The overall goal of this preclinical research program is to develop and evaluate the efficacy of a novel multi-modal tumor treatment regimen on overall survival in models of metastatic castration resistant prostate cancer (mCRPC). The research program has four specific technical objectives: Determine the maximum effective dose (MED) and therapeutic efficacy of radiolabeled 177Lu-BB2r antagonists when used as single agent therapy in xenograft models of CRPC. This will be accomplished by performing a combination of in vitro cell viability and clonogenic assays combined with in vivo pharmacokinetic analysis and escalating dose trials of a 177Lu-BB2r antagonist in xenograft models of CRPC. Individual internal organ radiation dosimetry estimates will be determined as well as a minimum effective dose (MED) with the primary goal of determining an optimum radiotherapeutic dose for treatment of CRPC. Evaluate in vitro / in vivo synergism and efficacy of multi-modal CRPC targeted radiotherapy combined with taxane chemotherapy (Docetaxel vs. Cabazitaxel) in CRPC cell lines. This will be accomplished using in vitro cell viability and clonogenic assays to assess cytotoxicity and synergism of the drug combinations (Docetaxel/177Lu-BB2r antagonist vs. Cabazitaxel/177Lu-BB2r antagonist) to evaluate CRPC cell responsiveness to treatment. In vivo synergism and efficacy of 177Lu-BB2r targeted radiotherapy combined with taxane chemotherapy (Docetaxel vs. Cabazitaxel) will be assessed using flank, tibial, and metastatic xenograft models of CRPC to evaluate tumor response (soft tissue and bone metastases) and identify which radiotherapy/taxane combination has superior tumor control properties. We will also concurrently evaluate the utility of using molecular imaging of BB2r expression as an effective biomarker of disease presence and tumor status. Evaluate the in vitro /in vivo synergism and efficacy of multi-modal CRPC targeted radiotherapy combined with novel tyrosine kinase inhibitor therapy (Cabozantinib). This specific objective will be carried out similarly to the studes involving taxanes with the goal of utilizing the unique radiosensitizing properties as a result of MET receptor inhibition to control CRPC. The proposed studies will involve a combination of in vitro cell viability and clonogenic assays combined with in vivo pharmacokinetic analysis and combination preclinical therapeutic assessment utilizing flank, tibial, and metastatic CRPC xenograft models. Perform FDA IND enabling studies that will permit submission of a physician sponsored IND to the FDA of a 177Lu-BB2r antagonist. This objective will be carried out over the course of the funding period and will include obtaining commercially prepared cGMP product, determining internal organ radiation dosimetry, toxicology evaluation, development and refinement of a standard operating procedure for the routine clinical preparation of 177Lu-BB2r antagonist, and performance of required preparative product runs to demonstrate that the 177Lu-BB2r antagonist meets end product specifications for human use.
Prostate cancer remains the second leading cause of male death and the most commonly diagnosed cancer in men in developed nations. The proposed VA Merit project will explore improved methods to treat veterans with prostate cancer by combining a novel form of tumor targeted radiation therapy with conventional and novel chemotherapy agents. This new combination of therapies may have potential to treat both early and advanced prostate cancers by directly targeting the primary and metastatic cancer while offering the possibility of lowered patient toxicities as a result of using decreased amounts of chemotherapy.