Multi-Faceted Targeting of Treatment-Sensitive and Treatment-Resistant Prostate Cancer

前列腺癌是最常见的前列腺癌，是退伍军人面临的主要医疗问题。 前列腺癌是一种激素驱动的疾病，因为它主要依赖雄激素生存和 传播。雄激素通过与体内的雄激素受体(AR)相互作用来提供这种生存信号 前列腺癌细胞。由于睾丸是雄激素的主要来源，标准的方法是 晚期前列腺癌的治疗是将性腺产生的雄激素降至最低，从而破坏 雄激素/AR信号传导。因此，雄激素剥夺疗法(Adt)是治疗转移瘤的主要手段。 疾病，以及与放射一起，也是治疗局部晚期/高危前列腺癌的一个组成部分。 癌症。虽然最初是有效的，但ADT并不能治愈，而且大多数晚期前列腺癌患者 ADT的癌症进展在几年内。 ADT失败的患者被认为患有去势抵抗前列腺癌(CRPC)。这类病人可于 最初，对雄激素/AR轴的进一步操作有反应，因为这一信号通路通常 在ADT失败的患者中恢复。因此，已经作出了相当大的努力，通过以下方式进一步瞄准这一途径 开发新一代雄激素生物合成和AR抑制剂。这一战略已被证明是 有益的，但再次在有限的一段时间内。晚期PC的另一种主要治疗方法是多西紫杉醇- 以化疗为基础的，通常用于进展期CRPC患者。值得注意的是，到目前为止，没有其他 添加到多西紫杉醇中的药物被证明比单一药物多西紫杉醇提供更好的结果，后者再次 在有限的时间内提供疾病控制。 鉴于这些挑战，我们的目标是使用定义明确的前列腺癌细胞培养模型，包括 一系列疾病状态，用于研究和询问集成了 前列腺癌代谢物。我们将针对调节增殖/合成代谢并与其相互作用的关键介质 和前列腺癌细胞中的抗增殖/分解代谢信号。更具体地说，我们将研究和定义 增殖型erb B-PI3K-Akt介导的合成代谢产物与抗增殖AMPK-2的相互作用 AR表达和非AR表达的前列腺癌细胞中介导的分解代谢途径。为了这些 研究，我们将利用已经在临床使用或正在积极进行临床开发的药物，这将 如果临床前研究成功，促进将这项工作转化为临床工作。在其他研究中，敲门 通过其中一些关键调节介体的siRNA或shRNA向下将提供额外的机制 对前列腺癌代谢组相互作用和反馈信号的洞察 耐药的前列腺癌细胞。我们将确定特定治疗或治疗的效果 通过评估药物-药物相互作用的指标对敏感和耐药的前列腺癌细胞进行组合 (协同、相加、拮抗)、细胞增殖/生长抑制、细胞周期和/或细胞凋亡。我们会 将部分研究扩展到基于SCID-小鼠的异种移植，以帮助进一步确定抗肿瘤活性和 体内环境中与治疗相关的潜在毒性。我们相信这些研究的组合， 一起，将具有直接的临床相关性，并可能有助于开发多种模式的治疗 前列腺癌。

The most common form of prostate cancer, adenocarcinoma, is a major healthcare problem facing Veterans. Prostate cancer is a hormonally driven disease in that it is primarily dependent on androgens for survival and propagation. Androgens provide such survival signals by interacting with androgen receptors (AR) within the prostate cancer cells. Since the testes are the primary source of androgenic steroids, the standard approach to treating advanced prostate cancer is to minimize gonadal production of androgens so as to disrupt androgen/AR signaling. Thus, androgen deprivation therapy (ADT) is the mainstay of treating metastatic disease, and in conjunction with radiation, is also an integral part of treating locally advanced/high risk prostate cancer. Although initially effective, ADT is not curative, and the majority of patients with advanced prostate cancer progress on ADT within a couple of years. Patients who fail ADT are deemed to have castration resistant prostate cancer (CRPC). Such patients may, at least initially, respond to further manipulation of the androgen/AR axis since this signaling pathway is often restored in ADT-failing patients. Hence, considerable efforts have been made to further target this pathway by developing newer generation of androgen biosynthesis and AR inhibitors. This strategy has proven to be beneficial, but again for a limited period of time. The other major treatment for advanced PC is docetaxel- based chemotherapy, which is generally used in men with progressive CRPC. Remarkably, to date, no other agent added to docetaxel has shown to provide better outcomes than single agent docetaxel, which again provides disease control for a limited period of time. Given these challenges, our goal is to use well-defined cell culture models of prostate cancer that encompass a range of disease states to study and interrogate certain ‘nodes’ that integrate specific components of the prostate cancer metabolome. We will target key mediators that regulate and interact with proliferative/anabolic and anti-proliferative/catabolic signals in prostate cancer cells. More specifically, we will study and define interactions between the proliferative erbB-PI3K-Akt-mediated anabolic and the anti-proliferative AMPK- mediated catabolic pathways in AR-expressing and non-AR-expressing prostate cancer cells. For these studies, we will utilize agents that are already in clinical use or in active clinical development, which will facilitate the translation of this work to the clinic if the pre-clinical studies are successful. In other studies, knock down via siRNA or shRNA of some of these key regulatory mediators will provide additional mechanistic insights into the interacting and feedback signals of the prostate cancer metabolome in treatment-sensitive and treatment-resistant prostate cancer cells. We will determine the effects of specific treatments or treatment combinations on the sensitive and resistant prostate cancer cells via metrics that assess drug-drug interactions (synergistic, additive, antagonistic), cell proliferation/growth inhibition, cell cycling and/or cell apoptosis. We will extend some of the studies to SCID-mouse based xenografts to help further define anti-tumor activity and potential treatment-related toxicities in the vivo setting. We believe these combinations of studies, taken together, will have direct clinical relevance, and may help in the development of multi-modal treatments for prostate cancer.