Metabolic Targets to Overcome Chemoradiation Resistance in Genotype-Defined Non-Small Cell Lung Carcinoma
Abstract
Scientific Objective and Rationale: Non-small cell lung carcinoma (NSCLC) can cause death through uncontrolled local tumor growth within the chest or metastatic spread. For tumors without metastases that cannot be surgically removed, radiation therapy (RT) is administered in curative intent. However, large tumors (= stage III) recur in the chest in up to 50% of patients after RT and chemotherapy (chemoRT), highlighting the need to identify more effective therapies. Improving chemoRT by combining it with drugs that specifically target the behavior of cancer cells may lead to better tumor eradication. A particular problem are NSCLCs that are resistant to RT at the outset; often those that carry mutations in genes such as KRAS, STK11, or KEAP1. Thus, these genes could serve as biomarkers to identify patients who would benefit from a more intensified treatment course of chemoRT plus a biological drug that is aimed at decreasing tumor recurrence rates and improving cures. There exists currently considerable excitement surrounding the possibility that altered metabolism in cancers could be exploited for improving therapies. Findings suggest that in NSCLC there can be increased production of lipids, for example, to generate energy or make cell membranes for tumor growth. We find that blocking the production of monounsaturated fatty acids (known as healthy type of fat) in NSCLC cells with mutated KRAS renders these more sensitive to RT. We propose to leverage a unique institutional screening platform to examine drugs that affect cancer metabolism together with chemoRT. We will test about 2,000 combinations of drugs with NSCLC genetic features using tumor models that are grown in the lab under 3D conditions that are more physiologic than traditional cell growth on flat plastic surfaces. We seek to acquire unprecedented insight into the variation of treatment responses of NSCLC with common mutations (including KRAS and others) and how we may overcome radiation resistance by, for example, manipulating lipid metabolism in specific cancers. Area(s) of Emphasis: This research will help us understand mechanisms of resistance to chemoRT, develop innovative strategies for the treatment of lung cancer through RT/drug combinations, and potentially identify predictive markers to assist with therapeutic decision making. Ultimate Applicability of the Research: There currently exist no biological drugs that are combined with chemoRT in principally curable, but radioresistant lung cancers. Our research may inform strategies to modify cancer lipid metabolism which may reduce radioresistance. This would be tested in clinical trials. What Types of Patients Will It Help and How Will It Help Them? Clinical trials informed by our research, and ultimately changes in clinical care, may benefit patients with locally advanced but non-metastatic NSCLC that are resistant to chemoRT. As a result, tumor regrowth would be less likely, patients may live longer and may have a higher chance to be cured. Interventions to overcome radioresistance could involve drugs that interfere with cancer lipid metabolism or may involve dietary supplements/modifications to achieve similar results. What Are the Potential Clinical Applications, Benefits, and Risks? Our foundational research will provide unique insight into the ability of a broad range of drugs to manipulate metabolism in laboratory models of NSCLC before it can then be tested in clinical trials. Clinical trials with novel drugs may benefit some patients but could also increase the toxicity of treatment. Therefore, it will be critical to identify biomarkers, such as KRAS mutations, to identify patients most likely to benefit from more aggressive treatments adding metabolic drugs to chemoRT. What Is the Projected Time Anticipated to Achieve a Clinically Relevant Outcome? We anticipate that a clinical trial based on the results of this research could be designed within about 3 ye
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310466
Entities
People
- Henning Willers
Organizations
- Massachusetts General Hospital
- United States Army