Targeting Microtubule Associated Protein Tau in Ovarian Carcinoma to Increase Efficacy of Paclitaxel

摘要 在过去的世纪，上皮性卵巢癌的死亡率没有显著变化。这种疾病仍然 仍然是最致命的妇科恶性肿瘤和妇女癌症死亡的第五大原因。的 转移是该病死亡的主要原因，也是预防的关键问题之一， 成功的治疗是化疗耐药性。我们实验室研究的长期目标是 描述调控卵巢癌转移及其复发化疗的分子机制- 抗性表型本提案中概述的研究目的是确定目标定位的有效性 微管相关蛋白tau增加紫杉醇反应。 晚期卵巢癌患者通常采用手术和联合化疗治疗 含有紫杉烷（最常见的是紫杉醇）和铂剂。此外，紫杉醇被用作 复发性铂难治性上皮性卵巢癌的二线药物。以前的研究已经将几个 紫杉醇耐药的不同分子机制;然而，迄今为止，尚无临床使用的策略 克服这些机制。最近的研究，包括我们实验室的研究， 紫杉醇耐药的浆液性卵巢癌组织中tau蛋白的表达我们的数据表明 与原发癌相比，转移癌中tau阳性病例的数量显著增加。我们有 还证明了细胞培养模型中tau表达的下调协同地使细胞对 紫杉醇。这表明，降低tau水平或其表达的策略可能有益于研究的结果。 紫杉醇治疗转移性卵巢癌 重要的是，由于异常的tau蛋白也与许多神经退行性疾病相关， 已经在该领域中做出努力来开发靶向tau的抑制剂和药物 条件然而，基于tau蛋白的药物和抑制剂是否可以用于 增加卵巢癌对紫杉醇敏感性。我们与神经科学家彼得·彭泽斯博士合作 （Northwestern University），以确定tau抑制剂在卵巢癌临床前模型中的功效。 在本申请中，我们假设靶向tau蛋白的药物，其最初被开发用于治疗 神经退行性疾病，将协同紫杉醇在增加其细胞毒性和减少克隆 HGSOC细胞的形成，导致体内肿瘤负荷显著降低。为了验证这个假设，我们 提出这些具体目的：1）验证基于tau的治疗剂和 紫杉醇在HGSOC的临床前模型中，和2）验证基于tau的治疗剂在其重新治疗HGSOC的功效。 使紫杉醇耐药卵巢癌对紫杉醇治疗敏感。拟议的实验将是 使用高级别浆液性卵巢癌的临床前模型进行，包括细胞培养和异种移植 模型

ABSTRACT Mortality from epithelial ovarian carcinoma has not changed significantly over the past century. This disease still remains the deadliest gynecologic malignancy and the fifth leading cause of cancer death in women. The metastasis is the main cause of death from this morbid disease, and one of the key problems preventing successful treatment is chemotherapy resistance. The long-term goal of the studies in our laboratory is to characterize molecular mechanisms regulating ovarian carcinoma metastasis and its recurrent chemotherapy- resistant phenotype. The objective of the study outlined in this proposal is to determine the efficacy of targeting the microtubule-associated protein tau to increase paclitaxel response. Patients with advanced ovarian carcinoma are typically treated with surgery and a combination chemotherapy containing a taxane (most commonly, paclitaxel) and a platinum agent. Furthermore, paclitaxel is used as a second line agent in relapsed platinum-refractory epithelial ovarian cancer. Previous studies have linked several different molecular mechanisms with paclitaxel resistance; however, so far, there are no clinically used strategies to overcome these mechanisms. More recent previous studies, including those from our lab, have linked expression of tau with resistance to paclitaxel in specimens of serous ovarian carcinoma. Our data suggest that the number of tau-positive cases in the metastasis significantly increases compared to primary cancer. We have also demonstrated that downregulation of tau expression in cell culture models synergistically sensitized cells to paclitaxel. This suggests that strategies to reduce tau levels or its expression could benefit outcomes of the paclitaxel treatment in metastatic ovarian carcinoma. Importantly, as aberrant tau has been also associated with a number of neurodegenerative diseases significant efforts in this field has been made to develop inhibitors and drugs targeting tau to treat these debilitating conditions. However, it remains to be established whether tau-based drugs and inhibitors could be used to increase paclitaxel sensitivity in ovarian carcinoma. We are partnering with a neuroscientist, Dr. Peter Penzes (Northwestern University) to determine the efficacy of tau inhibitors in preclinical models of ovarian cancer. In this application we hypothesize that drugs targeting tau, which were originally developed to treat neurodegenerative diseases, will synergize with paclitaxel in increasing its cytotoxicity and reducing clone formation of HGSOC cells, resulting in significantly reduced tumor burden in vivo. To test this hypothesis, we propose these specific aims: 1) to validate the efficacy of the combination of tau-based therapeutics and paclitaxel in pre-clinical models of HGSOC, and 2) to validate tau-based therapeutics in their efficacy to re- sensitize paclitaxel-resistant ovarian carcinoma to the paclitaxel treatment. The proposed experiments will be conducted using preclinical models of high grade serous ovarian carcinoma, including cell culture and xenograft models.