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.

新的治疗方法是迫切需要的高风险神经母细胞瘤的治疗，患者的结果没有显示在最近几十年的改善。目前临床上用于阻止神经母细胞瘤的癌细胞增殖的许多药剂通过诱导细胞衰老或准衰老状态来实现，在所述准衰老状态中，经治疗的神经母细胞瘤肿瘤逃避化疗。这种治疗诱导的衰老（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。新的PP2A活化剂将以两种方式施用。 首先作为衰老清除剂，通过恢复TIS后对细胞凋亡的敏感性。第二，它们将通过下调由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senomorphic剂。