Project Grant R01CA294647

PROAGIO IN PANCREATIC CANCER - SUMMARY/ABSTRACT CANCER ASSOCIATED FIBROBLASTS AND PANCREATIC STELLATE CELLS (PSC/CAF) AND ABNORMAL TUMOR BLOOD VESSELS ARE TWO MAJOR FACTORS THAT CONTRIBUTE TO TREATMENT FAILURE. PSC/CAF CONTRIBUTE TO THE COLLAGEN-RICH EXTRACELLULAR MATRIX (ECM) WHICH IMPAIRS DRUG DELIVERY, PROMOTES CANCER CELL SURVIVAL AND CONTRIBUTES TO AN IMMUNOSUPPRESSIVE ENVIRONMENT. CAF HAVE BEEN SHOWN TO HAVE A SIMILAR ROLE IN SUPPORTING METASTATIC SITES OF DISEASE IN PDAC. CURRENTLY, NO AGENT IS AVAILABLE THAT CAN SIMULTANEOUSLY SELECTIVELY REDUCE ACTIVATED PSC/CAF AND NORMALIZE ANGIOGENESIS. BOTH ACTIVATED PSC/CAF AND ANGIOGENIC ENDOTHELIAL CELLS SELECTIVELY EXPRESS HIGH LEVELS OF INTEGRIN V3. THERE IS NO EXPRESSION OF INTEGRIN V3 IN NORMAL TISSUE. WE DEVELOPED PROAGIO, AN INNOVATIVE PROTEIN DRUG WITH A DISTINCT MECHANISM OF ACTION FROM CURRENTLY AVAILABLE INTEGRIN-TARGETING AGENTS IN TARGETING INTEGRIN V3 AT A NOVEL NON-LIGAND BINDING SITE. PROAGIO INDUCES APOPTOSIS OF INTEGRIN V3 EXPRESSING PSC/CAF AND ANGIOGENIC ENDOTHELIAL CELLS WITH A HIGH EFFICIENCY BY RECRUITING AND ACTIVATING CASPASE-8 AT THE CYTOPLASMIC DOMAIN OF. OUR PRELIMINARY DATA SHOWS PROAGIO HAS ANTI-TUMOR ACTIVITY IN MULTIPLE PDAC MODELS AND ENHANCES THE EFFECT OF GEMCITABINE. HISTOLOGIC ANALYSES SHOWED PROAGIO DECREASED COLLAGEN AND DEPLETED PSC/CAF IN TUMORS. IN A PHASE I CLINICAL TRIAL, SINGLE AGENT PROAGIO HAS DEMONSTRATED EXCELLENT SAFETY PROFILE, PROMISING PHARMACOKINETIC PROFILE AND ANTI-TUMOR ACTIVITY IN PATIENTS WITH PDAC. WE HYPOTHESIZE THAT, BY INDUCING APOPTOSIS OF INTEGRIN V3 EXPRESSING CELLS, PROAGIO WILL SPECIFICALLY DEPLETE BOTH ANGIOGENIC ENDOTHELIAL CELLS AND ACTIVATED PSC/CAF LEADING TO INHIBITION OF COLLAGEN DEPOSITION IN PDAC TUMORS, WHICH WILL ENHANCE DRUG DELIVERY AND INCREASE THE SENSITIVITY OF PDAC TO ESTABLISHED THERAPIES. THIS PROJECT HAS THREE SPECIFIC AIMS: 1) TO CHARACTERIZE THE TOXICITY AND DETERMINE THE RECOMMENDED PHASE II DOSE OF PROAGIO IN COMBINATION WITH GEMCITABINE AND NAB-PACLITAXEL. WE WILL CONDUCT A PHASE I CLINICAL TRIAL OF PROAGIO IN METASTATIC PDAC PATIENTS WITH NO PRIOR THERAPY WITH GEMCITABINE AND NAB-PACLITAXEL. THE GOAL IS TO DETERMINE THE RECOMMENDED PHASE II DOSE, EVALUATE PHARMACOKINETICS OF PROAGIO, AND CHARACTERIZE TOXICITY. A SECONDARY OBJECTIVE IS TO OBTAIN PRELIMINARY ACTIVITY DATA (OVERALL RESPONSE RATE) FOR PROAGIO WITH GEMCITABINE AND NAB- PACLITAXEL IN PDAC. 2) TO ANALYZE THE EFFECT OF PROAGIO IN PATIENT TUMORS AND VALIDATE THE MECHANISM OF DRUG ACTION. PDAC PATIENTS ENROLLED IN THE EXPANSION PHASE WILL UNDERGO PAIRED PRE- AND POST-TREATMENT BIOPSIES. WE WILL VALIDATE MECHANISM OF PROAGIO ACTION BY ASSESSING CHANGES IN INTRATUMORAL COLLAGEN, BLOOD VESSELS, PSC/CAF SUBTYPES, IMMUNE CELLS, AND AVB3 EXPRESSION IN THESE PATIENT SAMPLES. SAMPLES WILL BE ANALYZED VIA MULTIPLEX IMMUNOFLUORESCENCE WITH SPATIAL QUANTIFICATION AND SINGLE CELL RNA SEQUENCING. 3) TO EVALUATE THE PHARMACODYNAMICS EFFECTS OF PROAGIO ON ANGIOGENESIS AND TUMOR PERFUSION. THE PERFUSION CHANGES IN TUMORS AFTER TREATMENT WITH PROAGIO PLUS CHEMOTHERAPY WILL BE MEASURED USING QUANTITATIVE DCE-MRI IN ALL PATIENTS.