Targeting Neuroendocrine Differentiation for Prostate Cancer Radiosensitization

摘要: Abstract : Radiotherapy (RT) is an important primary treatment for low-risk prostate cancer and the standard high-risk when combined with hormone therapy. Despite that many patients can be cured by RT, several studies suggest approximately 10% of up to 30-60% experience biochemical recurrence within five years after among them 20% die in 10 years. Neuroendocrine differentiation (NED) a process which cells transdifferentiate into neuroendocrine-like (NE-like) cells. NED associated disease progression failure. Based on our finding transcription factor cAMP response element (CREB) responsible fractionated ionizing radiation (FIR)-induced NED, we hypothesized targeting neuroendocrine sensitize radiation. We proposed two CREB strategies as model system test hypothesis. During first year grant support, have established multiple stable doxycycline/tetracycline-inducible cell lines express short hairpin RNAs (shRNAs) knock down or ACREB, dominant negative mutant CREB. examined effect ACREB expression FIR-induced death LNCaP cells, found induction during weeks (weeks 1-2), second 3-4), entire four 1-4) efficiently increased inhibited extent survival Further, clonogenic assays also showed sensitized dose-dependent manner. In support this notion, knockdown assays.