Development of PROTAC Degraders for VHL Synthetic Lethal Partner FTO in Clear Cell Renal Cell Carcinoma
Abstract
Scientific Background and Objective: The outcomes for patients with advanced/metastatic clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, that cannot be treated with surgery, are very poor because these tumors are not responsive to either radiotherapy, chemotherapy, or targeted therapy. Therefore, new classes of drugs are urgently needed to improve the survival of patients with metastatic ccRCC. Fat mass and obesity-associated (FTO) gene is expressed at high levels in ccRCC cancers compared to normal tissues. More importantly, drugs that block the function of FTO selectively kill ccRCC cells that have mutations in the von Hippel-Lindau (VHL) gene, which occurs in 90% of cases, but not in cells without these mutations, suggesting that ccRCC cells cannot survive when both VHL and FTO are not functional. The same phenomenon has been observed by two independent researcher groups, confirming that targeting FTO may be an effective therapy, particularly in VHL-mutated ccRCC. However, current FTO inhibitors cannot be used in patients because they not only inhibit FTO but also other proteins similar to FTO, causing toxic side effects. In addition, their ability to shut down FTO is insufficient in the dosages that can be given safely to patients. Therefore, we must develop novel potent and selective FTO inhibitors with low toxicity. Our team of chemists, urologists, and oncologists will use a cutting-edge technology called proteolysis-targeting chimaera (PROTAC), to make a new class of FTO-targeting drugs. PROTAC technology works by creating chemical compounds that hijack the cell s own protein recycling machinery. It works by coupling a chemical that binds to the protein of interest (in this case, FTO) to a chemical that attracts and activates the cell machinery to degrade that protein. Over 1,600 PROTACs have been made in a wide variety of diseases. There are several PROTAC drugs in clinical trials, demonstrating the efficacy of this new technology. However, a PROTAC-based degrader of FTO has not been reported to date. We have all the chemical pieces we need and will find the best combination to effectively and specifically target FTO in kidney cancer cells. We will test new drugs in ccRCC cells derived from human cancers, a unique resource we have developed in our laboratory. What is the important gap in patient care the study will focus on? There is an unmet need for novel and effective treatment for patients with advanced/ metastatic VHL-deficient ccRCC. Our study will focus on developing a potent and selective PROTAC inhibitor targeting FTO to eliminate VHL-deficient ccRCC cells based on synthetic lethality. Since this inhibitor will be effective only in VHL-mutated cancer cells, the treatment will be highly specific for the cancer cells, making it less likely to cause side-effects. As a result, we anticipate effective killing at doses tolerable to patients. Moreover, our drugs are likely to synergize with other therapies to improve clinical outcomes of ccRCC patients. For example, blocking FTO is particularly effective in killing VHL-deficient ccRCC cells with low expression of the protein HIF2alpha. In 2021, the Food and Drug Administration approved belzutifan, a drug that inhibits HIF2alpha. Very likely, combining our PROTAC degraders of FTO with belzutifan will be a new, highly effective therapy for VHL-deficient ccRCC patients. What are the innovative aspects of the proposed research project? Our proposal is designed around a number of innovative elements including concept and technology, which will lead to new areas of research in ccRCC. First, the concept of FTO inhibition for VHL-deficient ccRCC is novel and impactful, given the morbidities caused by advanced ccRCC. We are the first to hypothesize that FTO inhibition induced by its PROTAC degraders will kill VHL-deficient kidney cancer cells, but not normal cells since they do not have VHL mutations. Second,
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310170
Entities
People
- James D Brooks
Organizations
- Stanford University
- United States Army