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.

项目概要/摘要 结直肠癌（CRC）是美国癌症相关死亡的主要原因之一。开发小说 更有效的结直肠癌治疗是一个未满足的生物医学需求，因为大多数晚期和转移性结直肠癌 初始治疗后的进展对治疗反应不佳。溴结构域和额外末端 结构域 (BET) 家族蛋白（例如 BRD4）是控制关键致癌基因表达的表观遗传读取器 驱动 CRC 发生和进展的蛋白质。使用小分子靶向 BET 家族蛋白 抑制剂已成为一种有前途的治疗方法。然而，BET 抑制剂 (BETi) 作为单一药物 通常对包括结直肠癌在内的上皮癌无效。其背后的分子机制 BET 靶向药物的抗癌活性尚不清楚。最近，一类新的药物可以诱导 BET 蛋白的快速降解已经被开发出来。我们的初步研究表明，两个这样的 BET 降解剂 (BETd)、BETd260 和 BETd246 在 CRC 细胞中比其他 BET 靶向药物更有效 和患者来源的异种移植物（PDX）。我们确定了 BETd 的一种新颖的、靶向作用机制 转录激活死亡受体 5 (DR5)，外源性细胞凋亡途径的关键组成部分。 重要的是，DR5 的诱导对于 BETd 的细胞杀伤和化疗增敏作用至关重要，并且 导致 CRC 亚群中 BETd 敏感性增加，斑点型 POZ 中存在激活突变 蛋白（SPOP），BET 蛋白 E3 泛素连接酶的一个亚基。此外，我们的数据表明 BETd 通过诱导 DR5 介导的免疫原性细胞死亡 (ICD) 产生强大的免疫原性作用。的组合 BETd260 和抗 PD-1 抗体具有良好的耐受性，几乎可以根除小鼠 CT26 同基因肿瘤 DR5依赖方式。基于这些发现，我们假设 BETd 通过以下方式改善 CRC 治疗： 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 BETd 在 CRC 细胞中的有效抗癌活性；目标 2. 确定 BETd 的治疗效果 治疗难治性和转移性 CRC；目标 3. 描述并利用 BETd 的免疫原性作用 改善结直肠癌治疗。拟议的研究预计将提供新的机制见解并建立 使用 BETd 开发精准和个性化疗法的关键临床前参数 治疗难治性和无法治愈的 CRC。从长远来看，这些研究可能会带来新的和改进的疗法 对抗结直肠癌和其他类型的癌症。