(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(“化疗”)是癌症化疗的一个重要的不良后遗症，NCI已将其研究确定为一个知之甚少的问题，目前的管理或治疗策略对此有限或无效。我们的初步数据显示，在阿霉素或甲氨蝶呤加5-FU治疗的小鼠中，内质网(ER)上的神经元兰尼定受体/钙释放通道(RyR2)被氧化并“泄漏”。这些小鼠表现出认知功能障碍，可以使用一种新的口服小分子药物(Rycal，S107)来改善，该药物是由co-PI开发的，可以修复泄漏的RyR2通道。本应用的目标是：(1)建立并鉴定晚期人类乳腺癌的小鼠模型，该模型可用于研究通过氧化的神经元RyR2在内质网的钙泄漏是否是癌症化疗导致神经认知功能障碍的新机制；以及(2)测试修复体内泄漏的神经元RyR2通道的新药Rycal(S107)是否可以预防化学阻塞。拟议中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测试的两种密切相关的Rycal属于同一化学类别，到目前为止，这两种药物都具有极好的安全性。S107的优势在于，它在大脑中的浓度是原来的10倍。(虽然S107由哥伦比亚大学申请专利，美国8,710,045,2014年4月29日，但所有调查人员都可以获得该药物，申请人没有从其销售中获得任何收益)。这一应用得到了以下初步数据的支持：常用化疗药物会导致C57BL6小鼠的认知功能障碍，而使用Rycal S107可以预防这种功能障碍；我们发表的数据表明，泄漏的神经元RyR2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来改善。这项应用旨在建立化学屏障和PTSD之间的新机制联系-细胞内钙泄漏-并测试一种潜在的新疗法，以防止这种泄漏和防止化学屏障。

 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.