The most common metastatic site for hormone refractory prostate cancer (HRPC; PCa) is bone. While docetaxel can prolong the overall survival in patients with metastatic HRPC, current treatments do not provide a cure. Further complicating the matter, HRPC is a disease that affects a variety of patients differently, which can be problematic for physicians to provide standardized treatments with similar outcomes. African Americans (AAs) with HRPC can experience significantly lower rates of overall survival, faster rates of tumor progression and poor responses to chemotherapy than compared to European Americans (EAs) with this disease. Unfortunately, the mechanisms behind these PCa health disparities have not been well studied. 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 (to bone), and docetaxel response rates - the CXCL13:CXCR5 axis. We previously reported the functional expression of CXCR5 by PCa cell lines and that CXCL13 (the only ligand for CXCR5) can mediate PCa cell growth, migration, invasion, and docetaxel resistance. In addition, we reported significantly higher CXCR5 expression by prostate tumors from patients with advance PCa, than compared to normal matched or benign disease tissues. Our exciting preliminary data show CXCR5 expression by prostate tumors resected from AA patients are significantly (as much as two-fold) higher than EAs with the same disease stage. Previously, we demonstrated serum CXCL13 levels are significantly higher in PCa patients and this ligand is secreted by bone marrow endothelium under conditions found during this disease. Finally, we show that our murine anti-human CXCL13 antibody both prevented and shrunk HRPC xenografts established in femurs of SCID mice. In consideration of these findings, JYANT Technologies seeks to develop a novel humanized anti-human CXCL13 monoclonal antibody (CXCL13 HuMAB) for the treatment of HRPC and to address the disparities in clinical and therapeutic outcomes with this disease. To complete these objectives, we will use clinically relevant mouse models of osteolytic and osteoblastic HRPC as well as docetaxel-resistant xenografts to carry out the following aims:
Aim One will ascertain the immunogenicity, using nave B6 mice, and the PK/PD profile of CXCL13 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 CXCL13 HuMAB to inhibit prostate tumor growth and docetaxel-resistance in bone, using SCID mice challenged in femurs with hormone refractory (PC3-luc and C4-2b-luc) and/or docetaxel-resistant (PC3R-luc and C4-2bR-luc) PCa cell lines.

Public Health Relevance

To date, there is no cure for metastatic HRPC; chemoresistance, toxicities, and variable response rates hinder the use of many drugs (e.g., docetaxel) to treat PCa. Using clinically relevant HRPC models, this study tests the utility of targeting the CXCL13:CXCR5 axis, which is highly elevated in AAs than compared to EAs with HRPC.

Agency
National Institute of Health (NIH)
Institute
National Institute on Minority Health and Health Disparities (NIMHD)
Type
Small Business Technology Transfer (STTR) Grants - Phase I (R41)
Project #
1R41MD010320-01
Application #
8998175
Study Section
Special Emphasis Panel (ZMD1-MLS (07))
Program Officer
Tabor, Derrick C
Project Start
2015-08-01
Project End
2016-07-31
Budget Start
2015-08-01
Budget End
2016-07-31
Support Year
1
Fiscal Year
2015
Total Cost
$315,320
Indirect Cost
Name
Jyant, Inc.
Department
Type
DUNS #
832442771
City
Marietta
State
GA
Country
United States
Zip Code
30008