TGFBeta Receptor Mutations in Cancer and Other Diseases

描述（由申请人提供）：转化生长因子-？(TGF?)控制组织内稳态并协调对组织损伤和修复的反应。癌细胞逃避TGF？的稳态功能，但可以激活组织修复功能，以增强其侵袭/转移表型。这一概念导致了TGF？用于癌症治疗的途径拮抗剂。然而，缺乏TGF？“途径成瘾”是开发这些药物用于临床应用的主要障碍。我们的中心假设是，TGF？受体基因突变是途径成瘾的指示，并因此预测对拮抗剂的反应。超过40种与癌症相关的I型或II型TGF？受体基因（TGFBR 1，TGFBR 2）已被确定。我们最近发现，其中一些组成激活T？R-II受体激酶，一方面与Smad 2/3激活的丧失相关，另一方面与Smad 1/5的从头激活和高度运动和侵袭性表型相关。此外，治疗与选择性T？R-II激酶抑制剂逆转了转化的表型。与此同时，马凡氏综合征样遗传性疾病最近被归因于TGFBR 1或TGFBR 2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活化的表型。此外，癌症和马凡氏综合征相关的TGFBR突变之间存在着惊人的相似之处：（1）TGFBR 2基因突变比TGFBR 1突变更常见;（2）TGFBR 2突变聚集在T细胞的C叶; R-II激酶;和（3）人类癌症中的许多TGFBR 2突变与马凡样综合征中涉及的那些以及D.黑腹菌因此，从这三个非常不同的来源汇聚的实验证据强烈支持的假设，TGF？受体基因突变可赋予异常的活化细胞表型。我们的具体目标是：1.利用结构生物学方法预测TGFBR 2基因突变对与其他蛋白质相互作用的影响; 2.为了确定哪些TGFBR 2基因突变赋予D.黑腹型; 3.为了确定TGF β R 2基因突变对TGF β？哺乳动物细胞中的信号传导; 4.利用选择性化学T？R激酶抑制剂，以确定其对功能获得性TGFBR 2突变细胞的潜在治疗作用。这些研究是特别重要的，因为TGF？拮抗剂正处于临床（前）开发中，用于治疗（转移性）癌症以及纤维化病症。因此，我们的研究不仅将提供一个精确的了解致病的TGF β R突变的分子病理学，但他们也将通知TGF β R的临床发展？用于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.