Modulating Metabolism to Sensitize Lung Tumors to Proton Therapy
Abstract
Background: Glutamine is the most abundant amino acid in the body. Within cells, glutamine is metabolized by the enzyme glutaminase-1 (GLS1) to produce glutamate, which is essential for producing antioxidants and energy and for synthesizing amino acids, lipids and nucleotides. An essential antioxidant generated from glutamine metabolism is glutathione (GSH). Cancer cells have high metabolic rates that generate high levels of free radicals, which can react with cellular structures with detrimental effects and cell death if not managed. To maintain balanced levels of free radicals, cancer cells often develop mutations that increase their reliance on high levels of free radicals. One such mutation is in the protein KEAP1, which in cell metabolism pushes more glutamate to form antioxidants such as GSH. Thus, KEAP1-mutant cells rely on glutamine metabolism through GLS1 to maintain the glutamate levels needed to produce antioxidants. Notably, 15% of non-small cell lung cancer (NSCLC) tumors have mutations in KEAP1. NSCLC patients with KEAP1 mutations are prone to local recurrence after standard-of-care treatments such as radiotherapy (RT), emphasizing the need for new strategies to improve outcomes for NSCLC patients with KEAP-mutated tumors. GLS1 is a promising target that should act specifically on KEAP1-mutated tumors but not affect normal tissues. GLS1 inhibitors (GLS1i) are being tested in clinical trials as potential therapy, either alone or in combination with, for example, RT. GLS1 products (like GSH or proteins and nucleotides) are crucial in the cell response to radiation by neutralizing radiation-induced free radicals or repairing radiation-induced DNA damage. Our own work indicates that a novel GLS1 inhibitor (IACS-6274) currently being tested in a clinical trial led by Dr Yap (co-investigator of this proposal) profoundly sensitizes KEAP1-mutant lung cancer cells to proton therapy, a form of RT that specifically targets tumors while sparing normal tissues and that generates many more clustered DNA lesions and free radicals than conventional photon RT. Thus, protons+IACS-6274 hold promise for strengthening the effects of RT and could reduce local recurrence in patients with KEAP1-mutated NSCLC. Area of Emphasis: This project proposes an innovative strategy to treat lung cancer by establishing KEAP1 as a biomarker to identify tumors that will respond to the novel combination of protons+IACS-6274. Patient Population: Patients with KEAP1-mutated NSCLC have poor overall survival and high recurrence rates after RT. Because about 236,000 patients are diagnosed with lung cancer per year in the United States (85% of which will be NSCLC), and because 15% of those patients will have KEAP1 mutations, we expect our research to be relevant to more than 30,000 lung cancer patients per year. Clinical Application, Benefits, and Risks: Successful completion of this project will benefit a significant pro- portion of patients with KEAP1-mutated lung cancer with minimal risks, because proton therapy is part of standard treatment for lung cancer patients and because IACS-6274 is only mildly toxic in humans. Projected Time to Achieve Clinical Translation: Our team is uniquely qualified to accomplish the objectives of this project, with experts in radiobiology and proton therapy (Sawakuchi, Shaitelman, Lin, Bright), ferroptosis and metabolism (Gan), and the clinical use of IACS-6274 (Yap). We also have expertise in radiation oncology (Sawakuchi, Shaitelman, Lin), medical oncology (Yap), and medical physics (Sawakuchi). The Principal Investigator (Sawakuchi) is a board-certified medical physicist with experience in treating patients with proton therapy. Dr. Lin is an experienced radiation oncologist who treats lung cancer patients with proton therapy. Dr. Yap is an experienced medical oncologist who led a clinical trial on IACS-6274. Our combined expertise positions us well to ultimately translate the result
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310430
Entities
People
- Gabriel Sawakuchi
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army