INVESTIGATING THE ROLE OF THE TRANSCRIPTIONAL COREGULATOR SRC-2 IN CASTRATION RESISTANT PROSTATE CANCER

摘要 耐去势转移性前列腺癌(MCRPC)的治疗仍然是一个主要的临床问题 挑战。局限性或器官受限的前列腺癌可以通过手术或雄激素的组合治愈。 剥夺疗法(ADT)、放射治疗和/或化疗。然而，在某些情况下，肿瘤复发 男性由于ADT抗性克隆的发展，这在很大程度上导致了前列腺的致命性 癌症。侵袭性的mCRPC经常转移到远处的器官，如骨。结果就是治疗 变得具有挑战性，存活率下降。因此，迫切需要开发新的治疗方法来治愈 晚期前列腺癌。侵袭性疾病的发展得益于几种‘逃逸’的激活 类固醇受体共激活物-2(SRC-2/NCOA2)等AR共激活物在其中发挥作用的途径 对促进CRPC的生存和快速转移起关键作用。SRC-2促进体内的“代谢转换” 晚期肿瘤，使他们容易依赖谷氨酰胺产生能量和 生存和转移生长所需的大分子。SRC-2消融对前列腺癌的抑制作用 体内存活和转移，表明这可能是一种可行的治疗晚期患者的方法。所以我们的 本提案的目的是(1)研究促进谷氨酰胺代谢增加的机制 在肿瘤中，(2)识别刺激SRC-2转录反应的上游信号事件以调节 这种新陈代谢重新编程，以及(3)检查以这种“代谢开关”为靶点的治疗益处 阻止癌症的进展和转移。在K22大奖期间，我希望能确定分子间的联系 MCRPC中细胞代谢和致癌事件之间的关系，并检查靶向的潜在好处 这一途径选择性地损害前列腺癌的转移。这项研究将做出新的见解来描绘 改变代谢途径和潜在机制促进CRPC的出现，这可能导致 发现潜在的预后工具，以早期发现临床上重要的疾病。

Abstract Therapeutic management of metastatic castration-resistant prostate cancer (mCRPC) remains a major clinical challenge. Localized or organ-confined prostate cancer can be cured by surgery, or a combination of androgen deprivation therapy (ADT), radiotherapy and/or chemotherapy. However, tumor recurrence occurs in some men due to the development of ADT-resistant clones which greatly contributes to the lethality of prostate cancer. Aggressive mCRPC frequently metastasizes to distant organs such as bone. As a result treatment becomes challenging and survival rate drops. Hence, there is an urgent need to develop new therapies to cure advanced prostate cancer. Development of aggressive disease is favored by activation of several `escape pathways' among which AR- coactivators such as steroid receptor coactivator-2 (SRC-2/NCOA2) plays a critical role promoting the survival and rapid metastasis of CRPC. SRC-2 promotes a “metabolic switch” in advanced tumors that predispose them to be dependent on `glutamine' to generate energy and macromolecules required for survival and metastatic growth. Ablation of SRC-2 suppresses prostate tumor survival and metastasis in vivo, indicating this may be a viable approach to treat advanced patients. So our objectives in this proposal are (1) to investigate the mechanisms that promote increased glutamine metabolism in tumors, (2) identify the upstream signaling events that stimulate SRC-2 transcriptional responses to regulate this metabolic reprogramming, and (3) examine the therapeutic benefits of targeting this `metabolic switch' to block cancer progression and metastasis. During the K22 award I expect to identify the molecular links between cellular metabolism and oncogenic events in mCRPC, and examine the potential benefits of targeting this pathway to selectively impair prostate cancer metastasis. The study will make novel insights depicting the altered metabolic pathways and underlying mechanisms promoting the emergence of CRPC, which may lead to the discovery of potential prognostic tools for early detection of clinically significant disease.