Validation of Critical 1q21 Vulnerabilities in Multiple Myeloma

多发性骨髓瘤中关键 1q21 漏洞的验证

• 批准号: 10317060
• 负责人: Simona Colla
• 金额: $ 35.97万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317060
• 关键词: 1q21; Address; Antibodies; Antisense Oligonucleotides; Binding; Biological; Cancer Patient; Candidate Disease Gene; Cell Death; Cell Line; Cells; Cessation of life; Chromosomes; Clinic; Clinical; DNA Damage; DNA Repair; Data; Development; Disease; Dose; Drug resistance; Effectiveness; Enhancers; Essential Genes; Extinction (Psychology); Frequencies; Gene Expression; Genes; Goals; Growth; Hematologic Neoplasms; High Dose Chemotherapy; Human; In Vitro; Interleukins; Knowledge; Lesion; MCL1 gene; Malignant Neoplasms; Mediating; Medical; Molecular; Multiple Myeloma; Mutagens; Nucleotides; Oncogenes; Outcome; Pathogenesis; Patients; Pharmacologic Substance; Phenotype; Physiological; Prevalence; Probability; Prognosis; Public Health; Recurrence; Refractory; Regulation; Relapse; Research; Risk; Role; Sampling; Signal Transduction; Spliced Genes; Structure of germinal center of lymph node; Subgroup; Testing; Therapeutic; Therapeutic Agents; Translating; Validation; Work; Xenograft Model; Xenograft procedure; anti-cancer; base; clinically relevant; design; disorder risk; drug discovery; effective therapy; functional genomics; genetic approach; genetic element; high risk; improved; improved outcome; in vivo; insight; molecular subtypes; mouse model; new therapeutic target; novel; novel strategies; overexpression; patient subsets; pre-clinical; prognostic; response; small molecule; survival outcome; targeted treatment; therapeutic target; translational clinical trial; treatment response; validation studies

PROJECT SUMMARY Amplification of 1q21 defines one of the most common multiple myeloma (MM) subtypes with an adverse prognosis. The 1q21 amplicon contains many genes, and while it is unlikely that all contribute to the pathobiology of high-risk MM, the critical genes that do drive this high-risk phenotype have not yet been fully clarified. Identifying such genes and their contributions to this phenotype would enable the development of new and effective targeted therapy strategies for high-risk MM and thus improve their survival outcomes. In this application, we propose to investigate the biological and molecular mechanisms behind the 1q21 amplification's contribution to high-risk MM with the ultimate goal of obtaining a list of validated therapeutic targets to inform the design of novel translational clinical trials for this subgroup of patients. In preliminary functional genomic studies, we identified five 1q21 essential genes whose loss results in MM cell death and/or growth inhibition. Our initial mechanistic studies of one of these genes, ILF2 (interleukin enhancer binding factor 2), suggest that the gene is involved in the regulation of the DNA damage response and mediates drug resistance to genotoxic agents in a dose-dependent manner, which may explain why 1q21 MM patients benefit less from high-dose chemotherapy than non–1q21 MM patients do. On the basis of these data, we hypothesize that the five 1q21 gene candidates we have identified make essential contributions to the high-risk MM phenotype and that the preclinical validation of these critical 1q21 vulnerabilities will yield novel therapeutic targets for these patients. To test these hypotheses, we will pursue the following three specific aims: 1) To dissect the molecular mechanisms underlying 1q21 gene candidates' contributions to the high-risk MM phenotype, we will subject these candidates to in vitro functional validation studies using a panel of genomically characterized human MM cell lines, primary MM samples, and xenograft models. 2) To identify 1q21 gene candidates' roles in MM pathogenesis in vivo, we will employ a novel, physiologically relevant genetic approach that targets these genes' expression in the germinal center cells, considered to be the cell-of- origin of MM plasma cells. 3) To determine the feasibility of therapeutically targeting ILF2, we will collaborate with IONIS Pharmaceuticals to develop antisense oligonucleotides targeting ILF2 and functionally validate their effectiveness both alone and in combination with DNA-damaging agents in inhibiting MM growth/progression in preclinical xenograft mouse models of disseminated MM. We anticipate that the proposed study will not only expand our understanding of 1q21 genes' contributions to MM pathobiology but also inform the development of new targeted approaches to improve the outcomes of MM patients who have high-risk disease that is refractory to our approved therapeutic agents.

项目摘要 1 q21扩增定义了最常见的多发性骨髓瘤（MM）亚型之一， 预后1 q21扩增子包含许多基因，虽然不太可能所有基因都对1 q21扩增子有贡献。 虽然高风险MM的病理生物学，但驱动这种高风险表型的关键基因尚未完全确定。 明确了识别这些基因及其对这种表型的贡献将使新的基因的开发成为可能。 以及有效的靶向治疗策略，从而改善其生存结局。在这 应用，我们建议研究1 q21背后的生物学和分子机制 扩增对高风险MM的贡献，最终目标是获得一系列经验证的治疗药物， 旨在为该患者亚组的新型转化临床试验设计提供信息。初步 通过功能基因组研究，我们确定了5个1 q21必需基因，其缺失导致MM细胞死亡和/或 生长抑制我们对这些基因之一ILF 2（白细胞介素增强子结合蛋白）的初步机制研究 因子2），表明该基因参与调节DNA损伤反应并介导药物 以剂量依赖性方式对遗传毒性药物耐药，这可能解释了为什么1 q21 MM患者受益 与非1 q21 MM患者相比，高剂量化疗的作用更小。根据这些数据，我们假设 我们已经确定的5个1 q21基因候选者对高危MM有重要贡献， 这些关键的1 q21脆弱性的临床前验证将产生新的治疗方法， 这些患者的目标。为了验证这些假设，我们将追求以下三个具体目标：1） 剖析1 q21候选基因对高危MM的分子机制 表型，我们将这些候选人进行体外功能验证研究，使用一组 基因组学表征的人MM细胞系、原代MM样品和异种移植模型。2)以识别 1 q21基因候选者在体内MM发病机制中的作用，我们将采用一种新的，生理相关的 遗传方法，靶向这些基因在生殖中心细胞中的表达，被认为是细胞的， MM浆细胞的起源。3)为了确定治疗靶向ILF 2的可行性，我们将 与IONIS制药公司合作，开发靶向ILF 2的反义寡核苷酸， 验证它们单独和与DNA损伤剂组合抑制MM的有效性 在播散性MM的临床前异种移植小鼠模型中的生长/进展。 拟议的研究不仅将扩大我们对1 q21基因对MM病理生物学的贡献的理解， 还为开发新的有针对性的方法提供信息，以改善患有多发性骨髓瘤的患者的预后 我们批准的治疗药物难以治疗的高危疾病。