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

(PQ9) Bclw (bcl2l2) 在预防化疗引起的神经病变中的作用

基本信息

批准号：
9896777
负责人：
ROSALIND A. SEGAL
金额：
$ 57.75万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9896777
关键词：
Address Affect Afferent Neurons Affinity Animal Model Apoptotic Axon BCL-2 Protein BCL2L1 gene BH4 Domain Back Binding Bone Marrow Breast Calpain Cancer Patient Cancer Survivor Caspase Cell Survival Chemotherapy-Oncologic Procedure Chemotherapy-induced peripheral neuropathy Clinical Trials Cytotoxic Chemotherapy Data Development Dose Dose-Limiting Event Family Family member Fibroblasts Goals Human ITPR1 gene In Vitro Interruption Leucovorin Life MAP Kinase Gene MAPK8 gene Malignant Neoplasms Medical Methotrexate Modeling Molecular Motor Nerve Neurologic Neurologic Deficit Neurons Neuropathy Ovarian Paclitaxel Pain Pathologic Pathway interactions Patients Pegfilgrastim Peptide Hydrolases Peripheral Nerves Pharmaceutical Preparations Phosphotransferases Presynaptic Terminals Process Proteins Protocols documentation Quality of life Role Sensory Solid Symptoms Testing Therapeutic Therapeutic Intervention Time Touch sensation Toxic effect analog anticancer research axonal degeneration axonopathy base cancer therapy chemotherapeutic agent chemotherapy chemotherapy induced neuropathy design experience improved in vivo Model member mimetics motor disorder motor symptom novel strategies novel therapeutic intervention novel therapeutics preservation prevent prototype public health relevance receptor repaired therapeutic evaluation

项目摘要

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.

描述（由申请人提供）：挑衅性问题 9 提出：癌症治疗引起的严重不良后遗症的分子和/或细胞机制是什么？我们认为，癌症化疗导致的不可治疗、不可逆的神经功能缺损是一个主要的未满足问题。特别是，化疗引起的周围神经病变（CIPN）会导致触觉和运动功能缺陷，影响许多接受细胞毒性化疗的癌症患者。神经系统缺陷通常限制了可永久使用的化疗剂量，并对癌症患者和幸存者的生活质量造成重大且经常障碍。我们尚不了解化疗引起的轴突变性的潜在机制。任何有效治疗由此产生的神经病变的方法都令人失望，因此，为了为开发治疗方法提供坚实的基础，必须了解化疗引起 CIPN 的机制。我们的研究计划主要关注化疗药物紫杉醇和相关化合物引起的神经病变，这对于乳腺癌、卵巢癌和其他癌症的有效化疗至关重要。在使用体内模型和专门的体外隔室培养物进行研究的初步研究中，每年接受紫杉醇治疗的超过 100,000 名患者中的大多数都会出现神经病变症状。在紫杉醇诱导的感觉神经元变性中，我们发现紫杉醇直接作用于轴突以引发变性，并且紫杉醇降低了 Bclw（又名 Bcl2l2）的细胞内水平，Bclw 是感觉轴突终生保存所必需的蛋白质。 Bclw 与其密切相关的家族成员 Bcl2 和 BclxL 不同，因为只有 Bclw 会因化疗剂量而改变，从而导致轴突变性，并且只有 Bclw 可以预防紫杉醇引起的轴突变性。拟议的研究将阐明紫杉醇和其他化疗影响 Bclw 表达的机制，以及 Bclw 如何预防化疗引起的轴突变性。我们的初步研究表明了 Bclw 模拟物令人兴奋的可能性。可以为设计限制或逆转神经化疗引起的毒性的新疗法提供基础，就像亚叶酸救援用于限制和预防毒性一样来自甲氨蝶呤或 Neulasta 用于减轻化疗引起的骨髓毒性。