Molecular analysis and therapeutic targeting of PI3K signaling in thyroid cancer

描述(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年新增病例为6万例，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)治疗的组合成功地进行了治疗。然而，肿瘤可能以RAI难治性或转移性的形式出现或复发，在这种情况下预后较差，死亡很常见。间变性甲状腺癌虽然罕见，但通常在发病时不能切除，对治疗高度耐药，对RAI统一耐药，并与中位生存期不到一年有关。在美国，每年大约有2000名复发或晚期甲状腺癌患者死亡，其他许多人患有进展性、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方法。大量临床数据表明，PI3K/PTEN/AKT通路在分化型和间变性甲状腺癌中起重要作用。在之前的授予周期中，使用基因定义的小鼠模型，我们已经证明了PI3K信号的结构性激活易于发生转移性甲状腺癌，它与相关的其他相关基因改变是协同作用的。 诱导低分化和间变性甲状腺肿瘤，这些晚期肿瘤对PI3K抑制表现出快速适应性抵抗。此外，我们的初步数据表明，存在PI3K依赖的、AKT不依赖的通路，对甲状腺转化至关重要。目前的申请有两个广泛的长期目标。第一个目标是利用体内、体外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，并识别甲状腺细胞转化所需的关键信号节点和维持已建立的肿瘤所必需的信号节点，这可能提供新的治疗机会。第二个目标是在体内表征PI3K活性的甲状腺肿瘤细胞对PI3K抑制剂产生适应性耐药的细胞自主和非自主机制，并测试联合靶向治疗的效果。 抵抗的关键调解人。

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.