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.
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.
|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:|
Showing the most recent 10 out of 400 publications