Interrogating the Therapeutic Relevance of Targeting the Antiapoptotic BCL-XL Protein in Kidney Cancer
Abstract
Significance: Kidney cancer is among the top 10 most common forms of human cancer. This disease not only affects the general public, but also has a negative impact on military personnel and their families. The kidney is one of the major detoxifying organs in our body and exposure to environmental toxins, either during conflict or due to contaminated water sources around military bases, leads to direct harm to the kidney tissue. Lifestyle risk factors, including obesity and smoking, also negatively impact defense personnel. Together, these environmental and lifestyle factors predispose military personnel to an increased risk of kidney cancer. Despite major breakthroughs in the clinical management of kidney cancer in recent years, this disease remains ultimately incurable. There is, therefore, a clear clinical need to identify novel drugs to treat kidney cancer. Kidney cancer is stubbornly non-responsive to traditional chemotherapy, virtually eliminating the possibility of treatment with a large class of molecules that work against other cancers. This is particularly surprising because the cellular machinery that triggers cell death in response to chemotherapy is normally intact in kidney cancer cells. Why then do these tumors not die? And could we reprogram these cells to begin dying? Tumor cells constantly make life or death decisions in response to environmental cues. And, typically, even when faced with adversity that would prompt a normal cell to mount suicidal cell death responses, tumor cells choose life. Simply put, tumor cells are like revved-up cars facing the edge of a cliff, but protected by the action of some brake proteins. Making these brakes fail could be a therapeutic strategy. To identify these brake proteins, we exploited recent large-scale studies that have measured the impact of eliminating virtually every known protein on the growth of cancer cells. Our analysis identified BCL-XL, as a new brake protein in kidney cancer. Indeed, we found that eliminating functional BCL-XL triggers significant cell death in a number of kidney cancer cells. We argue, in this proposal, that turning BCL-XL off eliminates the cell s protective shield, causing them to die. This could be a novel usable therapeutic strategy in kidney cancer. Focus Area: Develop novel therapeutic strategies for treatment. Hypothesis and Objective: We hypothesize in this proposal that kidney cells are protected from cell death by the BCL-XL brake and propose the use of BCL-XL blockers as new drugs in kidney cancer therapy. Specific Aims: We have distilled this project into three aims. First, we propose to study a large collection of (age- and sex-matched) human kidney tumors to catalog their relative sensitivity to BCL-XL blockers. Based on this, we propose to identify biomarkers -- genes whose presence/absence can faithfully predict if a given tumor will respond to anti-BCL-XL therapy. A biomarker is any easily measurable feature that can faithfully predict a clinical pathology or response. For example, the well-known A1C test is a biomarker for blood glucose monitoring in diabetic patients. Second, we propose to combine BCL-XL blockade with existing therapies in kidney cancer. We reason that removing the protective BCL-XL brake would send kidney cancer cells hurtling toward (and maybe even over the) edge of the cliff. At least, we hope that BCL-XL blockers will make kidney tumors vulnerable to other therapies, such as rapalogues and immunotherapy. Finally, we propose to use cutting-edge CRISPR/Cas9 tools to find ways to make kidney tumors more responsive to anti-BCL-XL therapy. Altogether, our proposal not only addresses the biological role of the BCL-XL brake protein in kidney cancer, but also interrogates approaches that can accelerate the use of anti-BCL-XL therapy in the clinic. Innovation and Impact: Kidney cancer accounts for approximately 79,000 new diagnose
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310771
Entities
People
- Abhishek Chakraborty
Organizations
- Cleveland Clinic
- United States Army