Project Grant F31CA309960

LEVERAGING PIGR-MEDIATED ENDOCYTOSIS OF DIMERIC IGA IN PDAC TREATMENT - TITLE: LEVERAGING PIGR-MEDIATED ENDOCYTOSIS OF DIMERIC IGA IN PDAC TREATMENT. PANCREATIC CANCER IS THE THIRD-LEADING CAUSE OF CANCER-RELATED MORTALITY AND IS PROJECTED TO BECOME THE SECOND LEADING CAUSE BY 2030. OF THESE CASES, 90% ARE CLASSIFIED AS PANCREATIC ADENOCARCINOMA (PDAC). LATE-STAGE DIAGNOSIS AND LIMITED EFFICACY OF CURRENT TREATMENTS CONTRIBUTE TO A DISMAL 5-YEAR SURVIVAL RATE OF JUST 13%. NOVEL THERAPEUTIC APPROACHES ARE URGENTLY NEEDED TO TARGET ONCOGENIC SIGNALING THAT DRIVES TUMOR PROLIFERATION AND SURVIVAL. ONCOGENIC KRAS MUTATIONS ARE FOUND IN 90-95% OF PANCREATIC CANCER PATIENTS, WITH THE MOST COMMON BEING KRASG12D. THE INTRODUCTION OF MUTANT KRASG12D-SPECIFIC SMALL MOLECULE INHIBITORS (SMIS) SUCH AS MRTX1133 HAS DEMONSTRATED SIGNIFICANT PRE-CLINICAL ANTI-TUMOR ACTIVITY IN KRASG12D-DRIVEN CANCERS BUT HAS FAILED TO ACHIEVE SIGNIFICANT CLINICAL RESPONSES. THIS IS IN PART DUE TO THE SHORT HALF-LIFE OF CURRENT KRASG12D SMIS IN PATIENTS. ANTIBODY-MEDIATED TARGETING OF MUTANT KRAS USING ENGINEERED ANTI-KRASG12D DIMERIC IGAS (K-IGAS) SHOWS PROMISING PRE-CLINICAL EFFICACY IN OVARIAN AND LUNG CANCER. UNLIKE MUTANT KRAS INHIBITOR MRTX1133, WHICH HAS A HALF-LIFE OF APPROXIMATELY SIX HOURS IN PATIENTS, DIMERIC IGAS CAN CIRCULATE IN PATIENTS FOR UP TO SIX DAYS, ALLOWING FOR GREATER DRUG-TARGET INTERACTION AND SUSTAINED TARGET NEUTRALIZATION. K-IGAS CAN TARGET BOTH GTP AND GDP CONFORMATIONS OF MUTANT KRAS INTRACELLULARLY BY BINDING TO THE POLYMERIC IMMUNOGLOBULIN RECEPTOR (PIGR), A TRANSMEMBRANE PROTEIN UNIVERSALLY EXPRESSED IN MUCOSAL EPITHELIAL CELLS BUT ALSO ABERRANTLY EXPRESSED IN SEVERAL TUMORS, INCLUDING PDAC. PIGR-IGA BINDING GENERALLY TRIGGERS TRANSCYTOSIS OF DIMERIC IGAS IN MUCOSAL EPITHELIAL CELLS. PIGR EXPRESSION ON PDAC TUMOR CELLS OPENS THE POSSIBILITY FOR NOT JUST FOR TARGETING MUTANT KRAS, BUT OTHER INTRACELLULAR ONCOPROTEINS VIA PIGR-MEDIATED ENDOCYTOSIS OF TARGETING IGAS. HOWEVER, PIGR EXPRESSION WITHIN PDAC TUMORS IS HETEROGENEOUS, POTENTIALLY LIMITING THE EFFICACY OF PIGR-DIRECTED THERAPEUTICS. THEREFORE, METHODS TO ELEVATE PIGR EXPRESSION ON PDAC TUMOR CELLS ARE NEEDED TO ENHANCE THE EFFICACY OF THESE THERAPIES. THIS PROPOSAL AIMS TO INVESTIGATE PIGR-DIRECTED THERAPEUTICS FOR PANCREATIC CANCER. AIM 1 WILL CHARACTERIZE THE NEUTRALIZATION OF MUTANT KRAS BY K-IGAS IN VITRO AND EVALUATE THE EFFICACY OF K-IGA TARGETING MUTANT KRAS UTILIZING ORTHOTOPIC MODELS OF PDAC. AIM 2 WILL ESTABLISH PUTATIVE STRATEGIES TO MODULATE PIGR LEVELS IN VITRO AND IN VIVO BY INDUCING PRO-INFLAMMATORY SIGNALING AND ASSESS HOW THESE STRATEGIES INFLUENCE THE ANTI-TUMOR ACTIVITY OF K- IGA TREATMENT IN PDAC TUMOR-BEARING MICE. THIS PROJECT WILL EVALUATE A NEW METHOD OF KRAS INHIBITION IN PANCREATIC CANCER WITH THE LONG-TERM GOAL TO IMPROVE OUR CURRENT TREATMENT OPTIONS FOR PDAC PATIENTS.