Gene-environment Interactions and Novel Therapeutic Interventions in Prostate Cancer
Prostate cancer remains the second leading cause of death among men in developed nations. The primary therapeutic measures for metastatic disease rely on therapies impinging on androgen receptor (AR) activation. Androgen withdrawal is induced by inhibiting testosterone production by chemical or surgical castration and is referred to as androgen deprivation therapy (ADT). Although initially effective, the ADT treatment fails eventually, and patients develop castrate resistant prostate cancer (CRPC). Therapeutic failure is accompanied by restored AR activity, wherein the receptor becomes transcriptionally active irrespective of androgen withdrawal. The CRPC tumors are non-responsive to the currently available therapies. Therefore, identification of factors responsible for therapeutic failure as well as discovery of efficient therapeutics is urgently needed. ^ Here, environmentally available pesticide DDT/DDE is identified as a modulator of mutated-AR under androgen deprived condition. DDE increased AR recruitment at regulatory regions of AR-target genes, promoted target gene expression and cell proliferation. Investigation of underlying mechanisms indicated that DDE caused rapid phosphorylation of signaling molecules such as MAPK and VASP. This study identified that activation of both AR and MAPK pathways contribute to DDE mediated proliferation and may promote CRPC development. ^ Additionally, this dissertation describes the identification of the natural isoflavone curcumin as an adjuvant to the androgen deprivation therapy. Curcumin suppressed p300 and CBP occupancy and altered histone acetylation on chromatin. Subsequently, recruitment of pioneering factors (GATA2 and FOXA1) was reduced as indicated by kinetic assays, resulting in suppression of both ligand-dependent and ligand-independent AR residence on chromatin, thus inhibiting AR driven transcription. Biological relevance was further identified using in vivo xenograft models mimicking disease progression. Congruent with in vitro findings, curcumin cooperated with androgen deprivation as indicated by tumor growth retardation and delayed onset to castrate-resistant disease. Moreover, combination of curcumin with ADT inhibited therapeutic bypass development by DDE/DDT and by proteins known to promote CRPC (GATA2, FoxA1, AR and AR-splice variants). Furthermore, combination of curcumin with AR-antagonist (Casodex) showed synergistic inhibition of both ADT-sensitive and CRPC cancer cells. These findings indicate successful identification of an adjuvant treatment for both ADT-sensitive tumors and ADT-resistant CRPC tumors. Moreover, these data have identified p300/CBP as critical factors for AR function under androgen deprivation since inhibition of these proteins lead to subsequent loss of key regulatory proteins (e.g. GATA2, FOXA1 and AR) from chromatin. Since expression of these key proteins is correlated with poor prognosis, the dependence of these proteins on p300/CBP function may serve as a useful tool for further development therapeutics. ^ Combined, this dissertation identified a different means to curtail inappropriate AR activation known to cause CRPC development and discovered a novel compound as an adjuvant for ADT to increase the treatment efficacy. ^
Biology, Molecular|Biology, Genetics|Health Sciences, Oncology
"Gene-environment Interactions and Novel Therapeutic Interventions in Prostate Cancer"
(January 1, 2012).
ETD Collection for Thomas Jefferson University.