Taxol: Mechanisms of Action and Resistance

描述(由申请者提供)：本提案代表了一个研究药物开发的多方面的项目。天然产物盘状核苷有可能成为一种重要的抗肿瘤药物，特别是在紫杉醇耐药肿瘤中。我们实验室进行的临床前研究对紫杉醇的临床开发至关重要，我们相信有意义的盘状除草剂研究可以为其临床开发铺平道路。今天，人们对“靶向治疗”非常感兴趣，利用小分子和抗体来靶向癌细胞中的异常信号通路。然而，对于许多恶性肿瘤，标准的基于细胞毒的治疗，其中一些结合靶向治疗，仍将是主流。Discodermolide是一种天然产物，其化学结构与紫杉醇非常不同，但其作用机制有很大的相似之处，但也有明显而耐人寻味的差异。与紫杉醇相比，盘状避孕药处理的细胞产生获得性耐药的倾向较低。这归因于盘状糖胺能够加速衰老并经历长时间的增殖停滞状态。我们花了几年时间开发出一种盘状病毒耐药的癌细胞系，与紫杉醇耐药细胞不同，这些细胞没有紫杉醇耐药的经典机制，即β-微管蛋白突变或ATP依赖的药物外排泵P-糖蛋白的过度表达。盘状病毒的独特性质可能与其诱导衰老的能力有关，也可能与其作为免疫抑制剂的初步特征有关。这项建议将侧重于描述Disocodermolide对药物诱导衰老所涉及的分子途径的影响，以及这与4EBP的调节和mRNA的加工和翻译的关系。虽然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参与炎症和细胞外重塑的几条途径而参与肿瘤的发生(见[])，对于盘状核苷，这可能使一些患者更容易发生肺纤维化。因此，这项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综合的化学-生物学方法，以选择具有改善衰老诱导特性的盘状物的有希望的结构类似物。理想情况下，这些化合物将保留母体化合物非常有效和独特的微管结合特性，这一特性最初引起了我们对该药物治疗开发的关注，同时将衰老的可能性降至最低。这位合伙人S多年来一直致力于天然产物和药物开发，并召集了一批出色的爱因斯坦同事和一群独特的合成化学家作为合作者。

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.