(PQ#9)Targeting leaky ryanodine receptor (RyR2) to treat and prevent chemotherapy-associated cognitive dysfunction in patients with breast cancer.

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基本信息

批准号：
10328409
负责人：
THERESA A GUISE
金额：
$ 60.06万
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：
2016
资助国家：
美国
起止时间：
2016-05-10 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10328409
关键词：
PQ#9 Targeting leaky ryanodine receptor

项目摘要

DESCRIPTION (provided by applicant): This application is responsive to the NCI Provocative Question #9 (RFA-CA-15-008). Cognitive dysfunction ("chemobrain") is an important adverse sequel of cancer chemotherapy, the study of which has been identified by the NCI as a poorly understood problem for which current management or treatment strategies are limited or ineffective. Our preliminary data show that neuronal ryanodine receptor/calcium release channels (RyR2) on the endoplasmic reticulum (ER) become oxidized and "leaky" in mice treated with doxorubicin or methotrexate plus 5-FU. These mice exhibit cognitive dysfunction that can be improved using a novel orally available small molecule drug (Rycal, S107) developed by the co-PI that fixes leaky RyR2 channels. The goals of this application are to: (1) establish and characterize a murine model of advanced human breast cancer that can be used to study whether intracellular calcium (Ca2+) leak via oxidized neuronal RyR2 on the ER is a novel mechanism underlying cancer chemotherapy-induced neurocognitive dysfunction; and (2) test whether the novel drug Rycal (S107) that fixes leaky neuronal RyR2 channels in vivo can prevent chemobrain. The proposed studies will have important clinical relevance as the Rycal S107 is in the same chemical class as two closely related Rycals that are currently in clinical testing for heart and muscle disorders, and to date both have excellent safety profiles. S107 has the advantage that it is concentrated >10-fold in the brain. (Although S107 is patented by Columbia University, US 8,710,045, 04/29/14, the drug is available to all investigators and the applicant receives no proceeds from its sale). This application is bolstered by preliminary data showing that commonly used chemotherapeutics cause cognitive dysfunction in C57BL6 mice that can be prevented using the Rycal S107, and by our published data showing that leaky neuronal RyR2 channels can cause stress-induced cognitive dysfunction (post-traumatic stress disorder, PTSD) that can be ameliorated by oral treatment with S107. This application aims to make the novel mechanistic link between chemobrain and PTSD - intracellular Ca2+ leak - and to test a potential novel therapy that prevents this leak and prevents chemobrain.

描述（由申请人提供）：本申请是对 NCI 挑衅性问题 #9 (RFA-CA-15-008) 的回应。认知功能障碍（“化学脑”）是癌症化疗的一个重要不良后果，对此的研究已进行。 NCI 认为这是一个人们知之甚少的问题，目前的管理或治疗策略有限或无效。我们的初步数据表明，内质上的神经元兰尼碱受体/钙释放通道（RyR2）。在接受多柔比星或甲氨蝶呤加 5-FU 治疗的小鼠中，网状组织 (ER) 被氧化并“渗漏”。这些小鼠表现出认知功能障碍，可以使用 co-PI 开发的新型口服小分子药物（Rycal，S107）来改善这种功能障碍。该应用的目标是：（1）建立并表征晚期人类乳腺癌的小鼠模型，该模型可用于研究细胞内钙是否存在。 (Ca2+) 通过内质网氧化神经元 RyR2 泄漏是癌症化疗引起的神经认知功能障碍的一种新机制；(2) 测试体内修复泄漏神经元 RyR2 通道的新药 Rycal (S107) 是否可以阻止化疗脑研究。具有重要的临床相关性，因为 Rycal S107 与两种密切相关的 Rycal 属于同一化学类别，这两种药物目前正在进行心脏和肌肉疾病的临床测试，并且迄今为止两者都具有出色的安全性S107 的优点是它在大脑中浓度超过 10 倍（尽管 S107 已获得哥伦比亚大学专利，US 8,710,045，2014 年 4 月 29 日），但该药物可供所有研究人员使用，申请人不会从中获得任何收益。该申请得到了初步数据的支持，该数据显示常用的化疗药物会导致 C57BL6 小鼠认知功能障碍，而使用 Rycal S107 可以预防这种功能障碍，并且通过我们发表的数据显示，渗漏的神经元 RyR2 通道会导致应激性认知功能障碍（创伤后应激障碍，PTSD），而这种情况可以通过口服 S107 治疗来改善。本申请旨在建立化学脑和 PTSD 之间的新机制联系 - 细胞内。 Ca2+ 泄漏 - 并测试一种潜在的新型疗法，以防止这种泄漏并防止化学脑。