Modulation of Apoptosis in Prostate Cancer

描述（由申请人提供）： 前列腺癌（PCa）是退伍军人群体的主要健康问题。最初，前列腺癌表现为雄激素敏感性肿瘤，并对作为一线治疗的雄激素消融有反应，这导致癌症消退。然而，癌症经常复发，并且不再对雄激素水平的操纵有反应，即使雄激素受体可能存在于这些细胞中。这种形式的疾病被称为去势抵抗性PCa（CRPC），通常是致命的。因此，设计新的治疗方法的需要仍然至关重要。多年来，我们一直专注于丝氨酸/苏氨酸蛋白激酶信号称为CK 2，其参与前列腺病理生物学。我们发现CK 2不仅促进细胞增殖，而且还抑制细胞凋亡，这一发现提供了该信号与癌细胞表型的重要联系，因为癌细胞总是表现出细胞生长和细胞死亡的失调。事实上，细胞凋亡的抑制是PCa的一个特别明确的特征。重要的是，PCa中的CK 2信号在PCa的两种表型中具有相同的功能;特别是，那些雄激素敏感或不敏感的表型。该实验室是第一个提出CK 2作为PCa治疗的重要靶点的实验室，这是由于观察到CK 2的分子下调或小分子抑制剂对其的抑制导致PCa细胞的细胞死亡。在这项VA Merit审查提案中，我们的目标是继续研究针对CK 2的PCa治疗。我们的工作假设是CK 2的失调是致癌表型的关键特征，影响细胞凋亡、细胞生长和存活;因此，其特异性靶向于癌细胞的分子下调应诱导体内广泛的细胞死亡，可能导致原发性和转移性前列腺肿瘤的根除。本申请的重点是利用siRNA靶向CK 2的α和α '催化亚基。我们的治疗策略的一个新方面是，我们专注于设计治疗剂的递送，以仅在癌细胞中下调CK 2，而不影响正常细胞。治疗剂的这种选择性递送是有利的，因为CK 2信号在所有细胞中普遍存在并且是必需的。我们的新型药物递送方法具有将CK 2特异性siRNA定向递送至动物模型中原发和转移部位的癌细胞的强大潜力。我们已经在这些方面取得了沿着的进展，我们准备继续开发这种新的PCa治疗方法。我们希望这项创新的临床前研究将被判定为值得继续研究，因为这种类型的治疗可能实现疾病根除，而不仅仅是导致疾病稳定。我们的长期目标是将这种治疗模式转化为PC患者的水平。 公共卫生相关性： 前列腺癌（PCa）是退伍军人群体中的一个主要健康问题，目前还没有治疗方法可以根除这种晚期致命疾病。我们研究的重点是研究一种新的治疗方法，该方法将通过仅进入癌细胞而不是正常细胞来靶向生存基因信号（CK 2）。由于癌细胞不能在没有这种信号的情况下生存，结果将是它们的死亡。因此，我们希望这项临床前研究有潜力达到临床转化。

DESCRIPTION (provided by applicant): Prostate cancer (PCa) is a major health issue in the veteran's population. Initially, PCa presents as an androgen-sensitive tumor and responds to androgen ablation as the first line of therapy which results in regression of the cancer. However, the cancer frequently re-emerges and is no longer responsive to manipulation of androgen levels, even though the androgen receptor may be present in these cells. This form of the disease is termed castration resistant PCa (CRPC) and is generally fatal. Thus, the need for devising novel therapeutic approaches remains critical. Over the years, we have been focused on a serine/threonine protein kinase signal called CK2 for its involvement in the prostate pathobiology. Our discovery that CK2 not only promotes cell proliferation but also suppresses apoptosis has provided an important link of this signal to the cancer cell phenotype since cancer cells invariably demonstrate dysregulation of cell growth and cell death. In fact, suppression of apoptosis is a particularly defining feature of PCa. Importantly, the CK2 signal in PCa is equally functional in both phenotypes of PCa; specifically, those that are androgen-sensitive or -insensitive. This laboratory is the first to have proposed CK2 as an important target for PCa therapy prompted by the observations that molecular downregulation of CK2 or its inhibition by small molecule inhibitors results in cell death in PCa cells. In this VA Merit Review proposal, we aim to continue our studies on targeting CK2 for PCa therapy. Our working hypothesis is that dysregulation of CK2 is a key feature of the oncogenic phenotype, impacting apoptosis, cell growth, and survival; accordingly, its molecular downregulation specifically targeted in cancer cells should induce extensive cell death in vivo potentially resulting in eradication of primary and metastatic prostatic tumors. The focus of this submission is on the utilization of siRNA-based targeting of both the alpha and alpha` catalytic subunits of CK2. A novel aspect of our therapeutic strategy is that we have focused on devising delivery of therapeutic agents to downregulate CK2 only in cancer cells while sparing the normal cells. This selective delivery of the therapeutic agent is advantageous because the CK2 signal is ubiquitously present and essential in all cells. Our novel approach for drug delivery has a strong potential of directed delivery of the CK2-specific siRNA to the cancer cells in both primary and metastatic sites in animal models. We have made significant progress along these lines, and we are poised to move forward towards developing this novel therapeutic approach for PCa. We hope that this innovative preclinical study will be judged meritorious for continued investigation as this type of therapy may achieve disease eradication rather than simply resulting in disease stabilization. Our long term goal is to take this mode of therapy to the level of translation in PC patients. PUBLIC HEALTH RELEVANCE: Prostate cancer (PCa) is a major health issue in the veteran's population, and currently there is no therapy to eradicate this lethal disease in its advanced forms. The focus of our research is to investigate a novel therapeutic approach that will target an essential for survival gene signal (CK2) by entering only cancer cells but not the normal cells. Since cancer cells cannot survive without this signal the result will be their death. Thus, we are hopeful that this pre-clinical stuy has the potential to reach clinical translation.