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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.

项目总结