A Novel Approach to Exploit Metabolic Vulnerability in Metastatic Lung Cancer
Abstract
This proposal will address two areas of emphasis for the FY22 LCRP: 1. Identify innovative strategies for the treatment of lung cancer. 2. Identify innovative strategies for the prevention of recurrence of or metastases from lung cancer. Lung cancer is by far the leading cause of cancer-related death in the United States. Veterans and military personnel have high incidence of lung cancer and poorer survival compared to civilians due to the prevalence of tobacco smoking and the exposure to other risk factors such as Agent Orange, radon, asbestos, and depleted uranium. Most lung cancer patients eventually succumb to local and/or metastatic recurrence, including many patients with complete removal of primary tumor and no detectable metastasis at the time of surgery. Understanding molecular mechanisms underlying metastatic recurrence and developing novel anti-metastasis therapies is crucial to prolong the overall and metastasis-free survival of lung cancer patients. Recently, there is preclinical and epidemiology evidence suggesting that the biguanide family of metabolic drugs, such as metformin and phenformin, holds promise in the prevention and treatment of lung cancer. Biguanide drugs have been widely used in the treatment of type II diabetes and have been shown to have outstanding safety profile. However, the clinical trials using biguanides such as metformin for the treatment of cancer resulted in mixed success. This signify the importance to identify patients resistant to biguanides and to develop novel approaches ton increase sensitivities. Lung cancer cells with mitochondrial abnormalities, such as cancer cells with LKB1 mutation or mtDNA mutations are hypersensitive to biguanides, which suggested that reprograming lung cancer metabolism might be a viable approach to increase biguanide sensitivities. However, the challenge is how to specifically target mitochondrial metabolism without affecting other tissues when mitochondria plays a critical role (e.g., the heart). Fascin is a pro-metastasis protein that is highly upregulated in metastatic tumor while absent in most normal tissues. Our lab previously discovered that fascin promotes lung cancer metastasis in part by aberrantly promoting two branches of lung cancer cell metabolism, namely mitochondrial metabolism and glycolytic metabolism. Since the ability to promote lung cancer metabolism depends on its canonical actin-bundling activity and there is a fascin inhibitor currently in clinical trial, we hypothesize that this inhibitor could be employed to selectively target the aberrant metabolism in metastatic lung cancer and could be used to increase the efficacy of biguanide treatment. Notably, since fascin expression is very low or absent in most adult tissue (with the exception of the brain), the metabolic effect of G2-44 will likely be specific to lung cancer cells while sparing normal tissues. Our preliminary studies have provided excellent support for such hypothesis. In this proposal, we will further use patient-derived organoid models and patient-derived xenograft models to examine our hypothesis. The success of this proposal will provide strong rationale to use clinical-grade fascin inhibitor G2-44 to exploit metabolic vulnerability in lung cancer, alone or in combination with biguanide metabolic drugs.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310348
Entities
People
- Shengyu Yang
Organizations
- Penn State Milton S. Hershey Medical Center
- United States Army