BET degraders for improving colorectal cancer therapy

BET 降解剂可改善结直肠癌治疗

• 批准号: 10372054
• 负责人: Lin Zhang
• 金额: $ 41.65万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10372054
• 关键词: Antineoplastic Agents; Apoptosis; Apoptotic; Biological Assay; Biological Markers; Bromodomain; CT26; Cancer Cell Growth; Cancer Etiology; Cancer Patient; Carcinoma; Cell Death; Cell Proliferation; Cell Survival; Cells; Cessation of life; Chemosensitization; Colorectal Cancer; Colorectal Neoplasms; DNA; Data; Epigenetic Process; Exhibits; Genetic Transcription; Histones; Immune; Immunotherapy; Lead; Malignant Neoplasms; Mediating; Metastatic Neoplasm to the Liver; Mismatch Repair; Modeling; Molecular; Mus; Mutation; Oncogenic; Pathway interactions; Precision therapeutics; Protein Family; Proteins; Reader; Refractory; Resistance; TNFRSF10B gene; Tertiary Protein Structure; Testing; Therapeutic; Treatment Efficacy; Tumor Immunity; Tumor Suppression; anti-PD-1; anti-PD1 antibodies; anti-PD1 therapy; anti-tumor immune response; anticancer activity; base; c-myc Genes; cancer cell; cancer initiation; cancer type; cell killing; chemotherapy; colon cancer patients; colorectal cancer treatment; driver mutation; effective therapy; endoplasmic reticulum stress; immunogenic; immunogenic cell death; improved; inhibitor; insight; metastatic colorectal; mortality; novel; patient derived xenograft model; personalized medicine; pre-clinical; predictive marker; research clinical testing; small molecule; small molecule inhibitor; targeted agent; targeted treatment; tumor; tumor progression; tumor xenograft; ubiquitin-protein ligase

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the US. Developing novel and more effective CRC therapies is an unmet biomedical need as most of advanced and metastatic CRCs that progress after initial therapies respond poorly to therapeutic treatment. The bromodomain and extra-terminal domain (BET) family proteins such as BRD4 are epigenetic readers that control expression of key oncogenic proteins that drive CRC initiation and progression. Targeting the BET family proteins using small-molecule inhibitors has emerged as a promising therapeutic approach. However, BET inhibitors (BETi) as single agents are generally ineffective against epithelial cancers including CRCs. The molecular mechanisms underlying the anticancer activity of BET-targeting agents are not well understood. Recently, a new class of agents that induce rapid degradation of BET proteins has been developed. Our preliminary studies reveal that two such BET degraders (BETd), BETd260 and BETd246, are much more potent than other BET-targeting agents in CRC cells and patient-derived xenografts (PDXs). We identified a novel, on-target mechanism of action of BETd in transcriptionally activating Death Receptor 5 (DR5), a key component of the extrinsic apoptotic pathway. Importantly, the induction of DR5 is essential for the cell-killing and chemosensitization effects of BETd, and responsible for increased BETd sensitivity in a subset of CRCs with an activating mutation in Speckle-type POZ protein (SPOP), a subunit of the E3 ubiquitin ligase of BET proteins. Furthermore, our data suggest BETd have robust immunogenic effects by inducing DR5-mediated immunogenic cell death (ICD). A combination of BETd260 and anti-PD-1 antibody was well tolerated and nearly eradicated mouse CT26 syngeneic tumors in a DR5-dependent manner. Based on these findings, we hypothesize that BETd improve CRC therapies by inducing DR5-mediated CRC cell killing and antitumor immunity. Aim 1. Identify the mechanism and biomarkers of the potent anticancer activity of BETd in CRC cells; Aim 2. Determine the therapeutic efficacy of BETd against therapy-refractory and metastatic CRCs; Aim 3. Delineate and harness the immunogenic effects of BETd to improve CRC therapies. The proposed studies are expected to provide new mechanistic insights and establish key preclinical parameters for using BETd to develop precision and personalized therapies against therapy-refractory and incurable CRCs. In the long run, these studies may lead to new and improved therapies against CRCs and other types of cancer.

项目摘要/摘要 结直肠癌（CRC）是美国与癌症相关死亡的主要原因之一。发展小说 更有效的CRC疗法是未满足的生物医学需求，因为大多数高级和转移性CRC 初始疗法对治疗治疗的反应不佳。溴化域和末端 域（BET）家族蛋白（例如BRD4）是控制关键致癌性表达的表观遗传读取器 驱动CRC启动和进展的蛋白质。使用小分子靶向BET家族蛋白 抑制剂已成为一种有希望的治疗方法。但是，BET抑制剂（BETI）作为单个代理 通常对包括CRC在内的上皮癌症无效。分子机制 尚未充分了解靶向赌注的抗药性的抗癌活性。最近，一个诱发的新代理商 已经开发出BET蛋白的快速降解。我们的初步研究表明，两个这样的赌注 DEGRADER（BETD），BETD260和BETD246比CRC细胞中的其他针对BET靶向剂更有效 和患者衍生的异种移植物（PDXS）。我们确定了贝特的新颖，目标的作用机理 转录激活死亡受体5（DR5），这是外部凋亡途径的关键组成部分。 重要的是，DR5的诱导对于BETD的细胞杀伤和化学敏化作用至关重要， 负责在斑点型POZ中具有激活突变的CRC子集中的BETD灵敏度提高 蛋白质（Spop），BET蛋白的E3泛素连接酶的亚基。此外，我们的数据表明BETD有 通过诱导DR5介导的免疫原性死亡（ICD）来鲁棒的免疫原性作用。组合 BETD260和抗PD-1抗体的耐受性良好，几乎根除的小鼠CT26合成肿瘤在A中 DR5依赖性方式。基于这些发现，我们假设BETD通过 诱导DR5介导的CRC细胞杀伤和抗肿瘤免疫。目标1。确定机制和生物标志物 CRC细胞中BETD的有效抗癌活性；目标2。确定BETD的治疗功效 治疗 - 饮食和转移性CRC；目标3。划定和利用BETD的免疫原性作用 改善CRC疗法。预计拟议的研究将提供新的机械见解并建立 使用BETD来开发精度和个性化疗法的关键临床前参数 治疗 - 饮食和无法治愈的CRC。从长远来看，这些研究可能会导致新的和改进的疗法 反对CRC和其他类型的癌症。