Novel multivalent PSMA-targeted taxane-conjugates for bone metastases in prostate cancer

Project Title: “Novel multivalent PSMA-targeted taxane-conjugates for bone metastases in prostate cancer.” PA-24-245. PI: Sang Van Abstract Prostate cancer (PCa) is one of the most diagnosed cancers in the world and one of the leading causes of cancer-related deaths worldwide. The major cause of death from prostate cancer is not from the primary prostate cancer but from metastasis to the bone. Recent studies revealed that 90% of men who had died with metastases of PCa were diagnosed with bone metastases. In PCa patients with bone metastases, the 5-year survival rate was 33%. Thus, there is an urgent need for new therapeutic PCa options that include treatment of PCa in the bone. Docetaxel and paclitaxel are taxane chemotherapies used in the standard-of-care for many cancers, including metastatic PCa. However, they are highly insoluble in aqueous solutions, and their efficacy is limited by toxicity since they can cross cell membranes and enter any cell. Recent studies from other groups and our group have shown that PSMA-targeting urea-glutamic acid (DUPA) molecules can selectively bind to bone metastases and primary tumors in prostate cancer. In this Phase I small business innovation research (SBIR) grant, we propose to synthesize PSMA-targeted taxane drug-conjugates (MDCs) containing a single taxane payload with multiple DUPA targeting molecules. We hypothesize that conjugating taxanes with multiple DUPA targeting molecules will not only increase their water solubility but also allow them to selectively target PCa cells expressing high levels of PSMA and tackle both bone metastases and primary tumors. Paramita Therapeutics has a proprietary method that facilitates the rapid synthesis of the MDCs with high purity using homogenous synthetic chemistry reactions. The proposed studies include synthesizing the MDCs (Paramita) and evaluating them for their selectivity and cytotoxicity in vitro (Bui Lab). Finally, a lead MDC will be selected and further evaluated in a PCa PDX model which faithfully recapitulates bone metastatic PCa (Jamieson Lab). The results from this Phase I project will confirm that MDCs can be synthesized and can target both bone metastases and primary tumors in prostate cancer and lead to a Phase II SBIR project for scale-up, pharmacokinetic/phamacodynamic studies, and expansion of the technology to include two payloads to reduce resistance.