Castration resistant metastatic disease is the major cause of morbidity and mortality in men with advanced prostate cancer. The molecular mechanisms underlying metastasis and castration resistance are both varied and only partially defined. Novel targets and therapies directed against these targets are urgently needed to combat advanced prostate cancer. Likewise, rational combination therapies directed against multiple critical targets are urgently needed. We have recently identified and """"""""credentialed"""""""" N-cadherin as a novel target that contributes to and is required for both metastasis and castration resistance in prostate cancer. We have developed and validated in preclinical studies a murine monoclonal antibody that targets N-cadherin. This antibody is able to block metastasis, inhibit growth, and delay castration resistance of multiple prostate cancer cell lines and xenografts in vivo. Preliminary studies have uncovered the signal transduction pathways by which N-cadherin and N-cadherin-targeted antibody may act. These data support the novel hypothesis that N-cadherin is a significant molecular driver of castration resistant prostate cancer (CRPC) and a novel target for treatment of advanced prostate cancer. The overall goal of this grant proposal is to translate N-cadherin-targeted antibody therapy to the clinic. To do so, we will first examine the relationship of N-cadherin expression to the androgen receptor (AR) and determine whether N-cadherin is able to mediate resistance to AR-targeted therapies. Next, we will evaluate rational treatment combinations that might augment or synergize with antibodies that bind N-cadherin. These combinations will be based on an examination of N-cadherin signaling. Third, we will generate a lead human(ized) antibody capable of entering the clinic and evaluate its toxicity, pharmacokinetics and therapeutic activity in preclinical models. At the end of this project, we should know who to treat with N-cadherin antibodies, how to optimize targeting of this pathway, and have a lead biologic that can be manufactured and taken forward into the clinic.

Public Health Relevance

Prostate cancer is the second leading cause of cancer-related death in the U.S. Patients with metastatic castrate resistant disease need improved treatments, particularly those who fail the newest anti-androgens. This proposal explores the role of N-cadherin as a potential novel target for advanced prostate cancer and develops a candidate antibody therapeutic that can be advanced to the clinic to manage these patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA092131-12
Application #
8760358
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
12
Fiscal Year
2014
Total Cost
$253,601
Indirect Cost
$75,314
Name
University of California Los Angeles
Department
Type
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Mitra, Mithun; Lee, Ha Neul; Coller, Hilary A (2018) Determining Genome-wide Transcript Decay Rates in Proliferating and Quiescent Human Fibroblasts. J Vis Exp :
Zou, Yongkang; Qi, Zhi; Guo, Weilong et al. (2018) Cotargeting the Cell-Intrinsic and Microenvironment Pathways of Prostate Cancer by PI3K?/?/? Inhibitor BAY1082439. Mol Cancer Ther 17:2091-2099
Henning, Susanne M; Galet, Colette; Gollapudi, Kiran et al. (2018) Phase II prospective randomized trial of weight loss prior to radical prostatectomy. Prostate Cancer Prostatic Dis 21:212-220
Miller, Eric T; Salmasi, Amirali; Reiter, Robert E (2018) Anatomic and Molecular Imaging in Prostate Cancer. Cold Spring Harb Perspect Med 8:
Navarro, H├ęctor I; Goldstein, Andrew S (2018) HoxB13 mediates AR-V7 activity in prostate cancer. Proc Natl Acad Sci U S A 115:6528-6529
Mitra, Mithun; Ho, Linda D; Coller, Hilary A (2018) An In Vitro Model of Cellular Quiescence in Primary Human Dermal Fibroblasts. Methods Mol Biol 1686:27-47
Li, Jiayun; Speier, William; Ho, King Chung et al. (2018) An EM-based semi-supervised deep learning approach for semantic segmentation of histopathological images from radical prostatectomies. Comput Med Imaging Graph 69:125-133
Kang, Jung J; Reiter, Robert E; Kummer, Nicolas et al. (2018) Wrong to be Right: Margin Laterality is an Independent Predictor of Biochemical Failure After Radical Prostatectomy. Am J Clin Oncol 41:1-5
Lee, Ha Neul; Mitra, Mithun; Bosompra, Oye et al. (2018) RECK isoforms have opposing effects on cell migration. Mol Biol Cell 29:1825-1838
Aggarwal, Rahul; Huang, Jiaoti; Alumkal, Joshi J et al. (2018) Clinical and Genomic Characterization of Treatment-Emergent Small-Cell Neuroendocrine Prostate Cancer: A Multi-institutional Prospective Study. J Clin Oncol 36:2492-2503

Showing the most recent 10 out of 339 publications