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

 描述(由申请人提供)：挑衅性问题9问：癌症治疗引发严重不良后遗症的分子和/或细胞机制是什么？我们回应说，癌症化疗导致的无法治疗的、不可逆转的神经缺陷构成了癌症患者和癌症幸存者的主要未得到满足的医疗需求。特别是，化疗引起的周围神经病变(CIPN)，触觉和运动功能障碍，影响许多接受细胞毒性化疗的癌症患者。这些神经缺陷往往限制了可以使用的化疗剂量，并对癌症患者和幸存者的生活质量造成了重大的、往往是永久性的障碍。我们还不了解化疗导致轴突变性的潜在机制，也没有任何方法有效地治疗由此产生的神经病变。潜在疗法的经验临床试验一直令人失望。因此，为了为治疗学的发展提供坚实的基础，了解化疗导致CIPN的机制过程是非常必要的。拟议的研究将确定CIPN的分子机制，并针对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化疗药物紫杉醇引起的神经病变上。紫杉醇及其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研究紫杉醇诱导的感觉神经元变性的初步研究中，我们发现紫杉醇直接作用于轴突启动变性，并且紫杉醇降低Bclw(又名Bcl2l2)的细胞内水平，Bclw是终生保存感觉神经轴突所必需的蛋白质。值得注意的是，我们发现Bclw与其亲缘关系密切的家族成员Bcl2和BclxL的不同之处在于，只有Bclw被引起轴突变性的化疗药物剂量改变，并且只有Bclw可以防止紫杉醇引起的轴突变性。这项拟议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如何防止化疗诱导的轴突变性。我们的初步研究表明，令人兴奋的可能性是，Bclw模拟物可能为设计限制或逆转神经化疗毒性的新疗法提供基础，就像亚叶酸钙用于限制和预防甲氨蝶呤的毒性或Neulasta用于减轻化疗引起的骨髓毒性一样。

 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.