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

迫切需要新的治疗方法来治疗高危神经母细胞瘤，因为近几十年来患者的预后没有显示出任何改善。目前临床上用于抑制神经母细胞瘤癌细胞增殖的许多药物都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，治疗后的神经母细胞瘤肿瘤可以逃避化疗。由这种疗法引起的复发和疾病进展(TIS)是一个主要的问题和死亡原因。这项建议旨在评估一类新的化合物，这些化合物通过增加肿瘤抑制磷酸酶PP2A的活性来发挥作用。新型PP2A激活剂将在两个方面具有感官治疗作用。 首先作为感觉剂，恢复TIS后对细胞凋亡的敏感性。其次，它们将作为感觉剂，下调衰老神经母细胞瘤和其他肿瘤相关细胞类型表达的促炎蛋白(SASP)的表达。

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.