PQ12 Targeting HDAC6 for Chemotherapy-Induced Neuropathy and Chemobrain

PQ12 靶向 HDAC6 治疗化疗引起的神经病变和化疗脑

基本信息

批准号：
10376221
负责人：
Peter M Grace
金额：
--
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-22 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10376221
关键词：
Adverse effects Afferent Neurons Aftercare Axon Brain Cancer Control Cancer Patient Cancer Survivor Cells Chemotherapy-induced peripheral neuropathy Cisplatin Clinical Data Clinical Research Clinical Trials Cognitive deficits Cytosol Data Development Disease Drug Design Ensure Epigenetic Process FDA approved Goals HDAC6 gene Health Heat-Shock Proteins 90 Histone Deacetylase Histone Deacetylase Inhibitor Histones Impaired cognition Impairment Intervention Malignant Neoplasms Mediating Mitochondria Modeling Mus Neurodegenerative Disorders Neuroimmune Neurons Nociceptors Outcome Oxidative Stress Pathway interactions Patients Peripheral Peripheral Nerves Permeability Pharmaceutical Preparations Population Prevention Proteins Public Health Quality of life Reporting Research Resolution Solid Spinal Ganglia Synaptosomes T-Lymphocyte Testing Time Toxic effect Tubulin United States Food and Drug Administration anti-cancer antitumor effect cancer therapy chemobrain chemotherapy chemotherapy induced neuropathy clinical application improved inhibitor innovation mitochondrial dysfunction neuroinflammation neurotoxic neurotoxicity new therapeutic target novel novel strategies novel therapeutics pre-clinical preclinical study prevent repaired restoration side effect survivorship treatment effect tumor white matter

项目摘要

SUMMARY Chemotherapy-induced peripheral neuropathy (CIPN) and chemotherapy-induced cognitive impairment (CICI) are major side effects of cancer treatment that frequently persist long into survivorship. No drugs have been approved by the US Food and Drug Administration to prevent and/or adequately manage CIPN and CICI. This application aims at filling this void. A concern when designing drugs to manage CIPN and CICI is that they should not impair tumor control. Ideally, agents to control these neurotoxicities should also enhance tumor control. Recent findings indicate that inhibitors of histone deacetylase 6 (HDAC6) meet these goals. HDAC6 de-acetylates non-histone cytosolic proteins like tubulin without inducing epigenetic changes. Recent preclinical and clinical data show promise for HDAC6 inhibitors to improve tumor control. We recently showed that HDAC6 inhibition fully reverses established CIPN in cisplatin-treated mice. This was associated with restoration of mitochondrial health in sensory neurons. Preliminary data indicate that co- administration of HDAC6 inhibitors protect against CIPN by preventing mitochondrial damage. Additional preliminary data indicate that HDAC6 inhibition also reverses established CICI and associated brain mitochondrial damage. Our hypothesis is that HDAC6 inhibition prevents and reverses CIPN and CICI in mice with or without tumors by targeting mitochondrial health, oxidative stress, and downstream neuroimmune pathways. We will test our hypothesis in 3 specific aims: Aim1: Determine the capacity of HDAC6 inhibitors to prevent CIPN in mice with or without tumors. Aim 2: Determine the effect of HDAC6 inhibition on established CIPN. Aim 3: Determine whether the beneficial effects of HDAC6 inhibition extend to CICI. In aims 1 and 3, we will investigate the effect of HDAC6 inhibitors on tumor control and ensure that HDAC6 inhibitors also prevent CIPN and CICI in the presence of a tumor. This study is innovative because we propose to target HDAC6 activity in neurons to control neurotoxicities while at the same time enhancing cancer control. The expected outcome is significant because it will identify HDAC6 inhibition as a realistic novel approach to control CIPN and CICI. This will increase the quality of life of millions of cancer patients and survivors. Clinical trials to examine the effect of HDAC6 inhibitors on tumor control are already underway, and therefore the expected results of this project should rapidly convince clinicians to examine the value of HDAC6 inhibitors for management of both CIPN and CICI. Identification of HDAC6 inhibitors as drugs that can be used after completion of chemotherapy to completely resolve established CIPN and CICI will be of great benefit for cancer survivors suffering every day from these persistent neurotoxicities.

概括化疗引起的周围神经病变（CIPN）和化疗引起的认知障碍 (CICI) 是癌症治疗的主要副作用，通常会持续很长时间直至存活。没有药物有已获得美国食品和药物管理局批准用于预防和/或充分管理 CIPN 和 CICI。该应用程序旨在填补这一空白。设计药物来管理 CIPN 和 CICI 时需要考虑的一个问题是它们不应损害肿瘤控制。理想情况下，控制这些神经毒性的药物也应该增强肿瘤控制。最近的研究结果表明组蛋白脱乙酰酶 6 (HDAC6) 抑制剂可以实现这些目标。 HDAC6 使微管蛋白等非组蛋白胞浆蛋白去乙酰化，而不诱导表观遗传变化。最近的临床前和临床数据显示 HDAC6 抑制剂有望改善肿瘤控制。我们最近表明，HDAC6 抑制可完全逆转顺铂治疗小鼠中已建立的 CIPN。这是与感觉神经元线粒体健康的恢复有关。初步数据表明，共同 HDAC6 抑制剂的施用可通过防止线粒体损伤来预防 CIPN。额外的初步数据表明 HDAC6 抑制还可逆转已建立的 CICI 和相关大脑线粒体损伤。我们的假设是，HDAC6 抑制可预防和逆转患有或不患有这种疾病的小鼠的 CIPN 和 CICI。通过针对线粒体健康、氧化应激和下游神经免疫途径来治疗肿瘤。我们将通过 3 个具体目标检验我们的假设：目标 1：确定 HDAC6 抑制剂预防 CIPN 的能力有或没有肿瘤的小鼠。目标 2：确定 HDAC6 抑制对已建立的 CIPN 的影响。目标 3：确定 HDAC6 抑制的有益作用是否延伸至 CICI。在目标 1 和 3 中，我们将研究 HDAC6 抑制剂对肿瘤控制的作用，并确保 HDAC6 抑制剂还可以预防存在肿瘤时的 CIPN 和 CICI。这项研究具有创新性，因为我们建议针对神经元中的 HDAC6 活性来控制神经毒性，同时增强癌症控制。预期结果意义重大，因为它将确定 HDAC6 抑制作为控制 CIPN 和 CICI 的现实新方法。这将增加数百万癌症患者和幸存者的生活质量。检查 HDAC6 效果的临床试验肿瘤控制抑制剂已经在进行中，因此该项目的预期结果应该迅速说服临床医生检查 HDAC6 抑制剂对 CIPN 和 CICI 管理的价值。 HDAC6抑制剂鉴定为可在化疗完成后完全使用的药物解决已建立的 CIPN 和 CICI 将对每天遭受癌症折磨的癌症幸存者大有裨益这些持续的神经毒性。