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：
10685944
负责人：
Peter M Grace
金额：
$ 35.94万
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 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10685944
关键词：
Adverse effects Affect 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 Deacetylation 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 Therapeutic 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 preservation prevent repaired restoration side effect survivorship treatment effect tumor white matter

Adverse effects Affect 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 Deacetylation 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 Therapeutic 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 preservation prevent repaired restoration side effect survivorship treatment effect tumor white matter

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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.

概括化学疗法诱导的周围神经病（CIPN）和化学疗法诱导的认知障碍（CICI）是癌症治疗的主要副作用，经常长期存在于生存中。没有药物已获得美国食品和药物管理局的批准，以预防和/或充分管理CIPN和CICI。该应用程序旨在填补此空隙。设计用于管理CIPN和CICI的药物时的关注点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增强肿瘤控制。最近的发现表明，组蛋白脱乙酰基酶6（HDAC6）的抑制剂符合这些目标。 HDAC6脱乙酰酸盐含量非固定蛋白（如微管蛋白），而无需诱导表观遗传变化。最近的临床前和临床数据表明，HDAC6抑制剂可以改善肿瘤控制。我们最近表明，HDAC6抑制完全逆转了在顺铂治疗的小鼠中建立的CIPN。这是与感觉神经元中线粒体健康的恢复有关。初步数据表明共同通过预防线粒体损伤来防止HDAC6抑制剂预防CIPN。额外的初步数据表明HDAC6抑制作用还逆转了已建立的CICI和相关的大脑线粒体损伤。我们的假设是HDAC6抑制作用可防止并逆转具有或没有的小鼠CIPN和CICI 通过靶向线粒体健康，氧化应激和下游神经免疫性途径，肿瘤。我们将在3个特定目标中检验我们的假设：AIM1：确定HDAC6抑制剂防止CIPN的能力有或没有肿瘤的小鼠。目标2：确定HDAC6抑制对既定CIPN的影响。目标3：确定HDAC6抑制的有益作用是否扩展到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抑制剂也可以防止 CIPN和CICI在肿瘤存在下。这项研究具有创新性，因为我们建议靶向神经元中的HDAC6活性以控制神经毒性，同时增强了癌症控制。预期的结果很重要，因为它将识别HDAC6抑制作用是控制CIPN和CICI的一种现实新方法。这将增加数百万癌症患者和幸存者的生活质量。临床试验检查HDAC6的效果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迅速说服临床医生检查HDAC6抑制剂对CIPN和CICI的管理的价值。将HDAC6抑制剂鉴定为在化学疗法完成后可以使用的药物解决已建立的CIPN和CICI将对每天遭受痛苦的癌症幸存者带来巨大好处这些持续的神经毒性。