Project Grant K43TW012787

DEVELOPMENT OF A SMART TRANSFORMABLE NANOTHERAPEUTIC AGAINST CANCERS WITH ACQUIRED RESISTANCE TO EGFR-TARGETED THERAPIES CAUSED BY MET AMPLIFICATION - TITLE: DEVELOPMENT OF A SMART TRANSFORMABLE NANOTHERAPEUTIC AGAINST CANCERS WITH ACQUIRED RESISTANCE TO EGFR-TARGETED THERAPIES CAUSED BY MET AMPLIFICATION STUDY SECTION & AWARDING COMPONENT ASSIGNMENT REQUEST: FOGARTY INTERNATIONAL CENTER PROJECT SUMMARY/ABSTRACT: CANCER, A SIGNIFICANT PUBLIC HEALTH CHALLENGE, IS THE LEADING CAUSE OF MORTALITY IN THAILAND AND WORLDWIDE. THE ONGOING RISE IN CANCER CASES AMONG THAIS, RESULTING IN OVER A HUNDRED THOUSAND ANNUAL FATALITIES, HAS CREATED A COMPELLING NECESSITY AND DEMAND FOR THE DEVELOPMENT OF POTENT PHARMACEUTICALS TO ADDRESS DIVERSE TYPES OF CANCER. UNLIKE CONVENTIONAL CHEMOTHERAPY, TARGETED THERAPY MINIMIZES THE RISK OF SIDE EFFECTS BY SPECIFICALLY TARGETING PROTEINS OVEREXPRESSED OR ACTIVATED IN TUMORS. AMONG VARIOUS IDENTIFIED ONCOTARGETS, THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) REPRESENTS A PARTICULARLY APPEALING ONE, DUE TO ITS OVEREXPRESSION, AMPLIFICATION, AND GAIN OF FUNCTION IN SEVERAL TYPES OF CANCER. TWO CLASSES OF EGFR INHIBITORS HAVE BEEN CLINICALLY APPROVED, INCLUDING MONOCLONAL ANTIBODIES AND SMALL-MOLECULE TYROSINE KINASE INHIBITORS. DESPITE A GOOD INITIAL RESPONSE RATE TO THESE DRUGS, MOST PATIENTS EVENTUALLY DEVELOP DRUG RESISTANCE, MAINLY CAUSED BY A MESENCHYMAL-EPITHELIAL TRANSITION (MET) AMPLIFICATION. ONE PROMISING APPROACH THAT CAN OVERCOME DRUG RESISTANCE TO EGFR-TARGETED THERAPIES CAUSED BY MET AMPLIFICATION IS CO-TARGETING BOTH EGFR AND MET RECEPTORS USING A PEPTIDE-BASED NANOTHERAPEUTIC PLATFORM. THE SPECIFIC AIMS OF THE PROPOSED RESEARCH ARE (1) TO DESIGN AND SYNTHESIZE SMART TRANSFORMABLE EGFR/MET-TARGETING PEPTIDE NANOPARTICLES (PNPS) AND (2) TO ELUCIDATE THE ANTICANCER EFFECTS AND THE UNDERLYING MECHANISMS OF THE PNPS ON CANCERS RESISTANT TO EGFR-TARGETED THERAPIES DUE TO MET AMPLIFICATION IN VITRO AND IN VIVO. THE POTENTIAL EGFR/MET-TARGETING PEPTIDES WILL BE ACHIEVED BY THE COMBINATION BETWEEN A COMPUTER-AIDED PEPTIDE DESIGN STRATEGY AND AN ULTRA-HIGH-THROUGHPUT ONE-BEAD ONE-COMPOUND (OBOC) COMBINATORIAL LIBRARY TECHNOLOGY IN DR. KIT S LAM'S LABORATORY AT THE UNIVERSITY OF CALIFORNIA, DAVIS, USA. DR. LAM IS THE INVENTOR OF THE OBOC TECHNOLOGY. SUBSEQUENTLY, THE LEAD EGFR/MET-TARGETING PEPTIDES WILL BE USED FOR THE DESIGN AND SYNTHESIS OF SMART SUPRAMOLECULAR PEPTIDES CAPABLE OF (I) ASSEMBLING INTO NANOPARTICLES, (II) IN SITU TRANSFORMATION INTO NANOFIBRILS UPON BINDING TO EGFR/MET AT TUMOR SITES, (III) CAPTURING T EFFECTOR CELLS AND FACILITATING THEIR PROLONGED RETENTION WITHIN THE TUMOR MICROENVIRONMENT, AND (IV) RELEASING THE CYTOTOXIC DRUG FROM THE NANOFIBRILLAR NETWORK INTO CANCER CELLS, MAXIMIZING THE THERAPEUTIC EFFICACY. AT THE END OF THIS FIVE- YEAR PROJECT, AT LEAST ONE EFFICIENT PNP FOR TREATMENT OF CANCER WITH ACQUIRED RESISTANCE TO EGFR-TARGETED THERAPIES DUE TO MET AMPLIFICATION CAN BE OBTAINED, WHICH WILL BE CHOSEN FOR FURTHER CLINICAL STUDIES. THE PROPOSED CAREER DEVELOPMENT PLAN WILL ADVANCE NOT ONLY MY RESEARCH CAPACITY BUT ALSO ESSENTIAL SKILLS FOR MANUSCRIPT WRITING, NIH GRANT WRITING, AND LEADERSHIP, CULMINATING IN PUBLICATION OF HIGH-QUALITY RESEARCH ARTICLES, SUBMISSION OF R01 GRANT PROPOSAL, PROFESSIONAL NETWORKING, ACADEMIC PROMOTION, AND DEVELOPMENT INTO A SUCCESSFUL, INDEPENDENT RESEARCHER.