Targeting the DNA Damage Repair Network to Promote an Innate Immune Response in ccRCC
Abstract
Patients with clear cell renal cell carcinoma have shown promising clinical outcomes with therapies that help stimulate the immune system, called checkpoint inhibitors. However, not all patients are responsive to these agents. To address this clinical challenge, we have established a unique partnership focusing on studying the response of the tumor to DNA damage and its repair, termed DNA damage repair, and its effect on innate immunity. This research will directly improve treatment for patients with advanced renal cell carcinoma by developing tailored, tumor-specific combinations of checkpoint inhibitor therapy plus DNA damage repair inhibitors. Our preliminary data show that the DNA damage repair is defective in renal cell carcinoma, which results in the inappropriate leakage of bits of broken DNA outside the nucleus, where DNA usually resides. We have uncovered a previously unknown link between the alterations of the DNA damage repair network and the activation of a cellular system, termed innate immunity, that induces cells to send off a danger signal when the cell s own DNA starts appearing outside of the nucleus. This innate immune response is designed to alert the body s immune system when cells are infected or damaged, at which point the immune system attacks and kills these cells. Thus, in renal cell carcinoma, defective DNA damage repair will induce activation of innate immunity, and this interaction can be exploited to enhance response to checkpoint inhibitors. Based on our preliminary data, targeting DNA repair in renal cell carcinoma requires a personalized approach. Mutations in specific genes, including VHL, PBRM1 and NPRL2, alter the DNA damage repair network in fairly specific ways. A better understanding of this process may allow us to take advantage of unique therapeutic vulnerabilities in renal cell carcinoma tumors by using specific DNA damage repair inhibitors in combination with checkpoint inhibitors in tumors with specific mutations. Although checkpoint inhibitors are commonly used in renal cell carcinoma, DNA damage repair inhibitors are not, and we have the potential to come up with a completely new way and better way of treating renal cell carcinoma. In this application, we will test our hypothesis in three Specific Aims. In our first Aim, we will test whether specific mutations in renal carcinoma induce differential sensitivities to various DNA damage repair inhibitors. We believe cells deficient in VHL and PBRM1 will be sensitive to inhibitors of ATR, a DNA damage repair pathway protein. In contrast, VHL plus NPRL2 deficiency reduces expression of another protein in the DNA repair pathway called CHK1, which permits inappropriate cell cycle progression. We believe reduced CHK1 levels induced by NPRL2 deficiency will lead to sensitivity to WEE1 inhibitors. We will test this potential personalized approach to combination therapy in appropriate cell line models. In our second Aim, we will assess the concepts outlined in our first Aim using clinical resources available in our laboratories to characterize molecular changes in DNA damage response and innate immune responses in renal cell carcinoma patient specimens. This will provide valuable real world verification of our cell line observations. In our third Aim, we will develop and optimize combination regimens using specific DNA damage repair inhibitors in combination with checkpoint inhibitors in renal cell carcinoma tumor mouse models. Based on our preliminary studies, we hypothesize that specific DNA damage repair inhibitors will enhance innate immunity in a tumor mutation-specific manner and, in turn, enhance the efficacy of checkpoint inhibitors. Performing the work outlined in this grant will provide key preclinical data for developing optimized, tumor mutation-specific combination regimens, which can be translated into clinical trials within the next three years. We will be in a position to enter into discu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110930
Entities
People
- Eric Jonasch
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army