Novel Epigenetic regulators in cancer therapeutic resistance and as new targets

描述(由申请人提供)： 前列腺癌仍然是包括美国在内的发达国家男性死亡的主要原因之一，尽管它的诊断和治疗最近取得了进展。虽然晚期肿瘤最初对雄激素消融、抗雄激素或以紫杉烷为基础的化疗等治疗有效，但大多数肿瘤出现耐药，疾病复发。因此，迫切需要更好地了解耐药机制，确定个体化治疗和提高存活率的标志物和治疗靶点。目前的证据支持这样一种观点，即多种不同的途径和机制导致肿瘤对不同的治疗方法产生耐药性，包括化疗耐药。因此，如果能够确定连接看似复杂的通路阵列的关键阻力驱动因素，将具有非常重要的意义。这一建议是基于我们最近发现的一种表观遗传调节蛋白/组蛋白甲基酶蛋白，它是前列腺癌细胞存活、增殖的关键因素。 和肿瘤的生长。它是一种新型的AR和核因子-kB的联合激活剂，可诱导细胞存活、促炎基因和信号转导程序。有趣的是，它是由化疗药物诱导的，并在Gleason评分较高的前列腺癌肿瘤中过度表达。在这里，我们希望确定其在化疗耐药中的作用，并阐明其作为参与治疗耐药的多个途径的关键激活物的作用机制。我们还将研究表观遗传调节因子作为预后标志物和治疗靶点的潜在价值。

DESCRIPTION (provided by applicant): Prostate cancer is still one of the leading causes of death in men of developed countries including the U. S., despite of the recent progress in its diagnosis and treatment. Although the advanced tumors initially respond to therapies such as androgen ablation, anti-androgen or the taxane-based chemotherapy, most of them develop resistance and the disease relapses. Therefore, there is an urgent need for better understanding of the resistance mechanisms and to identify markers and therapeutic targets for personalized treatment and improving survival. Current evidence supports the notion that multiple diverse pathways and mechanisms drive tumor resistance to different therapies including chemoresistance. Therefore, it will be highly significant if key resistance driving factors that interface the seemingly complex arrays of pathways can be identified. This proposal is based on our recent identification of an epigenetic regulator/histone methylase protein as a key factor of prostate cancer cell survival, proliferation and tumor growth. It functions as a novel co-activator of AR and NF-kB for induction of cell survival, pro-inflammatory gene and kinase signaling programs. Interestingly, it is induced by chemotherapeutic drugs and is overexpressed in prostate cancer tumors with high Gleason scores. Here, we wish to establish its function in driving chemoresistance and elucidate its functional mechanism as a key activator of multiple pathways involved in therapeutic resistance. We will also examine the epigenetic regulator for the potential value as a prognostic marker and a therapeutic target.