(PQ9) The role of Bclw (bcl2l2) in preventing chemotherapy induced neuropathy

 描述（由申请方提供）：挑衅性问题9询问：癌症治疗诱导的重度不良后遗症发生的分子和/或细胞机制是什么？我们的回应是，癌症化疗导致的不可治疗、不可逆的神经功能缺损是癌症患者和癌症幸存者的一个主要未满足的医疗需求。特别是，化疗诱导的周围神经病变（CIPN），在触觉和运动功能的缺陷，影响许多癌症患者与细胞毒性化疗治疗。这些神经功能缺陷往往限制了化疗的剂量，并对癌症患者和幸存者的生活质量造成重大且往往是永久性的障碍。我们还不了解化疗引起的轴突变性的潜在机制，也没有任何有效治疗由此产生的神经病变的方法。潜在疗法的经验性临床试验令人失望。因此，为了提供一个坚实的基础来开发治疗方法，必须了解化学疗法引起CIPN的机制过程。拟议的研究将定义CIPN的分子机制，并为这些可怕的治疗后果启动新的治疗方法。我们的研究计划主要集中在由化疗药物紫杉醇引起的神经病变。紫杉醇和相关化合物对于乳腺癌、卵巢癌和其他癌症的有效化疗是必不可少的，每年接受紫杉醇治疗的10万多名患者中的大多数都有神经病变的症状。在使用体内模型和专门的体外隔室培养物研究紫杉醇诱导的感觉神经元变性的初步研究中，我们已经表明紫杉醇直接作用于轴突以启动变性，并且紫杉醇降低Bclw（aka Bcl 2l 2）的细胞内水平，Bclw是感觉轴突终身保存所必需的蛋白质。引人注目的是，我们发现Bclw与其密切相关的家族成员Bcl 2和BclxL不同，因为只有Bclw被导致轴突变性的化疗剂量改变，并且只有Bclw可以防止紫杉醇引起的轴突变性。拟开展的研究将阐明紫杉醇和其他化疗药物影响Bclw表达的机制，以及Bclw如何预防化疗诱导的轴突变性。我们的初步研究表明，Bclw模拟物可能为设计限制或逆转神经化学疗法诱导的毒性的新疗法提供基础，就像甲酰四氢叶酸救援用于限制和预防甲氨蝶呤的毒性或Neulasta用于减轻化疗诱导的骨髓毒性一样。

 DESCRIPTION (provided by applicant): Provocative question 9 asks: What are the molecular and/or cellular mechanisms that underlie the development of cancer therapy-induced severe adverse sequelae? We respond that untreatable, irreversible neurologic deficits due to cancer chemotherapy constitute a major unmet medical need for cancer patients and cancer survivors. In particular, chemotherapy-induced peripheral neuropathy (CIPN), with deficits in tactile sensation and motor function, affect many cancer patients treated with cytotoxic chemotherapies. These neurologic deficits often limit the doses of chemotherapy that can be used, and cause a major and often permanent impediment to quality of life in cancer patients and survivors. We do not yet understand the underlying mechanism for chemotherapy-induced axonal degeneration, nor do we have any way of effectively treating the resultant neuropathy. Empirical clinical trials for potential therapies have been disappointing. Therefore, to provide a solid basis to develop therapeutics it is imperative to understand the mechanistic process by which chemotherapies cause CIPN. The proposed studies will define the molecular mechanism of CIPN and initiate novel therapeutic approaches for these dire consequences of treatment. Our study plan focuses primarily on neuropathy caused by the chemotherapeutic agent, paclitaxel. Paclitaxel and related compounds are essential for effective chemotherapies for breast, ovarian and other cancers, and the majority of the more than 100,000 patients treated each year with paclitaxel experience symptoms of neuropathy. In preliminary studies using in vivo models and specialized in vitro compartmented cultures to study paclitaxel-induced degeneration of sensory neurons, we have shown that paclitaxel acts directly on axons to initiate degeneration, and that paclitaxel reduces the intracellular level of Bclw (aka Bcl2l2), a protein essential for the lifelong preservation of sensory axons. Strikingly we find that Bclw differs from its closely related family members, Bcl2 and BclxL, in that only Bclw is altered by doses of chemotherapies that cause axonal degeneration, and only Bclw can prevent axonal degeneration caused by paclitaxel. The proposed studies will elucidate the mechanisms whereby paclitaxel and other chemotherapies affect Bclw expression, and how Bclw prevents chemotherapy induced axonal degeneration. Our preliminary studies suggest the exciting possibility that Bclw-mimetics may provide the basis for designing new therapies that limit or reverse neurologic chemotherapy-induced toxicity, much as leucovorin rescue is used to limit and prevent toxicity from methotrexate or as Neulasta is used to alleviate chemotherapy induced bone marrow toxicity.