Molecular analysis and therapeutic targeting of PI3K signaling in thyroid cancer

甲状腺癌中 PI3K 信号传导的分子分析和治疗靶向

• 批准号: 10062869
• 负责人: Antonio Di Cristofano
• 金额: $ 42.25万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-02-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10062869
• 关键词: Aggressive behavior; Automobile Driving; BRAF gene; Cancer Patient; Cell Culture Techniques; Cell Line; Cell Proliferation; Cell Survival; Cessation of life; Chemotherapy and/or radiation; Clinical; Combined Modality Therapy; Complex; Critical Pathways; Cytotoxic Chemotherapy; Data; Development; Disease; Disease Progression; Disease model; Emergency Situation; Endocrine; Epithelial Cells; Event; FRAP1 gene; Feedback; Foundations; Genetic; Genetically Engineered Mouse; Goals; In Vitro; Incidence; Knowledge; MEKs; Malignant Neoplasms; Malignant neoplasm of thyroid; Maps; Mediating; Molecular; Molecular Analysis; Mutate; Mutation; Neoplastic Cell Transformation; Neurofibromin 2; Oncogenes; Oncogenic; Operative Surgical Procedures; Palliative Care; Pathway interactions; Patients; Physiological; Process; Prognosis; Protein Kinase; Radioactive Iodine; Refractory; Resistance; Resistance development; Role; Sgk protein; Signal Pathway; Signal Transduction; TP53 gene; Testing; Therapeutic; Thyroid Gland; Time; Unresectable; Woman; anaplastic thyroid cancer; base; cancer diagnosis; clinically relevant; combinatorial; design; effective therapy; genetic approach; in vivo; in vivo Model; inhibitor/antagonist; mouse genetics; mouse model; mutant; novel; overexpression; patient population; patient subsets; prototype; radioiodine therapy; resistance mechanism; response; targeted treatment; therapeutic target; therapy resistant; tumor; tumor growth; tumor progression

Thyroid cancer is the most common endocrine malignancy and ranks as the sixth most common cancer diagnosed in women. Rising incidence of thyroid cancer is reflected by the projected 52,000 new cases in 2019. 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. Among these, anaplastic thyroid cancer (ATC), although relatively rare, represents a true clinical emergency: ATC is typically unresectable at presentation, highly resistant to therapy, RAI-resistant, and associated with a median survival of less than 9 months when patients are treated with multimodal therapy, and less than 3 months with palliative care. Cytotoxic chemotherapy and radiation are generally ineffective in prolonging survival of ATC patients. Thus, ATC remains one of the most lethal tumors and needs novel, effective, and especially rational therapeutic approaches. The major obstacle to this goal is the lack of a detailed understanding of the pathways altered both in the early stages (drivers) and during progression of ATC. As the patient population is small, our mechanistic knowledge is based on the retrospective analysis of patient material and on cell lines often of dubious origin. We now know that TP53 is lost or mutated in 70% of ATCs, and that in almost 40% the PI3K cascade is constitutively activated. Additional common drivers include BRAF (40%) and RAS (27%) activating mutations. Despite this knowledge, it is increasingly clear that we are still missing a comprehensive wiring chart depicting all the interactions between different, cooperating driver pathways. Such detailed map is of paramount importance to design effective multidrug combinations that consider less known signaling conduits, mechanisms of resistance, and feedback pathway activation. 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 test the hypothesis that activation and/or overexpression of the SGK1 protein kinase are integral and essential components of the neoplastic transformation process initiated by constitutive activation of PI3K, RAS, and SRC in thyroid epithelial cells and that SGK1 targeting is essential for effective inhibition of tumor growth. The second objective is to use genetically engineered mouse models, as well as cell culture approaches, to test the hypothesis that mutations in mTORC1-activating pathways, including loss of NF2 and activation of PI3K signaling, cooperate with oncogenic RAS by contributing crucial signals needed for RAS-mediated transformation of thyroid epithelial cells. This genetic interaction opens a window of opportunity for targeted therapeutic approaches.

甲状腺癌是最常见的内分泌恶性肿瘤，在女性确诊的癌症中排名第六。预计2019年新增病例为5.2万例，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。其中，间变性甲状腺癌(ATC)虽然相对罕见，但代表了真正的临床紧急情况：ATC通常在出现时无法切除，对治疗高度抵抗，对RAI耐药，在接受多模式治疗时患者的中位生存期不到9个月，而接受姑息治疗的患者中位生存期不到3个月。细胞毒性化疗和放射治疗在延长ATC患者生存时间方面通常无效。因此，ATC仍然是最致命的肿瘤之一，需要新的、有效的、特别是合理的治疗方法。实现这一目标的主要障碍是缺乏对ATC早期阶段(驾驶员)和进展过程中改变的路径的详细了解。由于患者人数很少，我们的机制知识是基于对患者材料和来源不明的细胞系的回顾分析。我们现在知道，TP53在70%的ATC中丢失或突变，而在近40%的ATC中，PI3K级联是结构性激活的。其他常见的驱动因素包括BRAF(40%)和RAS(27%)激活突变。尽管有这些知识，但越来越明显的是，我们仍然缺少一张描述所有 不同的、相互协作的驾驶路径之间的相互作用。这种详细的图谱对于设计有效的多药组合至关重要，这些组合考虑了鲜为人知的信号通路、耐药机制和反馈途径激活。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、体外和体外方法相结合的方法来验证这样的假设，即SGK1蛋白激酶的激活和/或过表达是甲状腺上皮细胞中PI3K、RAS和SRC结构性激活所启动的肿瘤转化过程中不可或缺的基本成分，并且SGK1靶向对于有效抑制肿瘤生长是必不可少的。第二个目标是使用基因工程小鼠模型以及细胞培养方法来检验这一假设，即mTORC1激活途径的突变，包括NF2的丢失和PI3K信号的激活，通过提供RAS介导的甲状腺上皮细胞转化所需的关键信号，与致癌的RAS协同作用。这种遗传交互作用为目标用户打开了一扇机会之窗 治疗方法。