Metastatic castration resistant prostate cancer (CRPC; PCa) accounts for ~90% of PCa deaths and is associated with skeletal metastases. CRPC affects patients differently, making this disease difficult for physicians to provide standardized treatments with similar outcomes. Docetaxel can prolong the overall survival in patients with metastatic CRPC, but current therapies do not provide a cure. Docetaxel non- selectively targets rapidly dividing cell populations, but also causes systemic toxicities. CRPC cells have a relative slow growth rate. Hence, it is crucial to develop therapies to target less-proliferative, metastatic CRPC cells along with standard chemotherapies. To address these issues, investigators at Morehouse School of Medicine and JYANT Technologies, Inc. have identified a critical pathway that controls PCa cell growth, metastasis, and docetaxel response rates ? the CCL25:CCR9 axis. Our recently published and exciting supportive data show that i) CCR9 is highly expressed by PCa cells and tumors and mediates PCa progression, ii) CCL25, the sole ligand for CCR9, is elevated in prostate tumors and PCa patient serum, iii) bone marrow stromal cells of tumor-bearing mice significantly produce CCL25, and iv) blockade of the CCL25- CCR9 axis sensitizes PCa cells to docetaxel. Importantly, we show that our murine anti-human CCL25 antibody candidate shrinks CRPC xenografts established in femurs of SCID mice. In consideration of these findings, JYANT Technologies seeks to develop a humanized anti-human CCL25 monoclonal antibody (CCL25 HuMAB) for the treatment of CRPC. To complete these objectives, we will use clinically relevant mouse models of osteolytic and osteoblastic CRPC as well as docetaxel-resistant xenografts to carryout the following aims:
Aim One will ascertain the immunogenicity, using nave B6 mice, and the PK/PD profile of CCL25 HuMAB, in SCID mice bearing luciferase-expressing osteolytic (PC3-luc) and osteoblastic (C4-2b-luc) xenografts in femurs.
Aim Two will determine the systemic and immune toxicity as well as the efficacy of CCL25 HuMAB to inhibit prostate tumor growth and docetaxel-resistance in bone, using SCID mice challenged in femurs with castration resistant (PC3-luc and C4-2b-luc) and/or docetaxel-resistant (PC3R-luc and C4-2bR-luc) PCa cell lines.
To date, there is no cure for metastatic castration resistant prostate cancer (CRPC; PCa); chemoresistance, adverse drug events, and variable response rates hinder the use of many drugs (e.g., docetaxel) to treat PCa. Using clinically relevant metastatic CRPC models, this study tests the utility of targeting the CCL25:CCR9 axis.
