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: 9420186
• 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/9420186
• 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; 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; Interleukin-3; Knowledge; Laboratories; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Measures; Medical; Medicine; Mission; Modeling; Mus; Mutate; Mutation; NCAM1 gene; Names; Natural Killer Cells; 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; Stem cells; System; Testing; Therapeutic; Therapeutic Studies; Transplantation; Tumor Suppressor Proteins; United States National Institutes of Health; Validation; Woman; X Chromosome; X Inactivation; Xenograft procedure; 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/antagonist; innovation; insight; leukemia; loss of function mutation; lymph nodes; mRNA Precursor; male; men; mimetics; mutant; novel; optimal treatments; premature; sex; standard care; 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.

项目概要 母细胞性浆细胞样树突状细胞肿瘤（BPDCN）是一种孤儿血液系统恶性肿瘤，临床上 大多数患者在诊断后一年内具有攻击性和致命性。该病的发病机制主要是 未知，没有标准的治疗方法，并且 BPDCN 患者有明确的未满足的医疗需求。这 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。脱氧核糖核酸 BPDCN 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，ZRSR2 的功能丧失突变更加丰富。功能评估 患者肿瘤发现 BPDCN 独特地依赖于抗凋亡蛋白 BCL2，并且高度依赖于抗凋亡蛋白 BCL2。 对 BH3 模拟 Venetoclax 治疗敏感。新的树突状细胞基因工程模型 白血病和 BPDCN 患者来源的异种移植物提供了测试疾病影响的独特机会 剪接异常和治疗反应的等位基因。该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 创建可针对的漏洞。以申请人实验室强有力的初步数据和 通过建立专家合作者网络，这一中心假设将通过追求两个具体目标进行检验： 1）确定ZRSR2突变如何促进树突状细胞转化； 2）确定产生的因素 BPDCN 中独特的细胞凋亡依赖性。根据第一个目标，申请人将使用ZRSR2的遗传模型 树突状细胞和 BPDCN 的缺陷无法确定剪接突变如何改变转录组和 引起树突谱系的转变。他们还将测试 ZRSR2（位于 女性细胞中逃避 X 失活的 X 染色体导致了 BPDCN 的男性偏见， 对剪接调节剂疗法敏感。在第二个目标下，BCL2依赖性的机制 将在人类和小鼠造血过程中研究正常和恶性树突状细胞。适应 将测量 BPDCN 中的化疗以确定 BCL2 抑制是否可以克服化疗耐药性， 这是改善患者预后的主要障碍。该方法具有创新性，利用 来自正在进行临床试验的 BPDCN 患者的新型模型系统和样本。下游影响 ZRSR2 突变对 BPDCN 和男性癌症优势的影响尚未明确，其机制尚不清楚。 对正常和恶性树突状细胞凋亡的保护作用尚不清楚。拟议的研究是 意义重大，因为它有望定义临床相关突变的生物学作用 未被充分研究且高度致命的疾病。拟议研究的预期产出是知识 获得的结果对于 BPDCN 患者将立即具有临床意义，因为它将为新的治疗提供信息 目前缺乏重要的生物学和治疗见解的癌症治疗策略。