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)

• 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
• 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

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 母细胞性浆细胞样树突状细胞肿瘤（BPDCN）是一种罕见的血液系统恶性肿瘤， 大多数患者在诊断后一年内具有侵袭性和致命性。疾病的发病机制主要是 未知，没有标准治疗，BPDCN患者有明确的未满足的医疗需求。的 长期目标是通过更深入地了解疾病生物学来改善BPDCN的结果。DNA BPDCN的测序揭示了RNA剪接因子的高频率突变，特别是 与其他癌症相比，ZRSR 2中功能缺失突变的富集。功能评估 患者肿瘤发现，BPDCN是唯一依赖于抗凋亡蛋白BCL 2和高度依赖于抗凋亡蛋白BCL 2。 对BH 3模拟物维奈托克治疗敏感。树突状细胞的新基因工程模型 白血病和BPDCN患者来源的异种移植物提供了一个独特的机会来测试疾病的贡献 等位基因与剪接异常和治疗反应的关系。此应用程序的总体目标是测试 假设与BPDCN相关的遗传改变有助于树突状细胞转化， 创建可攻击的漏洞。根据申请人实验室的初步数据和 建立了专家合作者网络，将通过追求两个具体目标来检验这一中心假设： 1)确定ZRSR 2突变如何促进树突状细胞转化;和2）确定产生ZRSR 2突变的因素。 BPDCN中独特的凋亡依赖性。根据第一个目标，申请人将使用ZRSR 2的遗传模型 树突状细胞和BPDCN的缺陷，以确定剪接突变如何改变转录组， 导致树突细胞的转化。他们还将测试ZRSR 2基因的突变是如何发生的， 在雌性细胞中逃避X失活的X染色体，有助于BPDCN的雄性偏好， 对剪接调节剂疗法敏感。在第二个目标下，BCL 2依赖性的机制， 将在人和小鼠造血中研究正常和恶性树突细胞。适应性 将测量BPDCN中的化学疗法以确定BCL 2抑制是否可以克服化学抗性， 这是改善患者预后的主要障碍。该方法是创新的，利用了 新的模型系统和来自活跃临床试验的BPDCN患者的样品。的下游效应 BPDCN上的ZRSR 2突变和男性癌症优势尚未阐明，并且ZRSR 2突变的机制在BPDCN上是不稳定的。 在正常和恶性树突细胞中对凋亡的保护是未知的。拟议的研究是 重要的是，因为它预计将定义临床相关突变的生物学作用， 研究不足的高致命性疾病。拟议研究的预期产出是， 对于BPDCN患者，获得的信息将立即具有临床意义，因为它将告知新的治疗方法 这是目前缺乏重要生物学和治疗见解的癌症治疗策略。