Prostate cancer is the second leading cause of cancer death in men in the United States. Localized prostate cancer can be cured by androgen ablation, but when the disease escapes the confines of the gland, the prospects for cure decrease drastically and the disease becomes """"""""castrate resistant."""""""" Bone is the primary site of castrate-resistant disease progression, which is associated with a poor prognosis. The fibroblast growth factor (FGF)/FGF receptor (FGFR) complex, a signaling axis involving multiple FGF ligands and receptors, mediates tumor-stromal interactions and is one ofthe most commonly altered signaling pathways during prostate cancer progression. Expression of FGFR1, multiple FGF ligands, and FGFR adaptor, FRS2a has been observed in prostate cancer epithelial cells. Our recent studies have defined a mouse model of prostate cancer highly dependent on FGF signaling, and have implicated FGFQ in the osteoblastic progression of human prostate cancer cells in bone. The results of our preliminary studies support a notion that during bone metastasis, the prostate cancer cells that aberrantly express both FGF and FGFRs creates a new """"""""compartment"""""""" in bone as source and recipient of additional FGF-mediated signaling, thus subverting homeostasis. The implication ofthe FGF axis in prostate cancer progression suggests that FGFR blockade represents a new therapeutic opportunity for men with castrate-resistant prostate cancer. Recently, TKI258, a receptor tyrosine kinase inhibitor (TKl) with strong activity against FGFR1-3 (IC50 <40 nM), has become available and is being used as an experimental new drug for solid tumors. The main goal of this proposed project is to establish the feasibility of using TKI258 to modulate FGF signaling in men with castrate-resistant prostate cancer and to correlate FGF signaling modulation with clinical disease progression. We will assess the effect of TKI258 on human prostate cancer xenografts growing in the prostate and bone of castrated immunodeficient male mice (Aim 1), and also on mouse models of prostate cancer (Aim 2) to identify markers of response to TK1258 therapy directly related to FGF signaling. We will then perform a proof-of-principle clinical study with TKI258 in men with castrate-resistant prostate cancer and bone marrow infiltration (Aim 3). The study will create an annotated tissue resource and will permit validation of FGF signaling responsive markers emerging from Aims 1 and 2. This will be the first clinical study to assess the effect of TKI258 in prostate cancer.

Public Health Relevance

Prostate cancer is the second leading cause of cancer death in men in the United States. In the proposed study we will perform a proof-of-principle clinical study with a receptor tyrosine kinase inhibitor, TK1258 in men with castrate-resistant prostate cancer and bone marrow infiltration. The results of this study will be the foundation for development of further therapies of prostate cancer patients based on targeting the fibroblast growth factor signaling pathway.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA140388-05
Application #
8541602
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$268,383
Indirect Cost
$90,377
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Lin, Song-Chang; Yu-Lee, Li-Yuan; Lin, Sue-Hwa (2018) Osteoblastic Factors in Prostate Cancer Bone Metastasis. Curr Osteoporos Rep 16:642-647
Wang, Hong; Yang, Xu; Liu, Anna et al. (2018) ?-Tocopherol inhibits the development of prostate adenocarcinoma in prostate specific Pten-/- mice. Carcinogenesis 39:158-169
Velazquez-Torres, Guermarie; Shoshan, Einav; Ivan, Cristina et al. (2018) A-to-I miR-378a-3p editing can prevent melanoma progression via regulation of PARVA expression. Nat Commun 9:461
Zanoaga, Oana; Jurj, Ancuta; Raduly, Lajos et al. (2018) Implications of dietary ?-3 and ?-6 polyunsaturated fatty acids in breast cancer. Exp Ther Med 15:1167-1176
Zhang, Wei; Liu, Bo; Wu, Wenhui et al. (2018) Targeting the MYCN-PARP-DNA Damage Response Pathway in Neuroendocrine Prostate Cancer. Clin Cancer Res 24:696-707
Monroig-Bosque, Paloma Del C; Shah, Maitri Y; Fu, Xiao et al. (2018) OncomiR-10b hijacks the small molecule inhibitor linifanib in human cancers. Sci Rep 8:13106
Basourakos, Spyridon P; Davis, John W; Chapin, Brian F et al. (2018) Baseline and longitudinal plasma caveolin-1 level as a biomarker in active surveillance for early-stage prostate cancer. BJU Int 121:69-76
Pan, Tianhong; Lin, Song-Chang; Yu, Kai-Jie et al. (2018) BIGH3 Promotes Osteolytic Lesions in Renal Cell Carcinoma Bone Metastasis by Inhibiting Osteoblast Differentiation. Neoplasia 20:32-43
Yu-Lee, Li-Yuan; Yu, Guoyu; Lee, Yu-Chen et al. (2018) Osteoblast-Secreted Factors Mediate Dormancy of Metastatic Prostate Cancer in the Bone via Activation of the TGF?RIII-p38MAPK-pS249/T252RB Pathway. Cancer Res 78:2911-2924
Luo, Yong; Azad, Abul Kalam; Karanika, Styliani et al. (2018) Enzalutamide and CXCR7 inhibitor combination treatment suppresses cell growth and angiogenic signaling in castration-resistant prostate cancer models. Int J Cancer 142:2163-2174

Showing the most recent 10 out of 217 publications