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

摘要 上皮性卵巢癌的死亡率在过去的一个世纪里没有明显的变化。这种病还在 仍然是最致命的妇科恶性肿瘤，也是女性癌症死亡的第五大原因。这个 转移是这种病态疾病的主要死亡原因，也是预防的关键问题之一。 成功的治疗是化疗耐药。我们实验室研究的长期目标是 探讨调控卵巢癌转移及其复发化疗的分子机制 抗性表型。这项提案中概述的研究的目标是确定靶向治疗的效果 微管相关蛋白tau可增加紫杉醇的反应。 晚期卵巢癌患者通常采用手术和联合化疗。 含有紫杉烷(最常见的是紫杉醇)和铂试剂。此外，紫杉醇还被用作 二线药物治疗复发性铂类难治性上皮性卵巢癌。之前的研究已经将几个 紫杉醇耐药的不同分子机制；然而，到目前为止，还没有临床使用的策略 来克服这些机制。较新的先前研究，包括我们实验室的研究，已经将 卵巢浆液性癌组织中紫杉醇耐药tau蛋白的表达我们的数据表明 转移癌中tau阳性例数较原发癌明显增多。我们有 也证明了在细胞培养中下调tau的表达可以协同增敏细胞 紫杉醇。这表明降低tau水平或其表达的策略可能有益于 紫杉醇治疗转移性卵巢癌。 重要的是，tau的异常也与许多神经退行性疾病有关 在这一领域已经努力开发针对tau的抑制剂和药物来治疗这些衰弱。 条件。然而，基于tau的药物和抑制剂是否可以用于 增加卵巢癌患者对紫杉醇的敏感性。我们的合作伙伴是神经学家彼得·彭塞斯博士 (西北大学)确定tau抑制剂在卵巢癌临床前模型中的疗效。 在本申请中，我们假设针对tau的药物最初是为了治疗 神经退行性疾病，将与紫杉醇在增加其细胞毒性和减少克隆方面协同作用 HGSOC细胞的形成，导致体内肿瘤负担显著降低。为了检验这一假设，我们 提出这些具体目标：1)验证基于tau的疗法和 紫杉醇在HGSOC临床前模型中的应用，以及2)验证基于tau的治疗方法在重新治疗HGSOC方面的疗效。 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研究，包括细胞培养和异种移植 模特们。

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.