Molecular analysis and therapeutic targeting of PI3K signaling in thyroid cancer

描述（由申请人提供）：甲状腺癌是最常见的内分泌恶性肿瘤，在女性诊断的最常见癌症中排名第五。预计2013年将有60 000个新病例，这反映了甲状腺癌发病率的上升。大多数患者患有分化型甲状腺癌，并通过手术和放射性碘（RAI）治疗的组合成功管理。然而，肿瘤可能以RAI难治性或转移性的形式存在或复发，在这种情况下，它们具有较差的预后并且死亡是常见的。间变性甲状腺癌虽然罕见，但通常在就诊时不可切除，对治疗高度耐药，一致耐RAI，并且与少于一年的中位生存期相关。在美国，每年约有2,000名复发或晚期甲状腺癌患者死亡，还有许多其他患者患有进行性症状性疾病。因此，晚期甲状腺癌患者迫切需要更详细地了解所涉及的途径和新的靶向治疗。许多临床数据最近指出PI 3 K/PTEN/AKT通路在分化型和间变性甲状腺癌中起着至关重要的作用。在前一个资助周期中，我们使用遗传学定义的小鼠模型，证明了PI 3 K信号传导的组成性激活倾向于转移性甲状腺癌的发展，它与相关的其他相关遗传改变相配合。 诱导低分化和间变性甲状腺肿瘤，并且这些晚期肿瘤显示出对PI 3 K抑制的快速适应性抗性。此外，我们的初步数据表明，存在PI 3 K依赖性，AKT非依赖性途径甲状腺转化必不可少。目前的应用程序有两个广泛的长期目标。第一个目标是利用体内、离体和体外方法的组合来进一步剖析甲状腺肿瘤发生的早期阶段，并确定甲状腺细胞转化所需的关键信号传导节点，以及维持已建立的肿瘤所必需的信号传导节点，这可能提供新的治疗机会。第二个目的是在体内表征PI 3 K活性甲状腺肿瘤细胞对PI 3 K抑制剂产生适应性抗性的细胞自主和非自主机制，并测试靶向PI 3 K抑制剂的联合疗法的功效。 抵抗的关键媒介。

DESCRIPTION (provided by applicant): Thyroid cancer is the most common endocrine malignancy and ranks as the fifth most common cancer diagnosed in women. Rising incidence of thyroid cancer is reflected by the projected 60,000 new cases in 2013. A majority of patients have differentiated thyroid cancer and are managed successfully with a combination of surgery and radioiodine (RAI) therapy. However, tumors may present or recur as RAI-refractory or metastatic, in which case they have a poorer prognosis and death is common. Anaplastic thyroid cancer, although rare, is typically unresectable at presentation, highly resistant to therapy, uniformly RAI-resistant, and associated with a median survival of less than one year. Approximately 2,000 patients with recurrent or advanced thyroid cancer die each year in the U.S. and many others suffer from progressive, symptomatic disease. More detailed understanding of the pathways involved, and novel targeted therapies are thus desperately needed for patients with advanced thyroid cancer. Numerous clinical data have recently pointed to the PI3K/PTEN/AKT pathway as a crucial player in both differentiated and anaplastic thyroid cancer. During the previous granting cycle, using genetically defined mouse models, we have demonstrated that constitutive activation of PI3K signaling predisposes to the development of metastatic thyroid cancer, that it cooperates with relevant additional relevant genetic alterations to induce poorly differentiated and anaplastic thyroid tumors, and that these advanced tumors display rapid adaptive resistance to PI3K inhibition. Furthermore, our preliminary data suggest the existence of PI3K-dependent, AKT-independent pathways essential for thyroid transformation. The current application has two broad, long-term objectives. The first goal is to utilize a combination of in vivo, ex vivo, and in vitro approaches to further dissect the early stages of thyroid tumorigenesis and identify key signaling nodes required for thyrocyte transformation and essential for maintenance of established tumors, which may provide novel therapeutic opportunities. The second objective is to characterize in vivo the cell autonomous and non-autonomous mechanisms through which PI3K-active thyroid tumor cells develop adaptive resistance to PI3K inhibitors, and to test the efficacy of combination therapies targeting key mediators of resistance.