TOPIC 430: A NEW SMALL MOLECULE SENOTHERAPEUTIC FOR THE CHEMOPREVENTION OF THERAPY-RELATED COGNITIVE AGING

认知障碍是癌症幸存者，特别是儿童癌症幸存者的显著发病率和生活质量下降的原因。现在有大量证据支持促炎衰老相关分泌表型（SASP）作为认知老化和其他年龄相关疾病的主要贡献者的作用。小胶质细胞衰老对正常衰老大脑中的神经元活动和认知功能具有深远的影响，并且已知是由暴露于辐射和癌症化疗诱导的。这些研究已经证明了衰老清除剂减少化疗诱导的小胶质细胞活化、减少SASP因子表达从而改善年龄相关和癌症治疗相关的认知障碍的潜力。本项目的目标是开发新的合成齐墩果烷三萜类化合物（SOT），CDDO-2 P-Im（2 P-Im），作为用于治疗辐射（RT）诱导的中枢神经系统（CNS）毒性的有效的神经保护剂。该项目的目标是开发新型的口服生物可利用的合成齐墩果烷三萜类化合物（SOT），CDDO-2 P-Im（2 P-Im），作为神经保护剂用于对抗癌症治疗诱导的认知老化。拟定的临床前工作旨在验证口服给药2 P-Im将减轻目标人群中治疗相关毒性的风险，这些人群包括接受全身化疗或治疗性放疗（IR）的脑肿瘤和影响中枢神经系统（CNS）的转移性肿瘤个体。该I期计划的目标是明确定义口服施用CDDO-2 P-Im的能力，以：1）。抑制治疗诱导SASP因子的产生，2）。限制衰老细胞的积累，以及3）。预防慢性小胶质细胞活化，从而在小鼠中施用化疗（Aim 1）或放疗（Aim 2）后保留认知功能。

Cognitive impairment is a cause of significant morbidity and diminished quality of life for cancer survivors and particularly for survivors of childhood cancer. There is now substantial evidence supporting the role of the pro-inflammatory, senescence-associated secretory phenotype (SASP) as a major contributor to cognitive aging and other age-related diseases. Microglial senescence has profound consequences for neuronal activity and cognitive function in the normal aging brain and is known to be induced by exposure to radiation and to cancer chemotherapy. These studies have demonstrated the potential of senolytic agents to reduce chemotherapy induced microglial activation, reduce expression of SASP factors and to thereby improve age-associated, and cancer therapy-related cognitive impairment. The goal of this project is to develop the novel synthetic oleanane triterpenoid (SOT), CDDO-2P-Im (2P-Im), as an effective senotherapeutic for use in neuroprotection against therapeutic radiation (RT)-induced central nervous system (CNS) toxicity. The goal of this project is to develop the novel, orally bioavailable synthetic oleanane triterpenoid (SOT), CDDO-2P-Im (2P-Im), as senotherapeutic for use in neuroprotection against cancer therapy-induced cognitive aging. The proposed preclinical effort is designed to validate the oral administration 2P-Im will mitigate risk for therapy-related toxicity in target populations that include individuals undergoing either systemic chemotherapy or therapeutic irradiation (IR) of brain tumors and metastatic tumors affecting the central nervous system (CNS). The goals of this Phase I program are to clearly define the capacity of oral administration of CDDO-2P-Im to: 1). suppress therapy-induced production of SASP factors, 2). limit accumulation of senescent cells, and 3). prevent chronic microglial activation, thereby preserving cognitive function following administration of either chemotherapy (Aim 1) or radiation therapy (Aim 2) in mice.