Modulation of Radiation-induced Brain Injury in the Nonhuman Primate

描述(由申请人提供)：在接受分次局部或全脑照射(FWBI)治疗6个月后存活的原发和转移性脑瘤患者中，高达50%可能会出现进行性认知障碍；每年约有20万名患者接受脑部照射。虽然短期的临床干预可以调节认知障碍，但对于这种辐射引起的发病率，还没有经过证实的长期治疗或预防策略。啮齿动物模型为放射性脑损伤的发病机制提供了重要的见解，并为基于抗炎的治疗方法提供了理论基础，包括阻断肾素-血管紧张素系统。然而，由于担心这些结果对人类的适用性，这些结果在临床上的翻译受到了限制。啮齿动物的大脑结构和组织与人类非常不同，它们没有患者在接受脑辐射后经常会丧失的更高级别的执行功能。非人灵长类(NHP)在用于临床前研究时不太可能表现出这些限制。的确， 我们已经开发了一个NHP模型，在该模型中，成年雄性恒河猴的FWBI导致，i)更高阶执行功能的进行性下降，ii)在FWBI之前参与任务执行的大脑区域FDG-PET测量的葡萄糖摄取减少，iii)在FWBI之前没有参与任务的大脑区域的葡萄糖摄取增加，以及iv]组织病理学和MRI的变化，类似于在受照射的人脑中看到的变化。因此，我们假设，与类似的啮齿动物数据相比，使用这种新的NHP辐射诱导高阶认知障碍模型获得的纵向认知、干预和机制数据将更快、更可靠地转化为临床数据。为了检验这一假设，我们提出了以下建议 使用我们的NHP模型来确定具体目标。我们将，1]使用FDG-PET和MRI技术确定放射性认知障碍发生和发展的成像生物标志物和潜在机制，2]确定在FWBI前、中和后6个月应用血管紧张素1型受体拮抗剂(AT1RA)奥美沙坦是否可以永久性地预防或改善放射性认知损伤，并在放射后第一年通过非侵入性成像技术评估脑损伤，以及3]确定在放射后高级认知功能受损时开始服用AT1RA 6个月的奥美沙坦，可以预防或改善额外的辐射导致的认知损伤，并通过非侵入性成像技术对脑损伤进行调整，i)治疗6个月，ii)停止治疗后另外6个月。这些目标的成功实现将提供有关辐射引起的认知损害的发生和发展的新信息，并使我们能够更快、更可靠地将这些发现转化为临床试验，旨在提高接受FWBI的癌症患者的长期存活率和生活质量。

DESCRIPTION (provided by applicant): Progressive cognitive impairment can occur in up to 50% of primary and metastatic brain tumor patients surviving e6 months after treatment with fractionated partial or whole-brain irradiation (fWBI); ~200,000 patients/year receive brain irradiation. Although short-term clinical interventions can modulate cognitive impairment, there are no proven long-term treatments or preventive strategies for this radiation-induced morbidity. Rodent models have provided, i] important insights into the pathogenesis of radiation-induced brain injury, and ii] the rationale for anti-inflammatory-based therapeutic approaches, including blockade of the renin- angiotensin system. However, translation of these results to the clinic is limited by concerns about their applicability to humans. Rodents have a brain structure and organization that is very different from humans, and they do not have the higher-order executive functions most often diminished in patients after brain irradiation. Nonhuman primates (NHP) are much less likely to display these limitations when used for preclinical investigations. Indeed, we have developed a NHP model in which fWBI of adult male rhesus monkeys leads to, i] progressive decline in higher-order executive functions, ii] decreased glucose uptake measured by FDG-PET in brain areas involved in task performance prior to fWBI, iii] increased glucose uptake in brain areas previously not involved in the task prior to fWBI, and iv] histopathological and MRI changes that parallel those seen in the irradiated human brain. Thus, we hypothesize that the longitudinal cognitive, intervention, and mechanistic data obtained with this novel NHP model of radiation-induced higher order cognitive impairment will translate faster and more reliably to the clinic than similar rodent data. To test this hypothesis, we propose the following Specific Aims using our NHP model. We will, 1] identify imaging biomarkers and potential mechanisms for the onset and progression of radiation-induced cognitive impairment using FDG-PET and MRI techniques, 2] determine if administration of the angiotensin type 1 receptor antagonist (AT1RA), olmesartan, prior to, during, and for 6 months after fWBI can permanently prevent or ameliorate radiation-induced cognitive impairment and modulate the brain injury assessed by noninvasive imaging techniques during the first year postirradiation, and 3] determine if a 6 month administration of the AT1RA, olmesartan, starting at a postirradiation time when higher-order cognitive function is impaired, can prevent or ameliorate additional radiation-induced cognitive impairment and modulate the brain injury assessed by noninvasive imaging techniques over, i] 6 months of treatment, and ii] an additional 6 months after stopping treatment. Successful completion of these aims should provide new information about the onset and progression of radiation-induced cognitive impairment, and enable us to translate these findings faster and more reliably into clinical trials designed to enhance the long-term survival and QOL of cancer patients receiving fWBI.