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
Zumsteg, Zachary S; Chen, Zinan; Howard, Lauren E et al. (2017) Modified risk stratification grouping using standard clinical and biopsy information for patients undergoing radical prostatectomy: Results from SEARCH. Prostate 77:1592-1600
Freedland, Stephen J; Vidal, Adriana C; Howard, Lauren E et al. (2017) Race and risk of metastases and survival after radical prostatectomy: Results from the SEARCH database. Cancer 123:4199-4206
Tan, Nelly; Lin, Wei-Chan; Khoshnoodi, Pooria et al. (2017) In-Bore 3-T MR-guided Transrectal Targeted Prostate Biopsy: Prostate Imaging Reporting and Data System Version 2-based Diagnostic Performance for Detection of Prostate Cancer. Radiology 283:130-139
Klaassen, Zachary; Howard, Lauren E; de Hoedt, Amanda et al. (2017) Factors predicting skeletal-related events in patients with bone metastatic castration-resistant prostate cancer. Cancer 123:1528-1535
Minciacchi, Valentina R; Spinelli, Cristiana; Reis-Sobreiro, Mariana et al. (2017) MYC Mediates Large Oncosome-Induced Fibroblast Reprogramming in Prostate Cancer. Cancer Res 77:2306-2317
Flores, Aimee; Schell, John; Krall, Abigail S et al. (2017) Lactate dehydrogenase activity drives hair follicle stem cell activation. Nat Cell Biol 19:1017-1026
Wang, Piwen; Solorzano, Walter; Diaz, Tanya et al. (2017) Arctigenin inhibits prostate tumor cell growth in vitro and in vivo. Clin Nutr Exp 13:1-11
Priester, Alan; Natarajan, Shyam; Khoshnoodi, Pooria et al. (2017) Magnetic Resonance Imaging Underestimation of Prostate Cancer Geometry: Use of Patient Specific Molds to Correlate Images with Whole Mount Pathology. J Urol 197:320-326
Shenoy, T R; Boysen, G; Wang, M Y et al. (2017) CHD1 loss sensitizes prostate cancer to DNA damaging therapy by promoting error-prone double-strand break repair. Ann Oncol 28:1495-1507
Collins, Jeffrey; Waldmann, Christopher M; Drake, Christopher et al. (2017) Production of diverse PET probes with limited resources: 24 18F-labeled compounds prepared with a single radiosynthesizer. Proc Natl Acad Sci U S A 114:11309-11314

Showing the most recent 10 out of 315 publications