The overall goal of this preclinical research program is to develop and evaluate the efficacy of targeted alpha therapy (TAT) using an alpha emitting radiolabeled peptide antagonist which targets the bombesin receptor (BB2r) expressed in human prostate cancer. The research program has four specific technical objectives: ? Synthesis & Validation of 212Pb-RM2: The goals of this objective are to establish and optimize methods for synthesizing 212Pb-RM2 in high yield and purity starting with 212Pb obtained from commercially available 224Ra/212Pb radionuclide generators. Utilizing automated radiochemistry technology, routine SOP?s will be developed for the efficient production of clinical grade 212Pb-RM2. This will also entail developing procedures for assessing the quality control to assure that the final product meets FDA requirements for pH, sterility, and bacterial endotoxins. ? Evaluate Efficacy of 212Pb-RM2 In Vitro: The utility of 212Pb-RM2 will be assessed across a panel of human PC cell lines representing the spectrum of androgen dependence/independence as well as a panel of chemotherapy resistant cell lines that are resistant to docetaxel, enzalutamide, and abiraterone. Several chemotherapy resistant cell lines will be created during the course of this study. The effects of TAT on each cell line will be evaluated by assessing cytotoxicity, clonogenicity, DNA damage & repair, apoptosis, cell cycle, and protein expression of the targeted receptor, (BB2r), the androgen receptor (AR), and the most prevalent androgen receptor splice variant in PC,(ARV7). ? Evaluate Efficacy of 212Pb-RM2 In Vivo: Initially, the in vivo stability of 212Pb-RM2 will be assessed followed by determination of individual organ, tissue, and tumor radiation dosimetry based on 212Pb-RM2 pharmacokinetic data obtained using prostate cancer xenograft models. The maximum tolerated dose (MTD) of 212Pb-RM2 will be determined prior to performance of therapeutic efficacy evaluation. Employing a series of CRPC xenograft models (flank, tibial, and systemic), the efficacy of 212Pb-RM2 in controlling and reducing focal and systemic PC growth will be evaluated. Concurrent PET imaging using 68Ga-RM2 will be performed to assess BB2r expression concurrent with BB2r targeted treatment to validate the imaging biomarker as an accurate measure of treatment efficacy. ? Perform FDA IND Enabling Studies: Data from these studies will be used to prepare a physician sponsored IND for submission to the FDA of the TAT agent, 212Pb-RM2. 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, obtaining commercial single species toxicology evaluation data, development and refinement of a standard operating procedure for the routine automated clinical preparation of 212Pb-RM2, and performance of required preparative product scale-up runs to demonstrate that 212Pb-RM2 can be prepared in quantities and purity necessary to meet expected clinical demands.
Prostate cancer remains the third leading cause of male death and the most commonly diagnosed cancer among men in the United States. The proposed project will explore developing a novel form of a systemically administered radioactive drug therapy called targeted alpha therapy (TAT) to deliver effective prostate tumor targeted radiation therapy. TAT has the potential to be used in patients at all stages of disease, independent of androgen status or chemotherapy resistance status; thereby, offering a new paradigm in treatment for those patients who have progressive disease that is not controlled by currently available treatment options.
