Modulation of Apoptosis in Prostate Cancer

描述(由申请人提供)： 前列腺癌(PCA)是退伍军人群体中的一个主要健康问题。最初，前列腺癌表现为雄激素敏感的肿瘤，对雄激素消融的反应是导致癌症消退的一线治疗。然而，尽管雄激素受体可能存在于这些细胞中，但癌症经常会再次出现，不再对雄激素水平的操纵做出反应。这种疾病被称为去势抵抗前列腺癌(CRPC)，通常是致命的。因此，设计新的治疗方法的必要性仍然至关重要。多年来，我们一直关注一种名为CK2的丝氨酸/苏氨酸蛋白激酶信号，因为它参与了前列腺的病理生物学。我们的发现CK2不仅促进细胞增殖，而且抑制细胞凋亡，这一发现为该信号与癌细胞表型的关系提供了重要的联系，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，抑制细胞凋亡是前列腺癌的一个特别明确的特征。重要的是，在PCa中，CK2信号在两种表型的PCa中具有同等的功能；特别是那些对雄激素敏感或不敏感的PCa。本实验室首次提出将CK2作为PCa治疗的重要靶点，这是因为观察到CK2分子下调或小分子抑制剂抑制CK2导致PCa细胞死亡。在这份VA Merit Review提案中，我们的目标是继续我们针对CK2用于前列腺癌治疗的研究。我们的工作假设是，CK2的异常调节是肿瘤表型的一个关键特征，影响细胞的凋亡、细胞生长和存活；因此，它的分子下调特异性地针对癌细胞应该会在体内诱导广泛的细胞死亡，可能导致原发和转移性前列腺癌的根除。这份意见书的重点是利用基于siRNA的靶向CK2的α和α‘催化亚单位。我们治疗策略的一个新方面是，我们专注于设计治疗药物的递送，仅下调癌细胞中的CK2，同时保留正常细胞。这种治疗剂的选择性输送是有利的，因为CK2信号在所有细胞中普遍存在，并且是必不可少的。我们的药物递送新方法具有将CK2特异性siRNA定向递送到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重大进展，我们正准备朝着开发这一治疗PCa的新方法迈进。我们希望这项创新的临床前研究将被认为是值得继续研究的，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提升到PC患者的翻译水平。 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来根除这种晚期致命的疾病。我们的研究重点是探索一种新的治疗方法，通过只进入癌细胞而不是正常细胞来靶向生存所必需的基因信号(CK2)。由于癌细胞在没有这种信号的情况下无法存活，其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翻译。

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.