P2 - Developing New Strategies for Targeting PDGFR/PI3K/AKT Pathways in Sarcoma

P2 - 制定针对肉瘤中 PDGFR/PI3K/AKT 通路的新策略

• 批准号: 7976102
• 负责人: GARY K SCHWARTZ
• 金额: $ 22.09万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7976102
• 关键词: CCI-779; Chemotherapy-Oncologic Procedure; Clinical; Clinical Research; Clinical Trials; Complex; Critical Pathways; Data; Dependency; Development; Disease; Doxorubicin; Drug resistance; Ewings sarcoma; Generations; Genetic Variation; Growth Factor; Histologic; Imatinib; In Vitro; Malignant Neoplasms; Mediating; Multiprotein Complexes; Nutrient; PDGFRA gene; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Predisposition; Public Health; Publishing; Randomized Clinical Trials; Receptor Protein-Tyrosine Kinases; Reporting; SDZ RAD; Signal Pathway; Signal Transduction Pathway; Signaling Molecule; Sirolimus; Therapeutic; Tyrosine Kinase Inhibitor; Xenograft procedure; cell growth; chemotherapy; drug development; effective therapy; human monoclonal antibodies; inhibitor/antagonist; mTOR protein; neoplastic cell; programs; response; sarcoma; synovial sarcoma; therapeutic target; tumor; tumor growth; tumorigenesis

Sarcoma is a heterogeneous disease with at least 50 different subtypes. Given this genetic diversity, the developnnent of new targeted therapies is particularly challenging. However, one consistent theme now emerging is that receptor tyrosine kinase (RTK) activation of PI3K/Akt and mTOR pathways are critical for sarcoma tumor oncogenesis, proliferation, and survival across histologic subtypes. Despite the compelling rationale to target RTKs and mTOR in sarcomas, results from clinical studies have been disappointing. Hence, a new direction in drug development is needed to optimize therapeutic approaches directed at these rational targets. We hypothesize that PDGFRA represents a critical therapeutic target in a subset of sarcomas that can be effectively targeted in combination with mTOR inhibitors and chemotherapy. Our specific aims are to 1) conduct a phase Ib/ll clinical trial of imatinib and everolimus in PDGFRA expressing synovial sarcomas; 2) conduct a phase Ib/ll randomized clinical trial of doxorubicin with or without IMC-3G3, a human monoclonal antibody specific for PDGFRA; and 3) investigate anti-tumor mechanisms of PDGFRA inhibition in sarcoma tumors. Public Health Statement: Given the lack of effective chemotherapy, patients with advanced and metastatic sarcoma are in great need of new therapies. Combining new generation drugs that specifically inhibit pathways that promote sarcoma tumor growth (PDGFRA and mTOR) should result in major advances in the treatment and cure of this disease. Sloan-

肉瘤是一种至少有50种不同亚型的异质性疾病。考虑到这种遗传多样性，这种发展 新的靶向疗法的研究尤其具有挑战性。然而，现在出现的一个一致的主题是受体 酪氨酸激酶(RTK)活化的PI3K/Akt和mTOR通路在肉瘤的发生发展中起关键作用。 不同组织亚型间的增殖和存活率。尽管有令人信服的理由将RTK和MTOR作为目标 肉瘤，临床研究的结果一直令人失望。因此，需要一个新的药物开发方向。 以优化针对这些合理靶点的治疗方法。我们假设PDGFRA代表一个 肉瘤亚群中可与mTOR抑制剂联合有效靶向的关键治疗靶点 还有化疗。我们的具体目标是：1)进行伊马替尼和维罗莫司治疗PDGFRA的Ib/II期临床试验 2)进行阿霉素加或不加IMC-3G3的Ib/11期随机临床试验， 3)研究了PDGFRA抑制小鼠肿瘤生长的机制。 肉瘤肿瘤。公共卫生声明：由于缺乏有效的化疗，晚期和 转移性肉瘤非常需要新的治疗方法。结合了新一代的药物，特别是抑制 促进肉瘤肿瘤生长的途径(PDGFRA和mTOR)应在治疗方面取得重大进展 并治愈这种疾病。 斯隆-