Instnjctions): Current strategies for PCa treatment that target primarily the primary tumor or preserve bone have only modestly affected survival. The focus of this laboratory and collaborators for many years has been on Src family kinases (SFKs), the activation of which not only contribute to PCa metastasis in mouse models, by affecfing tumor cells, osteoclasts, osteoblasts and interacfions between these cells required for tumor cell growth in the bone. This project will test the central hypothesis that therapeutic strategies using Src inhibitors currently in clinical trial will prove efficacious in the treatment of PCa metastases in the bone. The rafionale for this hypothesis is that Src regulates signaling pathways both in tumor cells and in their microenvironment that contribute to the """"""""vicious cycle"""""""" of bone formafion, degradation and tumor growth, and is based, in part, on the promise of an ongoing phase l/ll clinical trial for metastafic prostate cancer using the combinafion of dasafinib (an SFK/AbI inhibitor) and docetaxel. This project will combine mechanistic-based strategies in preclinical mouse model systems to examine the specific contributions of Src in the host and tumor cell contribufing to growth in the bone with a phase III clinical trial using dasafinib.
The specific aims are to: (1) Determine the role of SFK inhibition in tumor cells, host cells, and both in affecting growth of PCa cells following intrafibial injecfion into nude mice;(2) Determine molecular alterafions in the tumor and host correlating with the effectiveness of dasatinib;and (3) Integrate this knowledge with a phase III trial using dasatinib in combinafion with docetaxel in a phase III trial in select pafients with castrate resistant prostate cancer and bone metastases, correlate changes in molecular markers of Src and bone preservation with clinical course of the disease. The trial will serve as a platform to associate markers of Src activation, with baseline and serial change(s) in bone turnover markers. Thus, the experiments in Project 3 are novel in that they build on a promising therapeutic strategy, which we also view as reiterative, where our increased knowledge of Src's effects in tumor/bone interacfion will help dictate clinical trial design, and the clinical trials will help refine modeling the disease in preclinical studies.

Public Health Relevance

Currently, no successful therapies exist for the treatment of late-stage prostate cancer (i.e. cancer that has metastasized, especially to the bone). However recent early-stage clinical trials using inhibitors of Src, which affects both tumor growth and interaction of tumor with its environment, have been promising. In this project, we will employ basic science strategies to understand which Src functions are crifical to this process, and use this knowledge in a phase III clinical trial to design better treatments for prostate cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
United States
Zip Code
Zhang, Tao; Tseng, Chieh; Zhang, Yan et al. (2016) CXCL1 mediates obesity-associated adipose stromal cell trafficking and function in the tumour microenvironment. Nat Commun 7:11674
Sun, Sheng; Sun, Le; Zhou, Xi et al. (2016) Phosphorylation-Dependent Activation of the ESCRT Function of ALIX in Cytokinetic Abscission and Retroviral Budding. Dev Cell 36:331-43
Hosoya, Hitomi; Dobroff, Andrey S; Driessen, Wouter H P et al. (2016) Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release. Proc Natl Acad Sci U S A 113:1877-82
Maity, Sankar N; Titus, Mark A; Gyftaki, Revekka et al. (2016) Targeting of CYP17A1 Lyase by VT-464 Inhibits Adrenal and Intratumoral Androgen Biosynthesis and Tumor Growth of Castration Resistant Prostate Cancer. Sci Rep 6:35354
Saha, Achinto; Blando, Jorge; Fernandez, Irina et al. (2016) Linneg Sca-1high CD49fhigh prostate cancer cells derived from the Hi-Myc mouse model are tumor-initiating cells with basal-epithelial characteristics and differentiation potential in vitro and in vivo. Oncotarget 7:25194-207
Han, Ying; Rand, Kristin A; Hazelett, Dennis J et al. (2016) Prostate Cancer Susceptibility in Men of African Ancestry at 8q24. J Natl Cancer Inst 108:
Varkaris, Andreas; Corn, Paul G; Parikh, Nila U et al. (2016) Integrating Murine and Clinical Trials with Cabozantinib to Understand Roles of MET and VEGFR2 as Targets for Growth Inhibition of Prostate Cancer. Clin Cancer Res 22:107-21
Fong, Eliza L S; Wan, Xinhai; Yang, Jun et al. (2016) A 3D in vitro model of patient-derived prostate cancer xenograft for controlled interrogation of in vivo tumor-stromal interactions. Biomaterials 77:164-72
Weiderhold, Kimberly N; Fadri-Moskwik, Maria; Pan, Jing et al. (2016) Dynamic Phosphorylation of NudC by Aurora B in Cytokinesis. PLoS One 11:e0153455
Qiao, Yuanyuan; Feng, Felix Y; Wang, Yugang et al. (2016) Mechanistic Support for Combined MET and AR Blockade in Castration-Resistant Prostate Cancer. Neoplasia 18:1-9

Showing the most recent 10 out of 167 publications