TGFBeta Receptor Mutations in Cancer and Other Diseases

说明(申请人提供)：转化生长因子-？(转化生长因子？)控制组织的动态平衡，协调对组织损伤和修复的反应。癌症逃脱了转化生长因子？的动态平衡功能，但可以激活组织修复功能，以增强其侵袭/转移表型。这一理念带动了转化生长因子的发展？用于癌症治疗的途径拮抗剂。然而，转化生长因子生物标志物的缺乏？“途径成瘾”是这些药物临床应用发展的主要障碍。我们的中心假设是转化生长因子？受体基因突变预示着通路成瘾，因此预示着对拮抗剂的反应。超过40个与癌症相关的I型或II型转化生长因子错义突变？受体基因(TGFBR1、TGFBR2)已被鉴定。我们最近发现，其中一些激活了T？R-II受体激酶，一方面与Smad2/3的失活有关，另一方面与Smad1/5的从头激活和高度运动性和侵袭性表型有关。此外，选择性T？R-11激酶抑制剂的治疗逆转了转化的表型。同时，类似马凡综合征的遗传性疾病最近被归因于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一种激活的表型。此外，癌症相关和马凡样综合征相关的TGFBR突变之间存在惊人的相似之处：(1)TGFBR2基因突变比TGFBR1突变更常见；(2)TGFBR2突变聚集在T？R-II激酶的C叶；(3)在人类癌症中，许多突变的TGFBR2与马凡样综合征相关的TGFBR2以及在黑腹葡萄球菌中的TGFBR2同源基因一致。因此，来自这三个非常不同来源的实验证据汇聚在一起，有力地支持了这样的假设：转化生长因子？受体基因突变可导致异常激活的细胞表型。我们的具体目标是：1.用结构生物学的方法预测TGFBR2基因突变对与其他蛋白质相互作用的影响；2.用遗传学方法确定哪些TGFBR2基因突变具有功能增益表型；3.确定TGFBR2基因突变对转化生长因子的影响？在哺乳动物细胞中的信号传递；4.利用选择性的化学T？R激酶抑制剂来确定它们对功能获得的TGFBR2突变细胞的潜在治疗作用。这些研究特别重要，因为转化生长因子？拮抗剂正在(前期)临床开发中，用于治疗(转移性)癌症和纤维性疾病。因此，我们的研究不仅将提供对致病的TGFBR突变的分子病理生物学的准确了解，而且还将为转化生长因子的临床发展提供信息。治疗癌症和其他疾病的途径抑制剂。

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.