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

基本信息

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
项目类别：
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

项目摘要

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-

肉瘤是一种异质性疾病，至少有 50 种不同的亚型。鉴于这种遗传多样性，发展新的靶向疗法的开发尤其具有挑战性。然而，现在出现的一个一致的主题是受体 PI3K/Akt 和 mTOR 通路的酪氨酸激酶 (RTK) 激活对于肉瘤肿瘤的发生至关重要，跨组织学亚型的增殖和存活。尽管以 RTK 和 mTOR 为目标有令人信服的理由肉瘤，临床研究结果令人失望。因此，药物开发需要新的方向针对这些合理目标优化治疗方法。我们假设 PDGFRA 代表肉瘤子集中的关键治疗靶点，可与 mTOR 抑制剂联合有效靶向和化疗。我们的具体目标是 1) 进行伊马替尼和依维莫司治疗 PDGFRA 的 Ib/ll 期临床试验表达滑膜肉瘤； 2) 在有或没有IMC-3G3的情况下进行阿霉素Ib/ll期随机临床试验， PDGFRA特异性人单克隆抗体； 3）研究PDGFRA抑制的抗肿瘤机制肉瘤肿瘤。公共卫生声明：由于缺乏有效的化疗，晚期和晚期患者转移性肉瘤非常需要新的疗法。结合特异性抑制的新一代药物促进肉瘤肿瘤生长的途径（PDGFRA 和 mTOR）应该会导致治疗的重大进展并治愈这种疾病。斯隆-