Targeting Prostate Tumor Microenvironment by a Novel Quinazoline

Prostate stromal microenvironment, primarily comprised of smooth muscle and extracellular matrix including stromal cells (fibroblasts and myofibroblasts), endothelial and inflammatory cells, plays an important role in prostate cancer initiation, progression and metastasis. Dysregulation of the insulin-like growth factor (IGF) axis is indicated in initiation and progression of prostate cancer. Up-regulation of IGF binding protein 3 (IGFBP3), is associated with TGF-?1-induced fibroblast-to-myofibroblast differentiation in primary human prostatic stromal cells and prostatic stromal tissues from patients. IGFBP3 induction is initiated by stroma remodeling and could be a potential target to develop anti-cancer therapies. A novel lead quinazoline-based Doxazosin® derivative, DZ-50, was generated and characterized in our laboratory. DZ-50 impairs prostate tumor growth via anoikis induction and angiogenesis inhibition in prostate cancer cells and in vivo xenograft models via an adrenoceptor-independent mechanism. Built on the preliminary evidence on the strong antitumor efficacy of DZ-50 against prostate cancer, this new class of quinazoline-based compounds exhibits therapeutic promise. Genome- wide gene array analysis to identify the molecular targets of DZ-50 in prostate cancer cells revealed genes involved in focal adhesion and anoikis resistance and EMT including IGFBP3. IGFBP3 promotes TGF-?1-mediated epithelial-to-mesenchymal transition (EMT), a key process promoting prostate cancer cells mobility and invasion. Our hypothesis that functional targeting of IGFBP3 by the novel quinazoline agent DZ- 50 proceeds via deregulation of TGF-?-mediated EMT in prostate cancer cells in context of tumor microenvironment impairs prostate cancer progression to metastasis.