Targeting vismodegib-resistant tumors using BH3 mimetics

使用 BH3 模拟物靶向 vismodegib 耐药肿瘤

基本信息

批准号：
9105124
负责人：
LAWRENCE LUM
金额：
$ 34.65万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-04-01 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9105124
关键词：
Adult Affinity Antineoplastic Agents Apoptosis Apoptotic Automobile Driving BCL-2 Protein BCL2 gene BH3 Domain Binding Cancerous Cell Communication Cell Death Cell Line Cells Chemicals Child Cultured Cells Cyclic AMP-Dependent Protein Kinases DNA-Binding Proteins Decision Making Degenerative Disorder Development Drug resistance Effectiveness Erinaceidae Event Family Family member Gene Family Genes Genetic Transcription Growth Homeostasis In Vitro Infant Informal Social Control Integral Membrane Protein MCL1 gene Malignant Neoplasms Mediating Molecular Molecular Conformation Mus Mutagenesis Mutation Neoplasm Metastasis Organism Outer Mitochondrial Membrane Pathway interactions Patients Phenotype Phosphorylation Prevention Proteins Reading Refractory Regulator Genes Repressor Molecules Resistance Rhabdomyosarcoma Role Signal Transduction Signaling Molecule Staging System Therapeutic Tissues Translating Tumor Suppressor Proteins base cDNA Library cancer cell cell growth cell suicide chemical genetics deviant feeding genetic approach genome-wide in vivo medulloblastoma mimetics mitochondrial membrane mouse model novel protein activation public health relevance research clinical testing small molecule small molecule inhibitor smoothened signaling pathway tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The secreted Hedgehog (Hh) signaling molecules are essential to the coordination of cell-fate decision-making in multicellular organisms. Approximately 50% and 40% of medulloblastomas found in infants and children, respectively, are caused by deviant activation of the seven transmembrane Hh pathway effector Smoothened (Smo), the target of the clinically approved anti-cancer agent Vismodegib. An additional 40% of infant medulloblastomas harbor mutations in Suppressor of fused (Sufu), a protein that directly suppresses the activity of the Gli DNA binding proteins which are essential to Hh-dependent transcriptional activities. Infants with medulloblastomas are thus additionally challenged by the frequent presence of Sufu mutations which cannot be countered by Smo antagonists. Despite the rapid onset of tumor regression observed in children and adult patients treated with Vismodegib, the re-engagement of Gli transcriptional activity by Smo-independent mechanisms in the majority of treated medulloblastoma patients suggests drug resistance will be nearly universal. To delineate novel chemical space for managing Hh-related cancers that are refractory to Smo antagonists, we have completed a genome-scale cDNA library screen and have identified three out of the five anti-apoptotic Bcl-2 family members (Mcl-1, Bcl-2, and Bcl- xL) to drive Gli protein activation by directly engaging a previously unidentified BH3 sequence in Sufu. This interaction results in decreased Sufu ability to bind to and suppress Gli-mediated transcriptional activity likely by stabilizing a low Gli affinity conformation in Sufu. The transcription of the same Bcl-2 genes is regulated by Gli activity, thus revealing a concerted role of prosurvival Bcl-2 proteins in self-regulation through feed-forward suppression of Sufu activity. Small molecules targeting prosurvival Bcl-2 proteins (BH3 mimetics) disrupt this cancer-promoting signaling mechanism by breaking Mcl-1/Bcl-2/Bcl-xL interactions with Sufu and thereby enabling the means to inhibit Gli activity regardless of cancer cell sensitivity to Vismodegib. The studies outlined in this proposal will leverage novel BH3 mimetics as well as those in late stage clinical testing for evaluating the therapeutic promise of our findings using phenotypic and molecular read-outs in rhabdomyosarcoma and medulloblastomas, two Hh- associated malignancies.

描述（由适用提供）：分泌的刺猬（HH）信号分子对于多细胞生物中细胞污染决策的协调至关重要。在婴儿和儿童中发现的髓母细胞瘤中约有50％和40％是由七个跨膜HH途径效应子平滑（SMO）的异常激活引起的，这是临床认可的抗癌剂Vismodegib的靶标。在熔融（SUFU）的抑制剂中，另外40％的婴儿髓母细胞瘤突变是一种直接抑制GLI DNA结合蛋白的活性，这对于HH依赖性转录活性至关重要。因此，患有髓母细胞瘤的婴儿经常存在SMO拮抗剂无法抵消的Sufu突变。尽管在接受Vismodegib治疗的儿童和成年患者中观察到的肿瘤消退迅速，但大多数治疗的髓母细胞瘤患者在大多数治疗的髓母细胞瘤患者中通过SMO独立机制重新参与了GLI转录活性，这表明耐药性几乎是普遍的。 To delineate novel chemical space for managing Hh-related cancers that are refractory to Smo antagonists, we have completed a genome-scale cDNA library screen and have identified three out of the five anti-apoptotic Bcl-2 family members (Mcl-1, Bcl-2, and Bcl-xL) to drive Gli protein activation by directly engaging a previously unidentified BH3 sequence in Sufu.这种相互作用可提高SUFU结合和抑制GLI介导的转录活性的能力，可能通过稳定SUFU中的低GLI亲和力构象。同一Bcl-2基因的转录受GLI活性调节，从而揭示了一致的作用 Prosurvival Bcl-2蛋白在自我调节中通过喂养向前抑制SUFU活性。靶向生物存在Bcl-2蛋白（BH3 Mimetics）的小分子通过破坏MCL-1/BCL-2/BCL-XL与SUFU的相互作用来破坏这种促进癌症的信号机制，从而使能够抑制Gli活性的手段，无论对Vismodegib的癌症细胞敏感而不管Gli的活性。该提案中概述的研究将利用新颖的BH3 Mimetics以及晚期临床测试中的研究来评估我们发现我们发现的治疗诺言，并使用横纹肌肉瘤和髓母细胞瘤中的表型和分子读出来，两种HH-HH-与HH-相关的恶性肿瘤。