Modulation of Apoptosis in Prostate Cancer

前列腺癌细胞凋亡的调节

基本信息

批准号：
8331841
负责人：
Khalil Ahmed
金额：
--
依托单位：
MINNEAPOLIS VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2016-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8331841
关键词：
Ablation Achievement Address Aging Alpha 1 Polypeptide Casein Kinase 2 Androgen Receptor Androgens Animal Model Apoptosis Area Bone neoplasms Castration Cell Death Cell Proliferation Cell Survival Cell physiology Cells Cessation of life Clinical Data Development Disease Dose Down-Regulation Drug Delivery Systems Encapsulated Future Genes Goals Health Human Investigation Knowledge Laboratories Lead Link Malignant Neoplasms Malignant neoplasm of prostate Medical Research Methods Mission Molecular Nature Normal Cell Oncogenic Pathogenesis Patients Phenotype Population Prostate Prostate Cancer therapy Prostatic Prostatic Diseases Protein-Serine-Threonine Kinases Quality of life RNA Interference Reporting Research Resistance Signal Transduction Site Small Interfering RNA Suggestion Sum TNFSF10 gene Technology Testing Therapeutic Therapeutic Agents Therapeutic Effect Toxic effect Translations Veterans Work Xenograft Model base bone cancer cell cancer regression cancer therapy casein kinase II cell growth human disease in vivo inhibitor/antagonist innovation men nanocapsule nanoparticle neoplastic cell novel novel strategies novel therapeutic intervention preclinical study programs response small molecule tumor

项目摘要

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.

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，PCa 表现为雄激素敏感肿瘤，对雄激素消融作为一线治疗有反应，从而导致癌症消退。然而，癌症经常重新出现，并且不再对雄激素水平的控制做出反应，即使这些细胞中可能存在雄激素受体。这种疾病称为去势抵抗性前列腺癌 (CRPC)，通常是致命的。因此，设计新的治疗方法的需求仍然至关重要。多年来，我们一直关注名为 CK2 的丝氨酸/苏氨酸蛋白激酶信号，因为它与前列腺病理学有关。我们发现 CK2 不仅促进细胞增殖，而且抑制细胞凋亡，这为该信号与癌细胞表型提供了重要联系，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 的一个特别重要的特征。重要的是，PCa 中的 CK2 信号在两种表型的 PCa 中具有同等的功能。具体来说，是那些对雄激素敏感或不敏感的人。该实验室首次提出将 CK2 作为 PCa 治疗的重要靶点，因为观察到 CK2 的分子下调或小分子抑制剂的抑制会导致 PCa 细胞的细胞死亡。在这项 VA 优异评审提案中，我们的目标是继续针对 CK2 进行 PCa 治疗的研究。我们的工作假设是，CK2 失调是致癌表型的一个关键特征，影响细胞凋亡、细胞生长和存活；因此，其专门针对癌细胞的分子下调应该会诱导体内广泛的细胞死亡，从而可能导致原发性和转移性前列腺肿瘤的根除。本次提交的重点是利用基于 siRNA 的 CK2 α 和 α` 催化亚基靶向。我们的治疗策略的一个新颖之处在于，我们专注于设计治疗药物的递送，仅在癌细胞中下调 CK2，同时不影响正常细胞。这种治疗剂的选择性递送是有利的，因为CK2信号在所有细胞中普遍存在并且是必需的。我们的药物递送新方法具有将 CK2 特异性 siRNA 定向递送至动物模型中原发性和转移性部位癌细胞的强大潜力。我们已经在这些方面取得了重大进展，并且准备继续开发这种新型前列腺癌治疗方法。我们希望这项创新的临床前研究将被认为有利于继续研究，因为这种类型的治疗可以实现疾病根除，而不是简单地导致疾病稳定。我们的长期目标是将这种治疗模式应用于 PC 患者。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，目前尚无治疗方法可以根除这种晚期形式的致命疾病。我们研究的重点是研究一种新颖的治疗方法，该方法将通过仅进入癌细胞而不是正常细胞来针对生存必需的基因信号（CK2）。由于癌细胞在没有此信号的情况下无法生存，因此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实现临床转化。