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

 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（“chemobrain”）是癌症化疗的重要不良后果，NCI已将其研究确定为目前管理或治疗策略有限或无效的知之甚少的问题。我们的初步数据表明，神经元兰尼碱受体/钙释放通道（RyR 2）的内质网（ER）变得氧化和“泄漏”的小鼠用阿霉素或甲氨蝶呤加5-FU。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，该药物可以修复泄漏的RyR 2通道。本申请的目的是：（1）建立和表征晚期人乳腺癌的鼠模型，其可用于研究经由ER上的氧化神经元RyR 2的细胞内钙（Ca 2+）渗漏是否是癌症化疗诱导的神经认知功能障碍的潜在新机制;以及（2）测试在体内固定渗漏的神经元RyR 2通道的新药Rycal（S107）是否可以预防化学性脑损伤。拟议的研究将具有重要的临床意义，因为Rycal S107与目前正在进行心脏和肌肉疾病临床试验的两种密切相关的Rycals属于同一化学类别，迄今为止，两者都具有良好的安全性。S107的优点是它在大脑中的浓度>10倍。（尽管S107由哥伦比亚大学申请专利，US 8，710，045，2014年4月29日，但该药物可供所有研究者使用，申请人未从其销售中获得任何收益）。本申请得到初步数据的支持，初步数据显示，常用的化疗药物导致C57 BL 6小鼠的认知功能障碍，可以使用Rycal S107预防，我们公布的数据显示，渗漏的神经元RyR 2通道可以导致应激诱导的认知功能障碍（创伤后应激障碍，PTSD），可以通过口服S107治疗来改善。本申请旨在使chemobrain和PTSD之间的新的机制联系-细胞内Ca 2+泄漏-并测试潜在的新疗法，防止这种泄漏和防止chemobrain。

 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.