Our studies and those of others have shown that for many normal cell types, stressors that produce DNA damage (such as radiation and chemotherapy) induce a response that includes the robust secretion of specific extracellular effector proteins that we term the DNA Damage Secretory Program (DDSP). The DDSP includes a spectrum of autocrine and paracrine-acting proinflammatory cytokines, proteases and mitogenic growth factors that can promote tumor growth, inhibit cellular differentiation, and enhance angiogenesis. Further, constituents derived from damaged fibroblasts can also induce an epithelial to mesenchymal transition (EMT) in carcinoma cells accompanied by enhanced resistance to chemotherapeutics. Thus, the reaction of any tumor cell to genotoxic stress may depend on both intrinsic damage response capabilities and context dictated by the amalgam of cellular interactions in the tumor microenvironment (TME). In this proposal, we will conduct pre-clinical and clinical trials designed to test the hypothesis that inhibiting components of the microenvironment-derived DNA damage secretory program will enhance the responses of prostate tumors to commonly used genotoxic cancer treatments. We propose two aims:
Aim 1 : To evaluate the effects of inhibiting key regulators and effectors of the microenvironment DNA Damage Secretory Program on therapy responses in preclinical models of prostate cancer. Rationale: defining convergent and divergent influences of master regulators and specific effectors of the microenvironment DDSP will inform pharmacological strategies to maximally inhibit the DDSP, reduce side effects, and improve therapy responses.
Aim 2 : To conduct a Phase l-ll trial evaluating the clinical effect of inhibiting master regulators and specific effectors of the DNA Damage Secretory Program in augmenting genotoxic chemotherapy in men with metastatic CRPC. Rationale: metastatic prostate cancer is essentially incurable. Augmenting chemotherapy responses by suppressing microenvironment resistance mechanisms has the potential to improve therapeutic outcomes produced by commonly used genotoxic chemotherapy.

Public Health Relevance

Metastatic prostate carcinoma is a disease with high lethality, attributable in part to the rapid development of resistance to anti-neoplastic drugs. The successful completion of our studies may alter current concepts of treatment resistance, both to genotoxic and to pathway directed therapeutics, by shifting the emphasis from molecular alterations intrinsic to tumor cells (rare, clonally-selected events) to a context-dependent (genotoxic damage) microenvironment influence on tumor cell phenotypes.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (M1))
Program Officer
Hruszkewycz, Andrew M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Fred Hutchinson Cancer Research Center
United States
Zip Code
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 :
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
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 :
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
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
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
Shui, Irene M; Kolb, Suzanne; Hanson, Christi et al. (2016) Trichomonas vaginalis infection and risk of advanced prostate cancer. Prostate 76:620-3
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 :
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
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

Showing the most recent 10 out of 323 publications