Upstream regulation of TAZ and YAP in sarcomas: towards combinatorial therapy targeting the Hippo Pathway

肉瘤中 TAZ 和 YAP 的上游调控：针对 Hippo 通路的组合治疗

• 批准号: 9235613
• 负责人: Munir Tanas
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2020-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9235613
• 关键词: 1-Phosphatidylinositol 3-Kinase; Affect; Amputation; Anatomy; Bioinformatics; Biological Models; Blood Vessels; Bone Tissue; Breast; Bypass; Chimeric Proteins; Clinical; Colon; Colon Carcinoma; Combined Modality Therapy; Complex; DNA Binding Domain; DNA Sequence Alteration; Data; Diagnostic; Family; Genes; Genetic Transcription; Goals; Health; Hemangioendothelioma; Herbicides; Human; Hypermethylation; In Vitro; Incidence; LATS1 gene; LATS2 gene; Life; Limb Salvage; Liver; Lung; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of lung; Malignant neoplasm of thyroid; Mitogen-Activated Protein Kinases; Modality; Mutation; Occupational Exposure; Oncogenes; Oncogenic; Oncoproteins; Organ Size; Outcomes Research; PTEN gene; Pathologist; Pathway interactions; Patients; Pharmacologic Substance; Pharmacology; Phosphotransferases; Population; Positioning Attribute; Primary Lesion; Protein-Serine-Threonine Kinases; Proteins; Regulation; Research; Salvage Therapy; Sampling; Secondary Lesion; Signal Transduction; Specimen; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Transcription Coactivator; Undifferentiated; Verteporfin; Veterans; Work; agent orange; base; combinatorial; diagnostic assay; in vivo; innovation; malignant breast neoplasm; melanoma; mouse model; new therapeutic target; novel; older patient; organ growth; personalized care; programs; promoter; sarcoma; soft tissue; targeted treatment; therapeutic candidate; tool; transcription factor; translational impact; tumor

Sarcomas are cancers arising within bone and soft tissue which rank among the most difficult cancers to treat. Limb-salvage therapy has reduced the incidence of disfiguring amputations, however many sarcomas involve crucial anatomical structures precluding this approach. Additionally, five year survival for metastatic sarcomas is only 16%, underscoring the need for new therapeutic targets. The Hippo pathway is a highly conserved serine/threonine kinase cascade which negatively regulates the TAZ and YAP transcriptional coactivators. TAZ and YAP have emerged as important oncogenes in a number of cancers including breast, colon, liver, lung, and thyroid cancers. Our preliminary data shows that TAZ/YAP are activated in the majority of sarcomas (66%), something that has not been previously demonstrated. Our long-term goal is to effectively target the Hippo- TAZ/YAP signaling axis in sarcomas for therapeutic benefit and to identify patients who would benefit from such therapy. Our objective in this proposal is to elucidate the upstream mechanisms by which TAZ and YAP are activated in sarcomas in order to identify additional targets for therapy. Our central hypothesis is that TAZ and YAP are activated in sarcomas because of abrogation of the Hippo pathway due to 1) loss of expression of the Hippo kinase components (primary lesion) or 2) activation of the PI3 kinase pathway which suppresses or bypasses the Hippo pathway (secondary lesion). We thus propose the following specific aims: Specific Aim 1: Test the hypothesis that loss of expression of the Hippo kinases is a major modality by which TAZ/YAP are activated to drive sarcomagenesis. Specific Aim 2: Test the hypothesis that the PI3 kinase pathway activates TAZ/YAP to drive sarcomagenesis. The approach is innovative in the applicant's opinion, for the following reasons. Although the Hippo field has focused almost entirely on post-translational mechanisms of regulating the Hippo-TAZ/YAP axis, using an unbiased, tissue based approach, we identified that loss of expression of the Hippo kinases at a protein level is a major mechanism by which the Hippo pathway is dysregulated in sarcomas and other cancers. This same approach and mouse modeling also identified the PI3 kinase pathway as a bona fide activator of TAZ/YAP; the first time this has been shown in vivo or in clinical cancer specimens. The proposed research is significant because it will identify novel therapeutic targets upstream of TAZ/YAP which we anticipate can be used combinatorially with anti-TAZ/YAP approaches in sarcomas and other cancers.

肉瘤是发生在骨和软组织中的癌症，是最难治疗的癌症之一。 保肢治疗降低了毁容截肢的发生率，尽管许多肉瘤涉及 关键的解剖结构排除了这种方法。此外，转移性肉瘤的五年存活率 只有16%，这表明需要新的治疗靶点。河马途径是一条高度保守的 丝氨酸/苏氨酸激酶级联负性调节TAZ和YAP转录共激活因子。Taz 和YAP已成为许多癌症的重要癌基因，包括乳腺癌、结肠癌、肝癌、肺癌、 和甲状腺癌。我们的初步数据显示，TAZ/YAP在大多数肉瘤中都被激活(66%)， 一些以前没有被证明过的东西。我们的长期目标是有效地打击河马- TAZ/YAP信号轴在肉瘤中的治疗益处和确定患者将受益于 这样的疗法。我们在这项建议中的目标是阐明TAZ和YAP的上游机制 在肉瘤中被激活，以确定更多的治疗靶点。我们的中心假设是TAZ 和YAP在肉瘤中被激活，原因是1)表达缺失导致河马途径被取消 河马激酶组分(原发病变)或2)PI3激酶途径的激活，抑制或 绕过河马通路(继发性损害)。因此，我们提出以下具体目标： 具体目标1：通过以下方式测试河马蛋白激酶表达缺失是一种主要方式的假设 哪些TAZ/YAP被激活来驱动肉瘤的发生。 特定目标2：验证PI3激酶途径激活TAZ/YAP驱动的假设 肉瘤发生学。 申请人认为，这种方法是创新的，原因如下。尽管河马场有 几乎完全关注调节Hippo-TAZ/YAP轴的翻译后机制，使用 无偏见的、基于组织的方法，我们发现河马蛋白激酶在蛋白质水平上的表达缺失 在肉瘤和其他癌症中，河马途径调节失调的主要机制。这是一样的 方法和小鼠模型也发现PI3激酶途径是TAZ/YAP的真正激活剂； 这是第一次在活体或临床癌症标本中显示出这一点。这项拟议的研究具有重要意义 因为它将确定TAZ/YAP上游的新治疗靶点，我们预计这些靶点可以用于 联合抗TAZ/YAP治疗肉瘤和其他癌症。