Exploiting DNA Repair Defects in Krebs Cycle-Deficient Renal Cell Carcinoma
Abstract
Rationale: Many forms of kidney cancer are associated with genetic predisposition including those associated with two well-characterized conditions, i.e., Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC) and Succinate Dehydrogenase (SDH) alterations. Both these conditions are related to inheriting a damaged gene involved in a key pathway in the breakdown of sugar, and in kidney cancers energy is produced without utilization of oxygen. Up to 15% of individuals with these conditions may develop very aggressive kidney cancers at a very early age and have limited treatment options. There are also tumors that occur sporadically that share features with these inherited forms, suggesting a similar treatment strategy can be used across this class of disease. We have recently found that the genetic code/DNA in this group of renal cancers is easily damaged due to its lacking normal repair mechanisms. In other tumors, causing further damage to the genetic material triggers a catastrophic event and tumors stop growing or die. This approach is now approved in prostate, ovarian, and breast cancers with similar problems repairing damaged DNA. To date it has not been evaluated in kidney cancer. Objective/Aims: The goal of this project is to see if we can exploit a vulnerability in this type of kidney cancer related to how the genetic code is repaired. We have shown this class of tumor has a high amount of pre-existing damage to the DNA due to poor repair mechanisms. We will evaluate drugs that can further harm the repair mechanisms or cause further damage to see if these are effective strategies. We have created new models to test these approaches, either in cells in a culture dish or when grown inside of mice to mimic a living environment. We hope to translate the most promising treatments to the clinic. How will this help patients and the kidney cancer research community? The studies proposed here address two key 2021 KCRP Focus Areas including development of novel therapeutic strategies and defining the biology of a rare kidney cancer. Currently, patients with inherited kidney cancers like HLRCC and SDH, as well as similar forms that can occur sporadically, have very limited treatment options and, unfortunately, very poor survival. Our discovery that this class of tumor lacks normal repair of DNA opens up completely new therapeutic approaches. The work described will allow us to evaluate the most promising strategy to attack these cancers by further damaging their DNA. The most promising strategy will be prioritized for clinical development in future trials of patients with metastatic disease or those with high risk of recurrence after nephrectomy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210549
Entities
People
- Brian Shuch
Organizations
- United States Army
- University of California, Los Angeles