Project Grant R44CA275590

THERANOSTIC FOR GASTRIC CANCER - PROJECT SUMMARY THE OVERARCHING OBJECTIVE OF THIS APPLICATION IS TO DEVELOP AN IMAGE-GUIDED THERAPY PARADIGM FOR IMPROVING THE MANAGEMENT OF GASTRIC CANCER (GCA) BY TARGETING FIBRIN IN THE TUMOR MICROENVIRONMENT. GCA IS THE FIFTH MOST COMMON CANCER AND THE THIRD LEADING CAUSE OF CANCER-RELATED DEATH WORLDWIDE. DESPITE PROGRESS IN MANAGEMENT OF ADVANCED GCA, THE PROGNOSIS REMAINS POOR WITH A MEDIAN SURVIVAL OF 12-14 MONTHS EVEN WITH COMBINATION CHEMOTHERAPY. THEREFORE, NOVEL THERAPEUTIC APPROACHES ARE OF UTMOST NEED TO IMPROVE CLINICAL OUTCOMES IN PATIENTS WITH ADVANCED DISEASE. THE CENTRAL HYPOTHESIS IS THAT HIGH ENERGY BETA PARTICLE RADIOTHERAPY TARGETED TO THE FIBRIN IN TUMOR MICROENVIRONMENT IMPROVES THE TREATMENT OUTCOME OF GCA. PRIMARY AND METASTATIC GASTRIC TUMORS HAVE LEAKY VASCULATURE WHICH RESULTS IN EXTRAVASATION OF BLOOD PROTEINS AND ABUNDANT DEPOSITION OF FIBRIN IN THE EXTRACELLULAR MATRIX (ECM). GIVEN THAT FIBRIN IS ONLY PRESENT IN THE TUMORS AND THROMBI, BUT NOT IN HEALTHY TISSUES, WE POSIT THAT FIBRIN COULD BE USED AS A THERAPEUTIC TARGET, REPRESENTING A LARGE DEPOT IN THE ECM FOR A HIGH ENERGY BETA PARTICLE TO KILL SURROUNDING TUMOR CELLS. COLLAGEN MEDICAL HAS DEVELOPED AND LICENSED PATENTED FIBRIN-SPECIFIC SHORT CYCLIC PEPTIDES AND DERIVATIZED THEM FOR IMAGING AND THERAPY. WE HAVE SHOWN THAT FIBRIN- TARGETED POSITRON EMISSION TOMOGRAPHY (PET) CAN DETECT THROMBI IN PATIENTS USING A COPPER-64 MODIFIED PEPTIDE, YET PROVIDES MINIMAL BACKGROUND PET SIGNAL IN TISSUES WHERE GCA METASTASIZES. OUR PRELIMINARY DATA SHOWS THAT THE FIBRIN-SPECIFIC PROBE, 64CU-CM500, DETECTS FIBRIN IN A MOUSE MODEL OF GCA. WE HAVE ALSO MODIFIED THE PEPTIDE TO INCORPORATE THE HIGH ENERGY BETA EMITTER YTTRIUM-90 FOR TARGETED THERAPY. BUILDING UPON THIS PRELIMINARY DATA, IN THIS FASTTRACK PROJECT WE PROPOSE TO ESTABLISH A THERANOSTIC APPROACH TO TREATING GCA BY USING 64CU-CM500 PET TO IDENTIFY PATIENTS WITH FIBRIN-RICH GASTRIC TUMORS AND THEN TREATING THEM WITH FIBRIN-TARGETED 90Y-CM600 BETA EMITTING RADIOTHERAPY. IN PHASE 1 WE WILL EVALUATE THE EXTENT OF FIBRIN DEPOSITION IN A WIDE RANGE OF HUMAN GCA TISSUE ARRAYS TO ESTIMATE THE PREVALENCE OF FIBRIN IN GCA. WE WILL ALSO DEMONSTRATE THE SPECIFICITY OF OUR COMPOUNDS FOR BOTH DETECTING TUMOR FIBRIN AND FOR TARGETING FIBRIN FOR RADIOTHERAPY. IN PHASE 2 WE WILL EVALUATE THE KINETICS OF 64CU-CM500 PET IN TUMORS IN GCA PATIENTS AND ESTIMATE HOW LONG THE PROBE REMAINS BOUND TO THE TUMOR. WE WILL ALSO DEMONSTRATE THE EFFICACY OF 90Y-CM600 RADIOTHERAPY IN MULTIPLE MOUSE MODELS OF GCA AND OPTIMIZE THE TREATMENT REGIMEN. LASTLY, TO ENABLE CLINICAL TRANSLATION OF THIS THERAPEUTIC, WE WILL SYNTHESIZE THE CM600 PRECURSOR UNDER CGMP CONDITIONS, VALIDATE THE 90Y RADIOLABELING METHOD, AND PERFORM IND ENABLING GLP TOXICITY, BIODISTRIBUTION AND DOSIMETRY STUDIES IN RODENTS.