Overcoming Autophagy to Induce Apoptosis in Castration-Resistant Prostate Cancer
Abstract
Abstract : In year 2, we extended our studies to in vivo animal experiments. Three animal models, LNCaP C4-2B MDV-R, LNCaP GRP Pro cells and CWR22 xenograft were used. In LNCaP C4-2B MDV-R study, we validated that using autophagy modulators such as clomipramine and metformin, tumor survival mechanism encountering enzalutamide treatment may be blocked. A much significant reduction of tumor growth (91% and 78% for combinational use of CMI and metf with enzalutamide, respectively) was observed. In the LNCaP GRP model, combinational treatment of enzalutamide and saracatinib provided the best tumor suppression. Both specific mechanisms GRP cells utilizes for aberrant AR activation, intracrine androgen synthesis and kinase pathway mediated AR activation in the absence of androgen, were prevented through combined target therapy. Lastly, castration resistant gene activation and tumor recurrence was inhibited by saracatinib treatment in the CWR22 xenograft model but could be further enhanced when combined with autophagy modulator like metformin.
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