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
基本信息
- 批准号:10521263
- 负责人:
- 金额:$ 42.25万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Aggressive behaviorAutomobile DrivingBRAF geneCancer PatientCell Culture TechniquesCell LineCell ProliferationCell SurvivalCessation of lifeChemotherapy and/or radiationClinicalCombined Modality TherapyComplexCritical PathwaysCytotoxic ChemotherapyDataDevelopmentDiseaseDisease ProgressionDisease modelDrug CombinationsEmergency SituationEndocrineEpithelial CellsEventFRAP1 geneFeedbackFoundationsGeneticGenetically Engineered MouseGoalsIn VitroIncidenceKnowledgeMEKsMalignant NeoplasmsMalignant neoplasm of thyroidMapsMediatingMolecularMolecular AnalysisMutateMutationNeoplastic Cell TransformationNeurofibromin 2OncogenesOncogenicOperative Surgical ProceduresPIK3CG genePalliative CarePathway interactionsPatientsPhysiologicalProcessPrognosisProtein KinaseRadioactive IodineRecurrenceRefractoryResistanceResistance developmentRoleSgk proteinSignal PathwaySignal TransductionTP53 geneTestingTherapeuticThyroid GlandTimeUnresectableWomananaplastic thyroid cancercancer diagnosisclinically relevantcombinatorialdesigneffective therapygenetic approachin vivoin vivo Modelinhibitormouse geneticsmouse modelmutantnoveloverexpressionpatient populationpatient subsetsprototyperadioiodine therapyrational designresistance mechanismresponsetargeted treatmenttherapeutic targettherapy resistanttumortumor growthtumor progression
项目摘要
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,在女性最常见的癌症中排名第六。预计2019年将有5.2万例新病例,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,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。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通常在出现时不可切除,对治疗高度耐药,对rai耐药,并且当患者接受多模式治疗时,中位生存期不到9个月,而姑息治疗则不到3个月。细胞毒性化疗和放疗通常对延长ATC患者的生存期无效。因此,ATC仍然是最致命的肿瘤之一,需要新颖,有效,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早期阶段(驾驶员)和ATC进展过程中路径改变的详细了解。由于患者人数较少,我们的机制知识是基于对患者材料的回顾性分析和来源可疑的细胞系。我们现在知道,在70%的ATCs中TP53缺失或突变,而在近40%的ATCs中,PI3K级联被组成性激活。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,但越来越清楚的是,我们仍然缺少一个全面的接线图来描绘所有的
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Antonio Di Cristofano其他文献
Antonio Di Cristofano的其他文献
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{{ truncateString('Antonio Di Cristofano', 18)}}的其他基金
Molecular Landscape-based Innovative Therapies for Anaplastic Thyroid Carcinoma
基于分子景观的甲状腺未分化癌创新疗法
- 批准号:
8738872 - 财政年份:2014
- 资助金额:
$ 42.25万 - 项目类别:
PI3K-mediated metabolic alterations in the pre-neoplastic thyroid
PI3K 介导的肿瘤前甲状腺代谢改变
- 批准号:
9193619 - 财政年份:2013
- 资助金额:
$ 42.25万 - 项目类别:
PI3K-mediated metabolic alterations in the pre-neoplastic thyroid
PI3K介导的肿瘤前甲状腺代谢改变
- 批准号:
8438668 - 财政年份:2013
- 资助金额:
$ 42.25万 - 项目类别:
PI3K-mediated metabolic alterations in the pre-neoplastic thyroid
PI3K介导的肿瘤前甲状腺代谢改变
- 批准号:
8600660 - 财政年份:2013
- 资助金额:
$ 42.25万 - 项目类别:
PI3K-mediated metabolic alterations in the pre-neoplastic thyroid
PI3K 介导的肿瘤前甲状腺代谢改变
- 批准号:
9122785 - 财政年份:2013
- 资助金额:
$ 42.25万 - 项目类别:
PI3K-mediated metabolic alterations in the pre-neoplastic thyroid
PI3K 介导的肿瘤前甲状腺代谢改变
- 批准号:
8780619 - 财政年份:2013
- 资助金额:
$ 42.25万 - 项目类别:
Genetic analysis of the P13K/Akt pathway in thyroid benign and malignant disease
P13K/Akt通路在甲状腺良恶性疾病中的遗传学分析
- 批准号:
8204981 - 财政年份:2009
- 资助金额:
$ 42.25万 - 项目类别:
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:
10297852 - 财政年份:2009
- 资助金额:
$ 42.25万 - 项目类别:
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 - 财政年份:2009
- 资助金额:
$ 42.25万 - 项目类别:
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:
9916668 - 财政年份:2009
- 资助金额:
$ 42.25万 - 项目类别:
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