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

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.