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

SBIR 第一阶段主题

• 批准号: 10928466
• 负责人: MICHAEL OHLMEYER
• 金额: $ 40万
• 依托单位: ATUX ISKAY GROUP LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2024-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10928466
• 关键词: Apoptosis; Cell Aging; Cell Proliferation; Cell model; Clinical; Development; Disease Progression; Evaluation; Inflammatory; Neuroblastoma; Outcome; Patient-Focused Outcomes; Pharmaceutical Chemistry; Phase; Phosphoric Monoester Hydrolases; Protein Phosphatase 2A Regulatory Subunit PR53; Proteins; Relapse; Small Business Innovation Research Grant; Therapeutic; Tumor Escape; Tumor Suppressor Proteins; cancer cell; cancer therapy; cell type; chemotherapy; high risk; improved; mortality; mouse model; novel; novel therapeutic intervention; novel therapeutics; scale up; senescence; tumor

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.

迫切需要新的治疗方法来治疗高危神经母细胞瘤，近几十年来患者的治疗结果没有任何改善。目前临床上使用的许多药物通过诱导细胞衰老或准衰老状态来阻止神经母细胞瘤的癌细胞增殖，在这种状态下，治疗的神经母细胞瘤肿瘤逃避化疗。这种疗法引起的衰老（TIS）导致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新的化合物，其通过增加肿瘤抑制磷酸酶 PP2A 的活性来发挥作用。新型 PP2A 激活剂将通过两种方式发挥治疗作用。 首先作为抗衰老剂，通过恢复 TIS 后对细胞凋亡的敏感性。其次，它们将通过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）的表达来充当衰老剂。