This renewal application builds on themes of our previous studies mechanistically defining &therapeutically targeting pathways driving castration-resistant prostate cancer (CRPC) progression. CRPC is attributed to reactivation of the androgen-receptor (AR) axis along with stress-activated cytoprotective chaperone and growth factor signaling pathways. With new potent AR pathway inhibitors like MDV3100 and abiraterone (ABI) approved in CRPC, emergence of resistance to these agents represents the next major clinical challenge. Recently, we identified activation of the Semaphorin 30 (SEMA3C) signaling pathway in CRPC and post-MDV3100 recurrent tumors. SEMA3C is a secreted growth factor associated with cancer metastasis and chemoresistance that we found associated with PTEN loss, clusterin over-expression, and regulation of AR protein levels and transcriptional activity. These findings link SEMA3C with PTEN loss and increased AKT &AR activity, 2 key pathways driving CRPC and MDV3100 treatment resistance. SEMA3C enhances PCa cell survival under castrate conditions, and we have developed 2 novel SEMA3C inhibitors that delay CRPC progression. Our overall aim is to define mechanisms of SEMA3C in promoting resistance to castration and MDV3100 therapies, and to develop preclinical mechanistic and anti-cancer activity data to support a first-in-man clinical trial of a novel SEMA3C inhibitor in CRPC.
Aim 1 will define changes in SEMA3C signaling pathway in CRPC and after treatment with MDV3100 or ABI in LNCaP or LUCaP35CR models, respectively.
Aim 2 will characterize the functional role of SEMA3C on MDV3100 treatment resistance and define cross-talk between SEMA3C signaling and AR activity in MDV3100 sensitive vs refractory CRPC.
Aim 3 will test in vivo activity of novel SEMA3C fusion protein and antisense inhibitors in preclinical models of CRPC as A) monotherapy;and B) in combination with i) MDV3100;ii) docetaxel, and iii) inhibitors of AR chaperone proteins Hsp27 (OGX-427), or Hsp90 (PF-04928473). The bench to bedside Aim 4 will conduct a Phase l/ll clinical trial of SEMA3C sema domain (SD) Fc fusion protein inhibitor in men with CRPC and examine the utility of serum SEMA3C as a clinical biomarker.

Public Health Relevance

We postulate that under selective pressures of castration and AR pathway inhibitor treatment, stress-activated networks increase SEMA3C activity to activate key RTK (c-Met, EGFR/ERBB2) and downstream (src, AKT, MAPK) pathways, including cross-talk and activation of the AR. Since these are important drivers of resistance to AR pathway inhibition, targeting SEMA3C has a strong biologic rationale, and is of clinical relevance since MDV3100 and ABI will shape CRPC treatment landscapes for the next decade.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA097186-12
Application #
8933575
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (M1))
Program Officer
Hruszkewycz, Andrew M
Project Start
2002-09-19
Project End
2018-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
12
Fiscal Year
2014
Total Cost
$200,715
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Viswanathan, Srinivas R; Ha, Gavin; Hoff, Andreas M et al. (2018) Structural Alterations Driving Castration-Resistant Prostate Cancer Revealed by Linked-Read Genome Sequencing. Cell 174:433-447.e19
Armenia, Joshua; Wankowicz, Stephanie A M; Liu, David et al. (2018) The long tail of oncogenic drivers in prostate cancer. Nat Genet 50:645-651
Plymate, Stephen R; Sharp, Adam; de Bono, Johann S (2018) Nuclear Circulating Tumor Cell Androgen Receptor Variant 7 in Castration-Resistant Prostate Cancer: The Devil Is in the Detail. JAMA Oncol 4:1187-1188
Russo, Joshua W; Gao, Ce; Bhasin, Swati S et al. (2018) Downregulation of Dipeptidyl Peptidase 4 Accelerates Progression to Castration-Resistant Prostate Cancer. Cancer Res 78:6354-6362
Sowalsky, Adam G; Ye, Huihui; Bhasin, Manoj et al. (2018) Neoadjuvant-Intensive Androgen Deprivation Therapy Selects for Prostate Tumor Foci with Diverse Subclonal Oncogenic Alterations. Cancer Res 78:4716-4730
Zhu, Yezi; Sharp, Adam; Anderson, Courtney M et al. (2018) Novel Junction-specific and Quantifiable In Situ Detection of AR-V7 and its Clinical Correlates in Metastatic Castration-resistant Prostate Cancer. Eur Urol 73:727-735
Chalfin, Heather J; Glavaris, Stephanie A; Malihi, Paymaneh D et al. (2018) Prostate Cancer Disseminated Tumor Cells are Rarely Detected in the Bone Marrow of Patients with Localized Disease Undergoing Radical Prostatectomy across Multiple Rare Cell Detection Platforms. J Urol 199:1494-1501
Inoue, Lurdes Y T; Lin, Daniel W; Newcomb, Lisa F et al. (2018) Comparative Analysis of Biopsy Upgrading in Four Prostate Cancer Active Surveillance Cohorts. Ann Intern Med 168:1-9
Cheng, Heather H; Plets, Melissa; Li, Hongli et al. (2018) Circulating microRNAs and treatment response in the Phase II SWOG S0925 study for patients with new metastatic hormone-sensitive prostate cancer. Prostate 78:121-127
Levesque, Christine; Nelson, Peter S (2018) Cellular Constituents of the Prostate Stroma: Key Contributors to Prostate Cancer Progression and Therapy Resistance. Cold Spring Harb Perspect Med 8:

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