Utilization of Radiogenomics to Identify Targetable MET Alterations for Lung Cancer Brain Metastasis
Abstract
Lung adenocarcinoma (LUAD) has the highest incidence of brain metastases (BM), which portends an extremely poor prognosis even when extracranial disease is controlled and remains a major clinical problem. As there are no targeted therapies for the treatment of LUAD-BM, the development of novel treatments to effectively prevent and treat LUAD-BM is urgently needed to improve patient survival. In our preliminary studies, we identified a significant enrichment of MET amplification in LUAD BM (19%, N=125) compared to primary LUAD (3%; N=477) or liver metastases (5%, N=80) using fluorescence in situ hybridization (FISH) (MET/CEP7 > 2). MET activating mutations (non-exon 14 skipping) were also significantly increased in LUAD BM (22%; N=74) compared to primary LUAD (12%; N=171). These results suggest that MET alterations are selected for in metastatic lesions to the brain, and that the MET pathway may be a therapeutic target for LUAD-BM. MET is a receptor tyrosine kinase that, upon binding hepatocyte growth factor (HGF), mediates tumor cell proliferation, epithelial-mesenchymal transition (EMT), motility, invasion, angiogenesis and metastasis. Critically, the MET pathway has emerged as a targetable oncogenic driver in NSCLC and now has U.S. Food and Drug Administration (FDA)-approved targeted therapies that have been shown to cross the blood-brain barrier. How HGF/MET signaling promotes BM is unknown; however, we have found that MET tumorigenesis is dependent upon the EMT transcription factor, TWIST1; the HGF/MET pathway regulates TWIST1 expression; and TWIST1 is overexpressed in LUAD BM. In this proposal, we will establish the HGF/MET/TWIST1 pathway as a therapeutic target for LUAD BM using innovative preclinical models. Further, we will develop a non-invasive radiomic approach to identify patients who may benefit from MET-directed therapy. This proposal addresses three areas of emphasis: (1) Identify innovative strategies for the prevention of recurrence of or metastases from lung cancer. (2) Develop or optimize prognostic or predictive markers to assist with therapeutic decision making. (3) Identify innovative strategies for lung cancer care delivery. Successful completion of this project will have immediate significance for all lung cancer patients as it will select patients that need more intensive MRI (magnetic resonance imaging) surveillance and for lung cancer patients with BM, identify patients that can receive targeted therapy, and pioneer the early detection of MET altered LUAD BM for earlier precision-based treatment strategies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210350
Entities
People
- Laura P Stabile
Organizations
- United States Army
- University of Pittsburgh