Project Grant K08CA279653

THE ROLE OF PROPIONATE METABOLISM IN NON-SMALL CELL LUNG CANCER - PROJECT SUMMARY/ABSTRACT DESPITE EXCITING ADVANCES, LUNG CANCER REMAINS THE LEADING CAUSE OF CANCER-RELATED DEATHS IN THE UNITED STATES. A CRITICAL GAP IN OUR UNDERSTANDING IS HOW LUNG CANCER CELLS BECOME METASTATIC AND RESISTANT TO OUR TREATMENTS. HISTORICALLY, LUNG CANCER RESEARCH HAS FOCUSED ON GENETIC DRIVERS AS THE MAIN CULPRITS OF DISEASE. BUT RECENT, LARGE DNA AND RNA SEQUENCING STUDIES HAVE SHOWN THAT GENETIC CHANGES ACCOUNT FOR ONLY 50% OF LUNG CANCER PROGRESSION, STRONGLY SUGGESTING THERE ARE UNIDENTIFIED NON-GENETIC MECHANISMS OF DISEASE PROGRESSION. THE PI'S PRELIMINARY DATA HAS IDENTIFIED THAT PROPIONATE METABOLISM-A METABOLIC PATHWAY PREVIOUSLY NOT KNOWN TO PLAY A ROLE IN CANCER-IS DYSREGULATED IN NON-SMALL CELL LUNG CANCER (NSCLC). INDEED, THEIR DATA SHOW THAT METHYLMALONIC ACID (MMA), A KEY METABOLIC BYPRODUCT OF PROPIONATE METABOLISM THAT CAN PROMOTE EPITHELIAL-TO- MESENCHYMAL TRANSITION (EMT), IS ELEVATED IN LUNG CANCERS AND IN THE SERUM OF PATIENTS WITH METASTATIC DISEASE. MOREOVER, THE PI HAS IDENTIFIED THAT MMA CAN ACTIVATE AND BIND TO G-PROTEIN COUPLED RECEPTORS, UNCOVERING A NOVEL SIGNALING AXIS. HIS PRELIMINARY DATA ALSO SHOWS THAT MMAB, A KEY REGULATORY GENE OF PROPIONATE METABOLISM, IS UNDEREXPRESSED IN NSCLC AND KNOCKING DOWN MMAB PROMOTES EMT AND DRUG RESISTANCE IN LUNG CANCER CELLS. THESE STUDIES HAVE LED TO THE CENTRAL HYPOTHESIS THAT PROPIONATE METABOLISM DYSREGULATION PROMOTES LUNG CANCER PROGRESSION AND DRUG RESISTANCE IN NSCLC AND IS AN IMPORTANT NON-GENETIC MECHANISM OF DISEASE PROGRESSION. THE GOAL OF THE PROPOSED STUDIES ARE TO UNDERSTAND I) THE MECHANISM BY WHICH MMA SIGNALS II) THE EFFECT OF MMAB LOSS IN NSCLC AND III) THE IN VIVO EFFECTS OF MMA IN NSCLC USING MOUSE MODELS. SUCCESSFUL COMPLETION OF THE PROPOSED WORK WILL IMPROVE OUR UNDERSTANDING OF A METABOLIC PATHWAY IN LUNG CANCER THAT IS POORLY UNDERSTOOD AND POTENTIALLY IDENTIFY A NEW PATHWAY THAT COULD BE TARGETED THERAPEUTICALLY. THIS PROPOSAL DESCRIBES A FIVE-YEAR TRAINING PROGRAM TO LAUNCH AN INDEPENDENT RESEARCH CAREER FOCUSING ON MECHANISMS OF NSCLC DRUG RESISTANCE AND METASTASIS. THE CANDIDATE, DR. BOBAK PARANG, IS A MEDICAL ONCOLOGY FELLOW AT WEILL CORNELL MEDICINE WHO HAS BEEN TRAINING TO BECOME A PHYSICIAN-SCIENTIST FOR OVER TEN YEARS. HE HAS OUTLINED A CAREER DEVELOPMENT PLAN THAT WILL BUILD ON HIS STRONG BACKGROUND IN CANCER BIOLOGY AND CLINICAL ONCOLOGY BY PROVIDING RIGOROUS TRAINING AND NEW SKILLS IN MOLECULAR BIOLOGY, METABOLOMICS, AND MOUSE MODELS OF LUNG CANCER. HE WILL PERFORM THE PROPOSED STUDIES UNDER THE MENTORSHIP OF DR. JOHN BLENIS, A WORLD RENOWNED EXPERT IN MOLECULAR BIOLOGY, CANCER METABOLISM, AND CELLULAR SIGNALING IN THE RICH INSTITUTIONAL ENVIRONMENT OF WEILL CORNELL MEDICINE. WITH THE MENTORSHIP TEAM HE HAS ASSEMBLED, HIS STRONG CLINICAL AND SCIENTIFIC BACKGROUND, AND HIS TRAINING PLAN, DR. PARANG IS IDEALLY POSITIONED TO DEVELOP INTO AN INDEPENDENT LABORATORY- BASED PHYSICIAN SCIENTIST WITH R01 FUNDING.