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 re-activation 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 3C (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 MDVS100 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 MDVS100 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 MDVS100 or ABI in LNCaP or LUCaP35CR models, respectively.
Aim 2 will characterize the functional role of SEMA3C on MDVS100 treatment resistance and define cross-talk between SEMA3C signaling and AR activity in MDVS100 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) MDVS100;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/II clinical trial of SEMA3C soma 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 MDVS100 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 #
2P50CA097186-11A1
Application #
8555013
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (M1))
Project Start
2002-09-19
Project End
2018-08-31
Budget Start
2013-09-17
Budget End
2014-08-31
Support Year
11
Fiscal Year
2013
Total Cost
$190,850
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Zhang, Ailin; Zhang, Jiawei; Plymate, Stephen et al. (2016) Classical and Non-Classical Roles for Pre-Receptor Control of DHT Metabolism in Prostate Cancer Progression. Horm Cancer 7:104-13
Uo, T; Dvinge, H; Sprenger, C C et al. (2016) Systematic and functional characterization of novel androgen receptor variants arising from alternative splicing in the ligand-binding domain. Oncogene :
Faltermeier, Claire M; Drake, Justin M; Clark, Peter M et al. (2016) Functional screen identifies kinases driving prostate cancer visceral and bone metastasis. Proc Natl Acad Sci U S A 113:E172-81
Lam, Hung-Ming; McMullin, Ryan; Nguyen, Holly et al. (2016) Characterization of an abiraterone ultraresponsive phenotype in castration-resistant prostate cancer patient-derived xenografts. Clin Cancer Res :
Saranchova, Iryna; Han, Jeffrey; Huang, Hui et al. (2016) Discovery of a Metastatic Immune Escape Mechanism Initiated by the Loss of Expression of the Tumour Biomarker Interleukin-33. Sci Rep 6:30555
Qu, Xiaoyu; Jeldres, Claudio; Glaskova, Lena et al. (2016) Identification of Combinatorial Genomic Abnormalities Associated with Prostate Cancer Early Recurrence. J Mol Diagn 18:215-24
Gulati, Roman; Cheng, Heather H; Lange, Paul H et al. (2016) Screening men at increased risk for prostate cancer diagnosis: Model estimates of benefits and harms. Cancer Epidemiol Biomarkers Prev :
Shui, Irene M; Kolb, Suzanne; Hanson, Christi et al. (2016) Trichomonas vaginalis infection and risk of advanced prostate cancer. Prostate 76:620-3
Coleman, Daniel J; Van Hook, Kathryn; King, Carly J et al. (2016) Cellular androgen content influences enzalutamide agonism of F877L mutant androgen receptor. Oncotarget 7:40690-40703
Pritchard, Colin C; Mateo, Joaquin; Walsh, Michael F et al. (2016) Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med 375:443-53

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