Analyzing the Therapeutic Impact of di-ABZI on PBRM1-Deficient ccRCC Tumors
Abstract
Kidney cancer is among the top ten most frequent cancers, both in incidence and mortality, in both men and women. Inactivation of multiple cancer driver genes is causal for the development of kidney cancer. Targeting pathways affected by the drivers has produced many effective treatments. PBRM1 is a major mutated driver in kidney cancer, and its mutation rate is the second highest and is only lower than that of VHL. Currently, there is no drug to target PBRM1 deficiency to treat ccRCC patients. Loss of function of the VHL tumor suppressor gene causes kidney cancer of clear cell type. We found that when VHL is lost, interferon stimulated gene factor 3 (ISGF3), a transcription factor that is usually triggered by viral infection, is activated. We also found that the hyperactive ISGF3 actually worked as a brake for tumor growth in kidney cancer, and the loss of PBRM1 could make this brake defective. Since ISGF3 is a very effective brake for tumor growth, activating it by a drug is akin to slamming the brake and could be therapeutically beneficial. To this end we identified a drug candidate compound developed by GlaxoSmithKline (GSK), a major pharmaceutical company in the U.S., that can activate ISGF3 strongly and cause changes that are likely tumor-suppressing in kidney tumors in mice. This compound has no reported toxicity to human or animals so far. Currently, a compound from the same chemical family is being tested by GSK on cancer patients with all sorts of solid tumors in a phase 1 clinical trial, but there is not a focus on kidney cancer yet. We will test whether this compound has strong antitumor activity in multiple PBRM1-deficient mouse models using human kidney cancer cell lines, patient-derived tumor grafts, and a genetically engineered mouse model of kidney cancer. Our proposal addresses Therapeutic Development and Chromatin and Gene Regulation Areas of Emphasis. If our study yields consistently positive data, it will form the foundation for us to collaborate with GSK to design a clinical trial to test such compounds on patients with clear cell-type kidney cancer, which accounts for about 80% of all kidney cancer. Within this group, it is likely that the patients whose tumors also have mutations in the PBRM1 gene might benefit the most, since the ISGF3 pathway, the brake for tumor growth, is partially but reversibly disabled. Since a phase 1 clinical trial is already underway, they could establish the safety and efficacy against cancers for this family of compounds within a few years. By working with GSK it is conceivable that within a decade a novel drug against PBRM1-deficient kidney cancer can be developed and approved. The short-term impact could be a gain of knowledge, that a novel target for treatment in kidney cancer will be established, which will encourage more research at the basic, translational, and clinical levels into this pathway. The long-term impact could be that a new class of drugs can be developed for kidney cancer, and a biomarker that indicates who will benefit the most can be identified. Since the male gender and exposure to dangerous chemicals are strong risk factors for kidney cancer development, Service Members and Veterans have a higher chance of developing kidney cancer. This proposal could provide benefits to Service Members, their families, Veterans, and the American public by identifying a major drug target and a compound for drug development. This proposal is innovative because it provides a new and comprehensive understanding of kidney cancer genetics. VHL mutations are the founding event that initiates the development of kidney cancer. VHL loss also activates ISGF3, which is tumor-suppressive, so this creates a selection pressure to disable this negative feedback loop. Inactivation of PBRM1 dampens ISGF3 activation, and this greatly enhances tumor growth. Our finding will also identify a new compound for drug development.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110923
Entities
People
- Haifeng Yang
Organizations
- Thomas Jefferson University
- United States Army