Understanding and Blocking Metabolic Deglycation in Lung Cancer
Abstract
Research Proposal: The ultimate goal of this project is to improve quality of life and discover new treatment options for lung cancer patients. Lung cancer carries very poor prognosis and is one of the most fatal cancers primarily due to lack of treatment options. Lung cancer cells grow very rapidly and therefore expend a lot of energy in synthesizing biomolecules required for their growth. Importantly, these cells have evolved to efficiently absorb glucose and glutamine from their environment, which can be diverted to different pathways that produce energy and raw materials required for growth. However, glucose as well as toxic byproduct produced by their breakdown called methylglyoxal can also react with essential proteins to form non-functional “protein adducts” by a process called glycation, which can be very harmful to cancer cells. To counter this detrimental effect of high glucose consumption, cancer cells are thought to rely on two different proteins that prevent the accumulation of these harmful “protein adducts” and ensure continued growth. Recently, others and I have shown that these deglycating proteins are essential for growth of certain cancers, but whether this is true for lung cancer is not known. Importantly, these enzymes are susceptible to pharmacologically inhibition and may provide a much-needed treatment option to combat this disease. My proposal will examine this in comprehensive detail and is a first step in identifying new feasible ways of treating the incurable and aggressive lung cancers. This proposal addresses two LCRP emphasis areas: (1) understanding the molecular mechanisms of initiation and progression to lung cancer and (2) identify innovative strategies for the treatment of lung cancer. Career Goals: I aspire to be in the forefront of lung cancer research. My career goal is to understand how lung cancer develops and grows and apply that knowledge to design new treatment strategies that can cure this deadly disease. I expect to start my own research group at a nationally recognized and NCI-designated cancer center soon. My research trainings first at Drexel University College of Medicine and then at the renowned Memorial Sloan Kettering Cancer Center have empowered me with all the necessary skill sets to successfully establish an independent lung cancer research program. A prestigious award like the Career Development Award from the Department of Defense will not only give me financial support to undertake this exciting and clinically important research, but will set me apart amongst my competitive peers and help me ascertain myself as a leading lung cancer biologist. Applicability: The overall goal of this study is to develop a rational therapy and improve patient survival in lung cancer. Glycation is an unexplored area in cancer research that provides new translational opportunities, and this will be a first study to comprehensively study it in lung cancer. Therefore, upon completion, I will have explored a new area of lung cancer biology with immediate therapeutic benefit. Briefly, proteins that prevent glycation and allow cancer cells to grow are viable drug targets, and this project will generate all the data required to expedite the development chemical inhibitors of deglycation that can be used in the clinic. Importantly, based on small animal studies loss of these proteins is not harmful to normal cells indicating minimal toxic side effects. While lung cancer patients are primary beneficiaries of this research, therapeutic ramifications of this project go well beyond. For example, patients with other aggressive cancers like liver and pancreatic as well as those suffering from metabolic diseases like diabetes may benefit from deglycation targeting drugs. I envision that the research proposed here will be a huge stepping stone toward curing lung cancer, and one can expect deglycation blockers to enter clinical trials in the next 3-5 years. Moreover, while m
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110377
Entities
People
- Viraj Sanghvi
Organizations
- Leonard M. Miller School of Medicine
- United States Army