 as a potential therapeutic for ccRCC. Our objectives are to dissect the mechanism of synthetic lethality in vitro, and assess AZD4573 efficacy in vivo, including its effects on anti-tumor immunity. We propose the following Specific Aims: 1) Dissect the mechanism of synthetic lethality of CDK9 inhibition with VHL loss in vitro, where we will test the hypothesis that there is a cross-talk between VHL and CDK9 pathways, affecting each other’s activity. We will also test the involvement of several candidate pathways downstream of CDK9 (MCL-1 and Bfl-1 pro-survival proteins) and VHL (HIF-1 and HIF-2) in synthetic lethality to determine the biomarkers of tumor response; and 2) Evaluate CDK inhibitor AZD4573 as a potential therapeutic in an orthotopic PDX-based and immunocompetent models of ccRCC, the latter conducted in combination with immune checkpoint inhibitor (ICI)—anti-PD1. ICIs represent a current front-line treatment for ccRCC, and literature indicates that CDK inhibition by Dinaciclib and a specific CDK9i induce anti-tumor immunity, potentiating their anti-tumor effects. Accordingly, our working hypothesis is that CDK9i will slow the tumor growth in immunodeficient model and cause tumor regression in immunocompetent model, especially when combined with ICI. Successful completion of the experimental plan will provide an efficient therapeutic strategy for VHL-deficient ccRCC—CDK9i + ICI combination treatment. Dissecting the mechanism of synthetic lethality will allow for patient stratification into potential responders and non-responders.
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