Project Grant F31CA290735

TARGETING EGFR THROUGH MODERN PEPTIDE MODELING AND DESIGN - PROJECT ABSTRACT NON-SMALL CELL LUNG CANCER (NSCLC), COLORECTAL CANCER (CRC), HEAD AND NECK SQUAMOUS CELL CARCINOMAS (HNSCC), AND GLIOBLASOMAS ARE LEADING CAUSES OF DEATH IN THE UNITED STATES. THESE CANCERS ARE OFTEN DRIVEN BY MUTATIONS IN AND DYSREGULATION OF THE EPIDERMAL GROWTH FACTOR (EGF) RECEPTOR (EGFR), A RECEPTOR TYROSINE KINASE (RTK) CRITICAL FOR EPITHELIAL AND EPIDERMAL TISSUE DEVELOPMENT AND HOMEOSTASIS. FOR CANCERS SUCH AS RAS/RAF WILD-TYPE METASTATIC COLORECTAL CANCER, TREATMENT WITH ANTI-EGFR ANTIBODIES IMPROVES SURVIVAL; HOW- EVER, OVERALL SURVIVAL (OS) ONLY INCREASES BY TWO TO FOUR MONTHS FOR COMBINED ANTIBODY AND CHEMOTHERAPY TREAT- MENT COMPARED TO CHEMOTHERAPY ALONE. THE OS INCREASE IS HINDERED BY EGFR ECTODOMAIN MUTATIONS THAT CAUSE ANTIBODY RESISTANCE. DEVELOPMENT OF ANTI-EGFR PEPTIDES IS AN ATTRACTIVE STRATEGY AS AN ANTIBODY ALTERNATIVE FOR TREATMENT OF EGFR-DRIVEN CANCERS SUCH AS CRC DUE TO THEIR FAVORABLE PEPTIDE PROPERTIES, INCLUDING LOW IMMU- NOGENICY, BETTER TUMOR PENETRANCE, AND CHEAPER PRODUCTION. FURTHER, PEPTIDES HAVE HIGH SPECIFICITY AND AFFINITY FOR THEIR TARGETS AND INCORPORATION OF NON-CANONICAL AMINO ACIDS CAN TUNE THEIR PROPERTIES AND INCREASE THEIR HALF- LIFE. ALTOGETHER, THESE PROPERTIES MAKE DEVELOPMENT OF PEPTIDES TO TARGET EGFR AND EMERGING EGFR ECTODOMAIN RESISTANCE MUTATIONS HIGHLY ATTRACTIVE. TO DESIGN AND SCREEN NOVEL ANTI-EGFR PEPTIDES, THE LABORATORY OF ALLISON WALKER (SPONSOR OF THIS APPLICATION) IS PARTNERING WITH THE LABORATORY OF JENS MEILER (CO-SPONSOR OF THIS AP- PLICATION) AND LEVERAGING EXTANT COLLABORATIONS WITH PEPTIDE PHAGE DISPLAY EXPERT DR. CHRISTINA LAMERS AND COL- ORECTAL CANCER EXPERT DR. BHUMINDER SINGH. THE MEILER LABORATORY WILL INTEGRATE STATE-OF-THE-ART PROTEIN MODELING AND PEPTIDE DESIGN METHODS TO GENERATE LEAD ANTI-EGFR PEPTIDE CANDIDATES. THE WALKER LABORATORY WILL COLLAB- ORATE WITH THE LAMERS LABORATORY TO SCREEN LANTHIPEPTIDES, PEPTIDES WITH POST-TRANSLATIONALLY ADDED LANTHIONINE RING SIDECHAIN CONJUGATIONS, USING PHAGE DISPLAY TO IDENTIFY EGFR BINDING PEPTIDES. LANTHIPEPTIDES HAVE FOS- TERED INTERSET DUE TO THEIR FREQUENTLY OBSERVED ANTIBIOTIC, ANTITUMOR, AND ANTIFUNGAL ACTIVITY. ALL GENERATED PEPTIDES WILL BE TESTED FOR ACTIVITY IN THE SINGH LABORATORY. THE CENTRAL OBJECTIVES OF THIS PROPOSAL ARE TO PRODUCE NOVEL ANTI- EGFR PEPTIDES WITH THERAPEUTIC APPLICATIONS AND TO DEVELOP NEW ALGORITHMS TO INCREASE THE SCOPE OF CURRENTLY DESIGNABLE PEPTIDES. IN SPECIFIC AIM I, I USE EXISTING PROTEIN DESIGN AND SCREENING TECHNIQUES INCLUDING COM- PUTATIONAL PEPTIDE MACROCYCLE DESIGN AND PHAGE DISPLAY WITH LANTHIPEPTIDES TO DESIGN AND SCREEN ANTI-EGFR PEPTIDES. IN SPECIFIC AIM II, I DEVELOP METHODOLOGY FOR MODELING AND ENGINEERING RIPPS TO ENSURE ACCURATE MODELING OF SIDECHAIN CONJUGATIONS AND TO ENABLE INCORPORATION OF MULTIPLE POST-TRANSLATIONAL MODIFICATIONS INTO A SINGLE PEPTIDE. AS THE METHODS IN AIM II BECOME AVAILABLE, THEY WILL BE INTEGRATED INTO AIM I TO MODEL AND OPTIMIZE IDENTIFIED ANTI-EGFR LANTHIPEPTIDES. HENCE, THESE AIMS ARE DESIGNED TO BE HIGHLY COMPLEMENTARY, YET INDEPENDENT, AND WILL FACILITATE THE RAPID DEVELOPMENT OF THERAPEUTIC PEPTIDES.