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

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， 新的靶向治疗是特别具有挑战性的。然而，现在出现的一个一致的主题是， PI 3 K/Akt和mTOR途径的酪氨酸激酶（RTK）活化对于肉瘤肿瘤发生是关键的， 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，临床研究的结果令人失望。因此，需要药物开发的新方向 优化针对这些合理目标的治疗方法。我们假设PDGFRA代表一种 肉瘤亚群中的关键治疗靶点，可与mTOR抑制剂组合有效靶向 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/II期临床试验 表达滑膜肉瘤; 2）进行多柔比星与或不与IMC-3G 3的Ib/II期随机临床试验， PDGFRA特异性的人单克隆抗体;和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，晚期和晚期乳腺癌患者 转移性肉瘤迫切需要新的治疗方法。结合新一代药物， 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 治愈这种疾病。 斯隆

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-