Targeting blastic plasmacytoid dendritic cell neoplasm (BPDCN)

靶向母细胞性浆细胞样树突状细胞肿瘤 (BPDCN)

基本信息

批准号：
10335170
负责人：
Andrew A Lane
金额：
$ 39.7万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10335170
关键词：
Acute Myelocytic Leukemia Address Alleles Apoptosis Apoptotic Area BCL-2 Protein BCL2 gene Biological Biological Assay Biological Models Biological Response Modifier Therapy Biology Blastic plasmacytoid dendritic cell neoplasm Blood Bone Marrow Cancer Biology Cells Chemoresistance Clinical Clinical Research Clinical Trials Complex Confusion Cutaneous Involvement DNA DNA sequencing Data Dendritic Cells Dependence Diagnosis Diphtheria Toxin Disease Female Frequencies Functional disorder GNB1 gene Genes Genetic Genetic Engineering Genetic Models Genetic Transcription Genetic study Goals Hematologic Neoplasms Hematopoiesis Heterotrimeric G Protein Subunit Human IL3RA gene Incidence Interleukins Knowledge Laboratories Leukemic Cell Leukemic Natural Killer Cell Lymphoma Malignant - descriptor Malignant Neoplasms Measures Medical Medicine Mission Modeling Mus Mutate Mutation NCAM1 gene Names Nature Neoplasms Oncogenes Ontology Orphan Outcome Output Pathogenesis Pathway interactions Patients Phenotype Public Health RNA Splicing Recurrence Refractory Relapse Research Resistance Role Sampling Sex Bias Signal Transduction Site Somatic Mutation Spliceosomes System Testing Therapeutic Therapeutic Studies Transplantation Tumor Suppressor Proteins United States National Institutes of Health Validation Woman X Chromosome X Inactivation base cancer type cell transformation chemotherapy clinically relevant clinically significant cohort effective therapy exome exome sequencing improved improved outcome in vivo in vivo Model inhibitor innovation insight loss of function mutation lymph nodes mRNA Precursor male men mimetics mutant novel optimal treatments patient derived xenograft model premature sex standard care stem cells targeted sequencing therapeutic target transcriptome treatment response treatment strategy tumor

项目摘要

Project Summary Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an orphan hematologic malignancy that is clinically aggressive and fatal in most patients within one year of diagnosis. The disease pathogenesis is largely unknown, there is no standard treatment, and patients with BPDCN have a clear unmet medical need. The long-term goal is to improve outcomes in BPDCN by deeper understanding of disease biology. DNA sequencing in BPDCN revealed a high frequency of mutations in RNA splicing factors, with particular enrichment in loss-of-function mutations in ZRSR2 compared to other cancers. Functional assessment of patient tumors found that BPDCN is uniquely dependent on the anti-apoptotic protein BCL2 and is highly sensitive to treatment with the BH3 mimetic venetoclax. New genetically engineered models of dendritic cell leukemia and BPDCN patient-derived xenografts offer a unique opportunity to test the contribution of disease alleles to splicing abnormalities and therapeutic response. The overall objective of this application is to test the hypothesis that genetic alterations associated with BPDCN contribute to dendritic cell transformation and create targetable vulnerabilities. Guided by strong preliminary data from the applicant's laboratory and an established network of expert collaborators, this central hypothesis will be tested by pursuing two specific aims: 1) Determine how ZRSR2 mutation promotes dendritic cell transformation; and 2) Identify factors that generate unique apoptotic dependencies in BPDCN. Under the first Aim, the applicant will use genetic models of ZRSR2 deficiency in dendritic cells and BPDCNs to determine how splicing mutations alter the transcriptome and cause transformation of the dendritic lineage. They will also test how mutations in ZRSR2, a gene located on the X chromosome that escapes X-inactivation in female cells, contributes to the male bias of BPDCN and sensitizes to splicing modulator therapy. Under the second Aim, the mechanisms of BCL2 dependence in normal and malignant dendritic cells will be investigated in human and mouse hematopoiesis. Adaptations to chemotherapy in BPDCN will be measured to determine if BCL2 inhibition can overcome chemoresistance, which is the major barrier to improved outcomes in patients. The approach is innovative by making use of novel model systems and samples from BPDCN patients on active clinical trials. The downstream effects of ZRSR2 mutations on BPDCN and male cancer predominance have not been clarified, and the mechanisms of protection from apoptosis in normal and malignant dendritic cells are unknown. The proposed research is significant, because it is expected to define the biological role of clinically-relevant mutations in an understudied and highly fatal disease. The expected output for the proposed research is that the knowledge gained will be immediately clinically significant for patients with BPDCN because it will inform new treatment strategies in a cancer that is currently lacking in significant biological and therapeutic insight.

项目摘要 Blastic浆细胞类动物树突状细胞肿瘤（BPDCN）是孤儿血液学恶性肿瘤，在临床上是诊断后的一年内，大多数患者的侵略性和致命。疾病发病机理在很大程度上未知，没有标准治疗，而BPDCN患者有明显的未满足医疗需求。这长期目标是通过对疾病生物学的更深入了解，改善BPDCN的预后。脱氧核糖核酸 BPDCN中的测序显示RNA剪接因子的突变频率很高，特别是与其他癌症相比，ZRSR2的功能丧失突变富集。功能评估患者肿瘤发现BPDCN独特地取决于抗凋亡蛋白Bcl2，并且高度高对用BH3模拟物质敏感的治疗敏感。树突细胞的新基因工程模型白血病和BPDCN患者衍生的异种移植物为测试疾病的贡献提供了独特的机会等位基因剪接异常和治疗反应。该应用程序的总体目的是测试假设与BPDCN相关的遗传改变有助于树突状细胞的转化和创建可定位的漏洞。以申请人实验室的强大初步数据为指导和建立的专家合作者网络，将通过追求两个具体目标来检验该中心假设： 1）确定ZRSR2突变如何促进树突状细胞的转化； 2）确定产生的因素 BPDCN中的独特凋亡依赖性。在第一个目标下，申请人将使用ZRSR2的遗传模型树突状细胞和BPDCN的缺乏，以确定剪接突变如何改变转录组和导致树突谱系的转化。他们还将测试ZRSR2中的突变，一个位于基因的基因逃避雌性细胞中X灭活的X染色体，有助于BPDCN的男性偏见和对剪接调节剂治疗的敏感。在第二个目标下，Bcl2依赖的机制正常和恶性树突状细胞将在人和小鼠造血中进行研究。适应将测量BPDCN中的化学疗法，以确定Bcl2抑制是否可以克服化学抗性，这是改善患者结局的主要障碍。通过利用这种方法是创新的来自BPDCN患者的新型模型系统和样品进行了主动临床试验。下游效应的效果尚未阐明BPDCN和男性癌症优势的ZRSR2突变，以及保护正常和恶性树突状细胞中的凋亡是未知的。拟议的研究是重要，因为预计它将定义临床上与临床相关的突变的生物学作用正在研究和高度致命的疾病。拟议研究的预期产出是知识对于BPDCN患者而获得的收益将立即具有临床意义，因为它将为新治疗提供信息目前缺乏重要的生物学和治疗见解的癌症策略。