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: 10332257
• 负责人: Andrew A Lane
• 金额: $ 17.41万
• 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/10332257
• 关键词: Alleles; Apoptosis; Apoptotic; BCL-2 Protein; BCL2 gene; Biological; Biological Models; Biological Response Modifier Therapy; Biology; Blastic plasmacytoid dendritic cell neoplasm; Cells; Chemoresistance; Clinical; Clinical Trials; DNA sequencing; Data; Dendritic Cells; Dependence; Diagnosis; Disease; Female; Frequencies; Genes; Genetic; Genetic Engineering; Genetic Models; Goals; Hematologic Neoplasms; Hematopoiesis; Human; Knowledge; Laboratories; Leukemic Cell; Malignant - descriptor; Malignant Neoplasms; Measures; Medical; Mission; Modeling; Mus; Mutation; Orphan; Output; Pathogenesis; Patients; Public Health; RNA Splicing; Research; Role; Sampling; Testing; United States National Institutes of Health; X Chromosome; X Inactivation; base; cell transformation; chemotherapy; clinically relevant; clinically significant; improved outcome; innovation; insight; loss of function mutation; male; mimetics; novel; patient derived xenograft model; standard care; 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 母细胞浆细胞样树突状细胞肿瘤(BPDCN)是一种临床上少见的血液系统恶性肿瘤 大多数患者在确诊后一年内具有侵袭性和致命性。该病的发病机制在很大程度上 未知，没有标准的治疗方法，BPDCN患者有明显的未得到满足的医疗需求。这个 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中的测序显示了RNA剪接因子的高频率突变，尤其是 与其他癌症相比，ZRSR2功能丧失突变的丰富。功能评估 患者肿瘤患者发现BPDCN是唯一依赖于抗凋亡蛋白BCL2的，并且高度 对BH3模拟文奈德治疗敏感。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一个独特的机会来测试疾病的贡献 剪接异常的等位基因与治疗反应。这个应用程序的总体目标是测试 假设与BPDCN相关的基因改变有助于树突状细胞转化和 制造有针对性的漏洞。根据申请者实验室和 在已建立的专家合作者网络中，这一中心假设将通过追求两个具体目标来检验： 1)确定ZRSR2突变如何促进树突状细胞转化；以及2)确定导致 BPDCN中独特的细胞凋亡依赖关系。在第一个目标下，申请者将使用ZRSR2的遗传模型 树突状细胞和BPDCNs缺陷以确定剪接突变如何改变转录组和 导致树突谱系的转变。他们还将测试ZRSR2基因的突变如何 在女性细胞中逃脱X失活的X染色体，有助于BPDCN和 对剪接调节器疗法敏感。在第二个目标下，BCL2依赖的机制 正常树突状细胞和恶性树突状细胞将在人类和小鼠的造血中进行研究。改编为 将对BPDCN中的化疗进行测量，以确定BCL2抑制是否可以克服化疗耐药， 这是改善患者预后的主要障碍。这种方法是创新的，它利用了 正在进行积极临床试验的BPDCN患者的新模型系统和样本。的下游影响 BPDCN上ZRSR2基因突变与男性肿瘤的关系尚不清楚，其发病机制尚不清楚。 正常和恶性树突状细胞对凋亡的保护作用尚不清楚。拟议的研究是 意义重大，因为它有望定义与临床相关的突变在 研究不足且致命性极强的疾病。拟议研究的预期产出是 对于患有BPDCN的患者来说，GAIN将立即具有临床意义，因为它将为新的治疗提供信息 目前缺乏重大生物学和治疗洞察力的癌症的治疗策略。