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

• 批准号: 9914096
• 负责人: Cobi J Heijnen
• 金额: $ 36.68万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-22 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9914096
• 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; Outcome; Oxidative Stress; Pain; 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/antagonist; 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

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.

摘要 化疗所致周围神经病与化疗所致认知功能障碍 (CiCi)是癌症治疗的主要副作用，通常会持续很长时间。没有毒品有 已被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。 这项申请旨在填补这一空白。在设计药物来管理CIPN和CiCi时，一个需要考虑的问题是 它们不应该损害肿瘤控制。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。最近的发现表明，组蛋白脱乙酰酶6(HDAC6)的抑制剂可以达到这些目标。 HDAC6去乙酰化非组蛋白胞质蛋白，如微管蛋白，而不会引起表观遗传学变化。 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 最近发现，HDAC6的抑制完全逆转了顺铂治疗的小鼠已建立的CIPN。这是 与感觉神经元线粒体健康的恢复有关。初步数据显示，co- 给予HDAC6抑制剂通过防止线粒体损伤来保护CIPN。其他内容 初步数据表明，HDAC6抑制也逆转了已建立的CiCi和相关的脑 线粒体受损。 我们的假设是，HDAC6抑制可以预防和逆转CIPN和CiCi 通过靶向线粒体健康、氧化应激和下游神经免疫途径来治疗肿瘤。我们会 在3个具体目标上验证我们的假设：目的1：确定HDAC6抑制剂预防CIPN的能力 无论有没有肿瘤的小鼠。目的2：确定HDAC6抑制对已建立的CIPN的影响。目标3： 确定HDAC6抑制的有益效果是否延伸到CiCi。在目标1和目标3中，我们将 研究HDAC6抑制剂在肿瘤控制中的作用并确保HDAC6抑制剂也能预防 CIPN和CiCi在肿瘤的存在。 这项研究具有创新性，因为我们提出以神经元中的HDAC6活动为靶点来控制 神经毒性，同时加强癌症控制。预期结果意义重大，因为 它将确定HDAC6抑制是控制CIPN和CiCi的一种现实的新方法。这将增加 数百万癌症患者和幸存者的生活质量。检测HDAC6疗效的临床试验 肿瘤控制的抑制剂已经在进行中，因此该项目的预期结果应该是 迅速说服临床医生检查HDAC6抑制剂在治疗CIPN和CiCi方面的价值。 HDAC6抑制剂作为化疗完成后可完全使用的药物的鉴定 解决已建立的CIPN和CiCi将为癌症幸存者带来巨大好处，这些患者每天都在遭受 这些持久的神经毒性。