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（由申请人提供）：分泌的 Hedgehog (Hh) 信号分子对于多细胞生物中细胞命运决策的协调至关重要，在婴儿和儿童中发现的髓母细胞瘤分别约 50% 和 40% 是由以下原因引起的。七跨膜 Hh 通路效应子 Smoothened (Smo) 的异常激活，这是临床批准的抗癌药物的靶标另外 40% 的婴儿髓母细胞瘤含有融合抑制蛋白 (Sufu) 突变，这种蛋白直接抑制 Gli DNA 结合蛋白的活性，而 Gli DNA 结合蛋白对于 Hh 依赖性转录活性至关重要，因此患有髓母细胞瘤的婴儿还受到以下因素的挑战。尽管在接受 Vismodegib 治疗的儿童和成人患者中观察到肿瘤迅速消退，但频繁存在 Sufu 突变，无法通过 Smo 拮抗剂来对抗。在大多数接受治疗的髓母细胞瘤患者中，不依赖于 Smo 的机制重新参与 Gli 转录活性表明耐药性几乎是普遍存在的。为了描绘新的化学空间来治疗对 Smo 拮抗剂无效的 Hh 相关癌症，我们已经完成了一项研究。基因组规模 cDNA 文库筛选，并鉴定了五个抗凋亡 Bcl-2 家族成员中的三个（Mcl-1、Bcl-2 和 Bcl-xL）来驱动 Gli 蛋白这种相互作用可能通过稳定 Sufu 中的低 Gli 亲和力构象而导致 Sufu 结合和抑制 Gli 介导的转录活性的能力降低。受 Gli 活动调节，从而揭示出协同作用通过前馈抑制 Sufu 活性来调节促存活 Bcl-2 蛋白的自我调节。靶向促存活 Bcl-2 蛋白（BH3 模拟物）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癌信号传导机制，从而无论癌细胞对 Gli 的敏感性如何，都能够抑制 Gli 活性。本提案中概述的研究将利用新型 BH3 模拟物以及后期临床测试的模拟物，通过表型和分子读数来评估我们的研究结果的治疗前景。横纹肌肉瘤和髓母细胞瘤，两种 Hh 相关恶性肿瘤。