Taxol: Mechanisms of Action and Resistance

描述（由申请人提供）：该提案代表了一个研究药物开发的多方面计划。天然产物discodermolide有可能成为一种重要的抗肿瘤药物，特别是在紫杉醇耐药的肿瘤中。在我们实验室进行的临床前研究对于紫杉醇的临床开发至关重要，我们相信对discodermolide进行有意义的研究可以为其临床开发铺平道路。今天，人们对“靶向治疗”产生了极大的兴趣，即利用小分子和抗体靶向癌细胞中的异常信号通路。然而，对于许多恶性肿瘤，标准的基于细胞毒性的治疗，一些与靶向治疗相结合，将仍然是主流。Discodermolide是一种天然产物，其化学结构与紫杉醇非常不同，但其作用机制有主要的相似之处，但也有明显和有趣的差异。相对于紫杉醇，经discodermolide处理的细胞发展获得性耐药性的倾向较低。这归因于discodermolide诱导加速衰老和经历增殖停滞的延长状态的能力。我们花了几年时间来开发一种对discodermolide耐药的癌细胞系，并且与紫杉醇耐药细胞不同，这些细胞不具有紫杉醇耐药的经典机制，即β-微管蛋白突变或ATP依赖性药物外排泵P-糖蛋白的过表达。很可能discodermolide的独特性质与其诱导衰老的能力以及其作为免疫抑制剂的最初特征有关。该提案将集中于描述disocodermolide对药物诱导的衰老中涉及的分子途径的作用，以及其如何与4 EBP和mRNA加工和翻译的调节相关。尽管癌细胞的衰老是公认的抑制肿瘤生长的机制，但衰老细胞可能通过诱导炎症和细胞外重塑中涉及的几种途径而促进肿瘤发生（[64]中综述），并且在discodermolide的情况下，这可能使一些患者易于发生肺纤维化。因此，该提案的一个基本组成部分是具体目标3，该目标详细说明了一种全面的化学-生物学方法，以选择具有修饰的衰老诱导特性的discodermolide的有前途的结构类似物。理想情况下，这些化合物将保留母体化合物的非常有效和独特的微管结合特性，这些特性最初吸引了我们对这种药物的治疗开发的注意力，同时最大限度地减少衰老的可能性。合作私家侦探。的已经有许多富有成效的多年工作与天然产品和药物开发，并已聚集了一个高超的小组的同事在阿尔伯特爱因斯坦和一个独特的小组合成化学家作为合作者。 公共卫生相关性：紫杉醇在治疗许多人类恶性肿瘤中是有效的，但许多患者经历严重的副作用和/或发展获得性耐药性。这促使人们寻找具有相同或上级治疗功效的紫杉醇类药物。将确定另一种紫杉醇样药物discodermolide的作用机制，并测试不同结构类似物的化疗活性。

DESCRIPTION (provided by applicant): This proposal represents a multifaceted program for studying drug development. The natural product, discodermolide has the potential to be an important antitumor drug, particularly in Taxol resistant tumors. The preclinical studies that were done in our laboratory were crucial for the clinical development of Taxol and we believe that meaningful research with discodermolide could pave the way for its clinical development. Today, there is an immense interest in "targeted therapies", utilizing small molecules and antibodies that target aberrant signaling pathways in cancer cells. However for many malignancies, standard cytotoxic-based therapies, some in combination with targeted therapies, will remain the mainstream. Discodermolide is a natural product with a chemical structure very different from Taxol, but whose mechanism of action has major similarities, but also has distinct and intriguing differences. Relative to Taxol, discodermolide-treated cells have a low propensity for developing acquired resistance. This is attributable to discodermolide's ability to induce accelerated senescence and undergo a prolonged state of proliferative arrest. It has taken us several years to develop a discodermolide-resistant cancer cell line and unlike Taxol-resistant cells, these do not have classic mechanisms of Taxol resistance, namely beta-tubulin mutations or overexpression of the ATP- dependent drug efflux pump, P-glycoprotein. It is likely that the unique properties of discodermolide are related to its ability to induce senescence and also to its initial characterization as an immunosuppressive agent. This proposal will focus on delineating the effect of disocodermolide on the molecular pathways involved in drug- induced senescence and how that relates to modulation of 4EBP and mRNA processing and translation. Although senescence in cancer cells is a recognized mechanism of suppressing tumor-growth, the possibility exists that senescent cells may contribute to tumorigenesis through the induction of several pathways involved in inflammation and extracellular remodeling (reviewed in [64]), and in the case of discodermolide, this may render some patients susceptible to the development of pulmonary fibrosis. Thus, a fundamental component of this proposal is specific aim 3 that details a comprehensive chemical-biological approach to selecting promising structural analogs of discodermolide that have modified senescent-inducing properties. These compounds ideally would retain the very potent and unique microtubule-binding properties of the parent compound that initially attracted our attention for the therapeutic development of this drug, while minimizing the potential for senescence. The co-P.I.'s have had many productive years working with natural products and drug development and have assembled a superb group of colleagues at Albert Einstein and a unique group of synthetic chemists as collaborators. PUBLIC HEALTH RELEVANCE: Taxol is efficacious in the treatment of numerous human malignancies, but many patients experience serious side effects and / or develop acquired resistance. This has motivated a search for Taxol-like drugs that have equal or superior therapeutic efficacy. The mechansim of action of another Taxol-like drug, discodermolide will be determined and different structural analogs will be tested for improved chemotherapeutic activity.