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发病率和生活质量下降的一个重要原因。现在有大量证据支持促炎，衰老相关分泌表型（SASP）作为认知衰老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的大脑中的神经元活动和认知功能具有深远的影响，已知是由暴露于辐射和癌症化疗引起的。这些研究表明，抗衰老药物有可能减少化疗诱导的小胶质细胞激活，减少SASP因子的表达，从而改善年龄相关和癌症治疗相关的认知障碍。本项目的目标是开发一种新的合成齐墩烷三萜（SOT）， CDDO-2P-Im (2P-Im)，作为一种有效的老年治疗药物，用于治疗放射（RT）诱导的中枢神经系统（CNS）毒性的神经保护。该项目的目标是开发一种新型的、口服的合成齐墩烷三萜（SOT）， CDDO-2P-Im (2P-Im)，作为一种老年治疗药物，用于神经保护，防止癌症治疗引起的认知衰老。拟议的临床前研究旨在验证口服2P-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照射（IR）的脑肿瘤和影响中枢神经系统（CNS）的转移性肿瘤。这个I期项目的目标是明确定义口服CDDO-2P-Im的能力：1)抑制治疗诱导的SASP因子的产生，2)限制衰老细胞的积累，以及3)防止慢性小胶质细胞激活，从而保持小鼠化疗（目标1）或放疗（目标2）后的认知功能。

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.