(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（适用提供）：挑衅性问题9问：癌症治疗引起的严重不良后遗症发展的分子和/或细胞机制是什么？我们回答说，由于癌症化学疗法而导致的不可治疗，不可逆转的神经系统防御构成了癌症患者和癌症幸存者的主要未满足医疗需求。特别是，化学疗法诱导的周围神经病（CIPN），触觉和运动功能方面缺乏，会影响许多接受细胞毒性化学疗法治疗的癌症患者。这些神经系统定义通常会限制可以使用的化学疗法剂量，并在癌症患者和生存中造成重大且通常是永久性的生活质量障碍。我们尚不了解化学疗法引起的轴突变性的潜在机制，也没有任何有效治疗所得神经病变的方法。潜在疗法的经验临床试验令人失望。因此，为了提供扎实的基础来发展理论，必须了解化学疗法引起CIPN的机械过程。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关注化学治疗剂紫杉醇引起的神经病。紫杉醇和相关化合物对于乳腺癌，卵巢和其他癌症的有效化学疗法至关重要，每年接受紫杉醇治疗的100,000多名患者中的大多数是神经病的症状。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研究中，我们表明紫杉醇直接作用于轴突以启动变性，而紫杉醇则可以减少BCLW（AKA BCL2L2）的细胞内的poter蛋白，并降低了protents neversent neverseang protery neverseang protery neverseang protery nevere nement nextean neveral intement。令人惊讶的是，我们发现BCLW与其密切相关的家族成员BCL2和BCLXL有所不同，因为只有BCLW会因导致轴突变性的化学疗法而改变，并且只有BCLW才能防止paclitaxel引起的轴突变性。拟议的研究将阐明紫杉醇和其他化学疗法影响BCLW表达的机制，以及BCLW如何阻止化学疗法诱导的轴突变性。我们的初步研究表明，BCLW-MIMETICS可能会为设计新疗法提供限制或逆转神经系统疗法诱导的毒性的基础的令人兴奋的可能性，就像白细胞蛋白营救一样限制和防止Neulasta的毒性来限制和防止Neulasta的毒性来使化学疗法化学疗法诱导诱导的骨骼骨骼毒性。