TGFBeta Receptor Mutations in Cancer and Other Diseases

癌症和其他疾病中的 TGFβ 受体突变

• 批准号: 7640954
• 负责人: Michael Reiss
• 金额: $ 29.33万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7640954
• 关键词: Advanced Malignant Neoplasm; Amino Acids; Apoptosis; Biological Assay; Biological Markers; Blood Vessels; Cell Cycle Progression; Cells; Chemicals; Clinical; Computer Simulation; Development; Disease; Dissection; Disseminated Malignant Neoplasm; Drosophila melanogaster; Employee Strikes; Epithelial Cells; Fibroblasts; Gene Mutation; Genes; Genetic; Genomics; Hand; Hereditary Disease; Homeostasis; Homology Modeling; Human; Individual; Injury; Lobe; Malignant Neoplasms; Mammalian Cell; Marfan Syndrome; Mediating; Missense Mutation; Molecular; Mutate; Mutation; NMR Spectroscopy; Pathway interactions; Patients; Phenotype; Phosphotransferases; Proteins; Receptor Gene; Research Personnel; Signal Transduction; Smooth Muscle Myocytes; Source; Syndrome; TGFBR1 gene; TGFBR2 gene; Therapeutic Effect; Thoracic Aortic Aneurysm; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Tumor Escape; Wound Healing; addiction; cancer therapy; cell motility; epithelial to mesenchymal transition; gain of function; inhibitor/antagonist; injury and repair; kinase inhibitor; malignant phenotype; mutant; novel therapeutic intervention; pre-clinical; protein folding; receptor; receptor function; repaired; response; structural biology; therapy development; tumor

DESCRIPTION (provided by applicant): Transforming Growth Factor-? (TGF?) controls tissue homeostasis and orchestrates the response to tissue injury and repair. Cancers escape from TGF? 's homeostatic function but can activate the tissue repair function to enhance their invasive/metastatic phenotype. This concept has led to the development of TGF? pathway antagonists for cancer treatment. However, the absence of biomarkers for TGF? "pathway addiction" is a major roadblock in the development of these agents for clinical use. Our central hypothesis is that TGF? receptor gene mutations are indicative of pathway addiction and, therefore, predictive of response to antagonists. Over 40 cancer-associated missense mutations of the types I or -II TGF? receptor genes (TGFBR1, TGFBR2) have been identified. We have recently found that some of these constitutively activate the T?R-II receptor kinase, associated with loss of Smad2/3 activation on the one hand, and with de novo activation of Smad1/5 and a highly motile and invasive phenotype on the other. Moreover, treatment with selective T?R-ll kinase inhibitors reversed the transformed phenotype. In parallel, Marfan syndrome-like genetic disorders have recently been attributed to mutations of TGFBR1 or TGFBR2. These mutations also confer an activated phenotype on patient fibroblasts and vascular smooth muscle cells. Moreover, striking parallels exist between cancer- and Marfan-like syndrome-associated TGFBR mutations: (1) TGFBR2 gene mutations are much more common than TGFBR1 mutations; (2) TGFBR2 mutations are clustered in the C-lobe of the T?R-II kinase; and (3) many of the TGFBR2 mutated in human cancers coincide with those involved in Marfan-like syndromes as well as with the TGFBR2 orthologue in D. melanogaster. Thus, converging experimental evidence from these three very different sources strongly supports the hypothesis that TGF? receptor gene mutations can confer an aberrant activated cellular phenotype. Our specific aims are: 1. To predict the effects of TGFBR2 gene mutations on interactions with other proteins using structural biology approaches; 2. To determine which TGFBR2 gene mutations confer gain-of- function phenotypes using genetic assays in D. melanogaster; 3. To determine the effects of TGFBR2 gene mutations on TGF? signaling in mammalian cells; 4. To utilize selective chemical T?R kinase inhibitors to determine their potential therapeutic effects on gain-of-function TGFBR2 mutant cells. These studies are particularly important because TGF? antagonists are in (pre)clinical development for the treatment of (metastatic) cancer as well as fibrotic disorders. Thus, not only will our studies provide a precise understanding of the molecular pathobiology of disease-causing TGFBR mutations, but they will also inform the clinical development of TGF? pathway inhibitors for cancer and other disorders.

描述（由申请人提供）：改变生长因子 - ？ （TGF？）控制组织稳态并策划对组织损伤和修复的反应。癌症从TGF逃脱了吗？的稳态功能，但可以激活组织修复功能以增强其侵入性/转移性表型。这个概念导致了TGF的发展？癌症治疗的途径拮抗剂。但是，TGF缺乏生物标志物？ “途径成瘾”是这些临床用途开发的主要障碍。我们的中心假设是TGF？受体基因突变指示途径成瘾，因此可以预测对拮抗剂的反应。 I型I或-II TGF的40多个相关的错义突变？已经鉴定出受体基因（TGFBR1，TGFBR2）。我们最近发现，其中一些组成型激活T？r-II受体激酶，一方面与SMAD2/3激活的丧失有关，以及SMAD1/5的从头激活以及另一方面的高度运动和侵入性表型。此外，选择性T？r-LL激酶抑制剂的治疗逆转了转化的表型。同时，Marfan综合征样遗传疾病最近归因于TGFBR1或TGFBR2的突变。这些突变还赋予患者成纤维细胞和血管平滑肌细胞的激活表型。此外，在癌症和Marfan综合征相关的TGFBR突变之间存在惊人的相似之处：（1）TGFBR2基因突变比TGFBR1突变更为普遍。 （2）将TGFBR2突变聚集在T？R-II激酶的C-Lobe中； （3）在人类癌症中突变的许多TGFBR2与D. melanogaster中的TGFBR2直源性涉及的TGFBR2综合症以及TGFBR2直系同源物相吻合。因此，从这三个截然不同的来源收集的实验证据强烈支持TGF的假设？受体基因突变可以赋予异常活化的细胞表型。我们的具体目的是：1。使用结构生物学方法来预测TGFBR2基因突变对与其他蛋白质相互作用的影响； 2。确定哪种TGFBR2基因突变使用D. melanogaster中的遗传测定赋予功能表型； 3。确定TGFBR2基因突变对TGF的影响？哺乳动物细胞的信号传导； 4。利用选择性化学T？r激酶抑制剂来确定其对功能获得的TGFBR2突变细胞的潜在治疗作用。这些研究特别重要，因为TGF？拮抗剂正在（前）临床发育，以治疗（转移性）癌症和纤维化疾病。因此，我们的研究不仅会为引起疾病的TGFBR突变的分子病理生物学提供精确的理解，而且还将为TGF的临床发展提供信息？癌症和其他疾病的途径抑制剂。