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，在女性最常见的癌症中排名第五。2013年预计的6万例新病例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，通过手术和放射性碘（RAI）治疗的联合治疗成功。然而，肿瘤可能出现或复发为rai难治性或转移性，在这种情况下，他们有一个较差的预后和死亡是常见的。间变性甲状腺癌虽然罕见，但通常在发病时不可切除，对治疗高度耐药，一致抗rai，中位生存期不到一年。在美国，每年大约有2000名复发性或晚期甲状腺癌患者死亡，还有许多人患有进行性、有症状的疾病。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。近期大量临床数据表明，PI3K/PTEN/AKT通路在分化型和间变性甲状腺癌中都起着至关重要的作用。在之前的授权周期中，我们使用遗传定义的小鼠模型，证明PI3K信号的组成性激活易导致转移性甲状腺癌的发展，并与相关的其他相关遗传改变合作

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.