Studying BAP1 in Regulating Glucose Dependency in Renal Cancer: Mechanisms and Preclinical Translation
Abstract
Just as we need food and nutrients to survive and to do our work, cancer cells also need nutrients, such as sugars and amino acids, to enable them to survive and grow. Certain genetic mutations in cancer cells rewire their metabolism networks and make such cancer cells highly dependent on particular nutrients for survival, such that some cancer cells will undergo robust cell death when certain nutrients are limiting, while under the same conditions normal cells or other types of cancer cells can survive and grow well. Our understanding of this phenomenon, so-called nutrient dependency in cancer cells, can provide important therapeutic implications in cancer treatment, as it suggests that drugs that disrupt nutrient uptake or metabolism may be effective in killing tumor cells that are highly dependent on such nutrients for survival while sparing normal cells. As one notable example, asparaginase has been used in the clinic to treat acute lymphoblastic leukemia (ALL) for decades. The rationale for this treatment is that normal cells, but not ALL cells, can make one of their own amino acids called asparagine, so ALL cells have to be highly dependent on asparagine provided from medium or blood for survival. Supplementation of asparaginase disrupts asparagine and thus pushes ALL cells to undergo cell death. BAP1 is a tumor suppressor that normally functions as a molecular brake in our cells. BAP1 is lost through gene mutation or deletion in up to 15% clear cell renal cell carcinoma (ccRCC, which is the predominant RCC subtype that accounts for up to 75% of all RCC cases). Just as a car will speed out of control when its brakes are broken, BAP1 loss can lead to renal tumor development. Importantly, RCCs with BAP1 mutations are particularly bad, with poorest overall survival, more aggressive phenotypes, and rapid progression to multiple metastatic sites. When a car brake is broken, we can repair the car simply by replacing a good brake. However, in clinic it is generally challenging to replace a good copy of a tumor suppressor when it is lost in tumors. Currently, there is no effective therapy to treat RCC patients with BAP1 mutation or deficiency, and there is an urgent need to develop efficacious targeted therapies to treat these RCC patients. We found that BAP1-deficient renal cancer cells are highly dependent on glucose, one type of sugar that provides a major energy source (in the form of ATP) in our cells, for survival. Correspondingly, glucose deprivation induces massive cell death in BAP1-deficient renal cancer cells. Similarly, we found that these BAP1-deficient renal cancer cells are also vulnerable to the treatment of drugs called GLUT inhibitors that block glucose uptake into cells. We thus hypothesize that GLUT inhibitors might be effective therapeutic strategies to treat RCC patients with BAP1 mutation or deficiency. In this application, we propose a series of experiments, including experiments from renal cancer patient-derived mouse models, to test our hypothesis. In addition, we will also study the mechanism that causes glucose dependency in BAP1-deficient renal cancer cells. The research proposed in this application will address the FY18 KCRP Areas of Emphasis on (i) targeted therapies, (ii) metabolism, (iii) chromatin and gene regulation, and (iv) biomarker development. Our proposal is highly innovative, because it focuses on a previously unexplored paradigm that fills in the current gap to link nutrient dependency to renal cancer treatment. If successful, our proposed studies will have significant impact on both understanding fundamental metabolic vulnerabilities in renal cancer and identifying effective therapeutic strategies to treat renal cancer patients with BAP1 mutation or deficiency. By collaborating with Kadmon, a pharmaceutical company that has developed potent GLUT inhibitors, and our clinician colleagues at MD Anderson Cancer Center, we expect to bring the drugs that are
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910818
Entities
People
- Boyi Gan
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army