Modulation of Radiation-induced Brain Injury in the Nonhuman Primate

描述（由申请方提供）：在接受分次部分或全脑照射（fWBI）治疗后存活6个月的原发性和转移性脑肿瘤患者中，高达50%的患者可能发生进行性认知障碍;每年约有200，000例患者接受脑照射。虽然短期的临床干预措施可以调节认知障碍，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战略。啮齿类动物模型提供了i]对辐射诱导的脑损伤的发病机理的重要见解，和ii]基于抗炎的治疗方法的基本原理，包括阻断肾素-血管紧张素系统。然而，将这些结果转化到临床上受到对其对人类适用性的担忧的限制。啮齿类动物的大脑结构和组织与人类非常不同，并且它们不具有脑辐射后患者中最常减少的高阶执行功能。当用于临床前研究时，非人灵长类动物（NHP）不太可能显示这些限制。的确， 我们已经开发了一种NHP模型，其中成年雄性恒河猴的fWBI导致：i）高级执行功能的进行性下降，ii）在fWBI之前参与任务执行的脑区域中通过FDG-PET测量的葡萄糖摄取减少，iii）在fWBI之前先前不参与任务的脑区域中葡萄糖摄取增加，和iv]组织病理学和MRI变化，其与在被照射的人脑中观察到的变化相似。因此，我们假设，与类似的啮齿动物数据相比，用这种辐射诱导的高阶认知障碍的新型NHP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。 为了验证这一假设，我们提出以下建议： 使用我们的NHP模型的具体目标。我们将，1]使用FDG-PET和MRI技术鉴定放射诱导的认知损害的发病和进展的成像生物标志物和潜在机制，2]确定在放射治疗之前、期间、fWBI后6个月可永久预防或改善辐射-诱导的认知损害并调节在放射后第一年期间通过非侵入性成像技术评估的脑损伤，和3]确定6个月施用AT 1 RA，奥美沙坦，在辐射后高级认知功能受损时开始，可以预防或改善额外的辐射诱导的认知损伤，并调节在6个月的治疗中通过非侵入性成像技术评估的脑损伤，和ii]停止治疗后再延长6个月。这些目标的成功完成应该提供关于辐射诱导的认知障碍的发作和进展的新信息，并使我们能够更快，更可靠地将这些发现转化为旨在提高接受fWBI的癌症患者的长期生存率和QOL的临床试验。 公共卫生相关性：每年大约有10万名癌症患者在接受分次部分或全脑照射（fWBI）后存活足够长的时间，以发展辐射诱导的认知障碍;目前没有经过证实的长期治疗或预防策略。使用我们的非人灵长类动物模型，我们将确定是否阻断肾素-血管紧张素系统可以防止或减轻辐射诱导的高阶认知障碍。这些结果将使我们能够更快，更可靠地将这些发现转化为临床试验，旨在提高接受fWBI的癌症患者的长期生存率和生活质量。

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. PUBLIC HEALTH RELEVANCE: Approximately 100,000 cancer patients per year survive long enough after fractionated partial or whole-brain irradiation (fWBI) to develop radiation-induced cognitive impairment; no proven long-term treatments or preventive strategies are currently available. Using our nonhuman primate model, we will determine if blockade of the renin-angiotensin system can protect against or mitigate radiation-induced higher-order cognitive impairment. The results should allow us to translate these findings faster and more reliably into clinical trials designed to enhance the long-term survival and quality of life of cancer patients receiving fWBI.