Project Grant R01CA291827

OPTIMIZING THERANOSTIC DOSIMETRY AND KIDNEY BIOMARKERS FOR ALPHA-EMITTER RADIOLIGAND THERAPY IN NEUROENDOCRINE TUMORS - SUMMARY THE SOMATOSTATIN SUBTYPE 2 RECEPTOR (SSTR2) IS EXPRESSED IN 80-100% OF NETS. SSTR2 TARGETED ALPHA-EMITTER RADIOLIGAND THERAPY (A-RLT) IS EMERGING AS AN EXCITING ALTERNATIVE TO BETA-EMITTER RADIOPHARMACEUTICALS DUE TO THE HIGHER LINEAR ENERGY TRANSFER AND DENSE IONIZATION TRACKS THAT RESULT IN ENHANCED FORMATION OF DOUBLE STRANDED DNA (DSDNA) DAMAGE WITH UP TO 80% TUMOR RESPONSE RATES IN EARLY CLINICAL STUDIES. HOWEVER, PRECLINICAL STUDIES SHOW THAT A-RLTS CAN CAUSE A DOSE DEPENDENT LATE NEPHROTOXICITY CHARACTERIZED BY LATE TUBULAR INJURY, FIBROSIS, AND INFLAMMATION. BUILDING ON RECENT BREAKTHROUGH FROM OUR GROUP WE WILL TEST THE OVERALL HYPOTHESIS THAT [212PB]PB-VMT-A-NET (212PB-VMT) TUMOR RESPONSES CAN BE MAXIMIZED THROUGH A TREATMENT SCHEME THAT INCORPORATES BIOMARKERS OF TUBULAR INJURY, DOSIMETRY, DOSE FRACTIONATION, AND A NEPHROPROTECTIVE SUPEROXIDE DISMUTASE MIMETIC TO MITIGATE NEPHROTOXICITY. IN AIM 1, WE WILL DEVELOP A DETAILED UNDERSTANDING OF THE ROLE OF SUPEROXIDE DISMUTATION IN TUBULAR DSDNA REPAIR FOLLOWING [212PB]PB-VMT-A-NET TREATMENT. IN AIM 2, WE WILL IDENTIFY [212PB]PB-VMT-A-NET DOSING REGIMENS TO ACHIEVE MAXIMAL TUMOR RESPONSES AND REDUCE NEPHROTOXICITY USING A SUPEROXIDE DISMUTASE MIMETIC. WE WILL INCORPORATE THE FOLLOWING INNOVATIVE METHODS: (1) A NOVEL A-RLT [203PB/212PB]PB-VMT-A-NET THERANOSTIC PAIR TARGETING SSTR2; (2) INNOVATIVE SSTR2 EXPRESSING TUMOR MODELS; (3) URINE BIOMARKERS FOR NON-INVASIVE DETECTION OF TUBULAR INJURY; (4) DSDNA INJURY/REPAIR TOOLS TO STUDY MECHANISM OF EARLY SUBCLINICAL TUBULAR DSDNA DAMAGE FOLLOWING A -RLT; AND (5) A NOVEL NEPHROTOXICITY MITIGATION STRATEGY BASED ON SUPEROXIDE SCAVENGING THAT SHOWS PROMISING TUMOR RESPONSE IMPROVEMENT TO EXTERNAL BEAM RADIATION. IF SUCCESSFUL, WE EXPECT THESE FINDINGS AND ADVANCES BE TRANSFERABLE TO A BROAD RANGE OF A-RLTS, NOT ONLY FOR PANCREATIC NETS AND NEUROBLASTOMA, BUT ALSO FOR PROSTATE, BREAST, MELANOMAS, AND OTHER DIFFICULT TO TREAT CANCERS AMENABLE TO A-RLT.