Project Abstract Castrate resistant prostate cancer is a uniformly lethal disease and, although there have been a number of new therapeutic agents approved, there is still a large need for more effective treatments in this patient population. In this proposal, we will study a radioligand therapy (RLT) that targets the prostate specific membrane antigen (PSMA), a molecule that is expressed on the majority of prostate cancer cells. In multiple small studies, PSMA RLT has shown to have remarkable efficacy in heavily pretreated patients, with over 40% of patients having decreased PSA of over 50%. PSMA RLT relies on two basic premises: targeting the radiation to PSMA and the radiosensitivity of the tissue to the deposited radiation. First, we will understand how PSMA expression is regulated, allowing us to pharmacologically target cancer cells to increase their PSMA expression. Second, we will understand whether tumors respond because of intrinsic sensitivity to radiation or high doses of deposited radiation. This knowledge will be critical to determine if patients need higher expression of PSMA or increased tumor cell sensitivity in order to improve the response to this therapy. We will test treatments capable of increasing the sensitivity of tumors to radiation as well as potential therapies that can increase expression of PSMA. This work will be used to inform the development of a clinical trial that will involve PSMA RLT and a co-administered therapy to increase its already promising efficacy.