SBIR PHASE I TOPIC #446 - DEVELOPMENT OF SENOTHERAPEUTIC AGENTS FOR CANCER TREATMENT

目前迫切需要新的治疗方法来治疗高风险神经母细胞瘤，近几十年来，患者的预后没有任何改善。目前临床上用于阻止神经母细胞瘤癌细胞增殖的许多药物是通过诱导细胞衰老或准衰老状态来实现的，在这种状态下，已治疗的神经母细胞瘤肿瘤逃避化疗。这种治疗引起的衰老（TIS）的复发和疾病进展是一个主要问题和死亡原因。该提案旨在评估一类通过增加肿瘤抑制磷酸酶PP2A活性而起作用的新化合物。这种新型的PP2A激活剂将在两个方面发挥老年治疗作用。

New therapeutic approaches are urgently required for the treatment of high-risk neuroblastoma where patient outcomes have shown no improvement over recent decades. Many of the agents currently used clinically to arrest cancer cell proliferation of neuroblastoma do so by inducing cellular senescence, or a quasi-senescent state, in which treated neuroblastoma tumors evade chemotherapy. Relapse and disease progression from this therapy induced senescence (TIS)is a major problem and cause of mortality. This proposal aims to evaluate a new class of compounds that act by increasing the activity of a tumor suppressor phosphatase, PP2A. The novel PP2A activators will be senotherapeutic in two ways. First as senolytic agents by restoring sensitivity to apoptosis after TIS. Second, they will act as senomorphic agents by down regulating the expression of pro-inflammatory proteins (SASP) expressed by senescent neuroblastoma and other tumor associated cell types.