Exploiting Epigenetic Dysregulation to Identify Targetable Vulnerabilities in ccRCC
Abstract
ECI s Training, Goals, and Sustainibility: I have had the privilege of being trained in some of the best academic and research institutions both in India and in the United States. Throughout this training I have had an established record of academic excellence and research contributions. Some of my academic honors have included a "best student" award, university gold medals, and a travel scholarship awarded to only a select number of top American graduate students to present their work annually at the National Institutes of Health. As a postdoctoral research fellow at Dana-Farber Cancer Institute/Harvard Medical School, I worked under Dr. William Kaelin, a towering figure in kidney cancer research, and a recent recipient of the Albert Lasker award (considered colloquially as the American Nobel Prize). In my time in Dr. Kaelin s laboratory, I published several high-impact papers in kidney cancer (and other areas) in top research journals, such as Cell, Nature, and Science. These contributions have included the discovery of an enzyme named EZH1 as a potentially novel therapeutic target in kidney cancer and more fundamental discoveries linking lack of oxygen availability (or hypoxia), which is often seen in tumors, as a driver of a more tumor-like cell state. I have now begun developing these discoveries in my own research laboratory at the Cleveland Clinic, one of the nation s top hospital/clinical research centers. My goals are to continue studying fundamental errors in the way DNA is organized in kidney cancer to identify weaknesses that can be therapeutically actionable. I have identified exciting research problems, assembled a great team of support staff and trainees, found a great team of research mentors, and established collaborations with world-class kidney cancer clinicians, to make my research program sustainable in the long term. Rationale, Hypothesis, and Evidence: My laboratory studies clear cell renal cell carcinomas (ccRCC), the most common form of adult kidney cancer. Despite major strides in therapy, ccRCC remains incurable; thus, identifying novel targets remains crucial. Renal tumors have mutations in genes that regulate chromatin. Chromatin is a complex spooled state in which the DNA thread, our genetic source-code, is wrapped. Spooling DNA into chromatin not only ensures better protection from chemical insults, but also allows exquisite control over turning genes on/off as per the cell s needs. Therefore, we reasoned that mutations in genes that control spooling erroneously cause undesired (onco)genes to be switched on in kidney tumors. Using cutting-edge protein and genomic analysis tools, we probed this idea and found that this was indeed true. By mapping changes in DNA spooling and measuring its consequences, we identified ~100 genes that were erroneously switched on in cancerous renal cells. First in batches, and then individually, we analyzed which (or how many) of these genes could contribute to cancer development in a mouse model of renal cancer. Our preliminary analysis and subsequent secondary (validation) studies spanned nearly two years of work and ultimately identified a protein named EAAT3 as a potential new oncogene in renal cancer. EAAT3 resides on the kidney cell surface and picks up important amino acids, such as aspartate and glutamate, before they are excreted in urine. These very amino acids, however, are critical nourishment for a cancer cell. Our studies thus suggest that cancer cells have hijacked a process that was intended to prevent waste and instead turned it into a source of building blocks to fuel its metabolic needs. Understanding these metabolic needs, however, can allow us to overcome this hostile takeover. This is the crux of this proposal. We propose to first understand why renal cells acquire errors in spooling to lead to erroneous levels of EAAT3 (and other proteins in the cell). But, perhaps more importantly, because so little is known a
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010804
Entities
People
- Abhishek Chakraborty
Organizations
- Cleveland Clinic
- United States Army