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

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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.