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

最常见的前列腺癌，腺癌，是退伍军人面临的主要医疗保健问题。 前列腺癌是一种生殖驱动的疾病，因为它主要依赖于雄激素生存， 传播雄激素通过与细胞内的雄激素受体（AR）相互作用提供这种存活信号。 前列腺癌细胞由于睾丸是雄激素类固醇的主要来源， 治疗晚期前列腺癌的方法是最大限度地减少雄激素的性腺产生， 雄激素/AR信号传导。因此，雄激素剥夺疗法（ADT）是治疗转移性前列腺癌的主要方法。 疾病，并结合放射治疗，也是治疗局部晚期/高危前列腺的一个组成部分， 癌虽然最初有效，但ADT不是治愈性的，大多数晚期前列腺患者 癌症在几年内就发展了。 ADT失败的患者被认为患有去势抵抗性前列腺癌（CRPC）。这样的患者，在 至少在最初，对雄激素/AR轴的进一步操纵有反应，因为这种信号传导途径通常是 在ADT失败的患者中恢复。因此，已经做出了相当大的努力来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 这是有益的，但也是有限的时间。晚期PC的另一种主要治疗方法是多西他赛- 基于化疗，通常用于进展性CRPC男性。值得注意的是，迄今为止，没有其他 与多西他赛联合用药的结局优于单药多西他赛， 在有限的时间内提供疾病控制。 考虑到这些挑战，我们的目标是使用明确的前列腺癌细胞培养模型， 一系列疾病状态，以研究和询问某些“节点”，这些节点整合了 前列腺癌代谢组。我们将针对调节增殖/合成代谢和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 增殖性erbB-PI 3 K-Akt介导的合成代谢和抗增殖性AMPK- 在表达AR和不表达AR的前列腺癌细胞中的介导的分解代谢途径。为这些 研究中，我们将利用已经在临床使用或正在积极临床开发的药物， 如果临床前研究成功，则促进将这项工作转化为临床。在其他研究中， 通过siRNA或shRNA下调这些关键调节介质中的一些将提供额外的机制， 深入了解治疗敏感性前列腺癌代谢组的相互作用和反馈信号， 治疗抵抗性前列腺癌细胞。我们将确定具体治疗或治疗的效果 通过评估药物-药物相互作用的指标， （协同的、相加的、拮抗的）、细胞增殖/生长抑制、细胞周期和/或细胞凋亡。我们将 将一些研究扩展到基于SCID小鼠的异种移植物，以帮助进一步确定抗肿瘤活性， 体内环境中潜在的治疗相关毒性。我们相信这些研究的结合， 一起，将有直接的临床相关性，并可能有助于多模式治疗的发展， 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.