Targeting High-Risk Lymphoid Neoplasms

针对高风险淋巴肿瘤

• 批准号: 10227080
• 负责人: David Marc Weinstock
• 金额: $ 102.1万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10227080
• 关键词: Academia; Acute Lymphocytic Leukemia; Area; Award; B-Cell Acute Lymphoblastic Leukemia; Biology; Biomedical Engineering; Biopsy; Chemicals; Clinical Trials; Collaborations; Data; Diagnostic; Disease Progression; Down Syndrome; Environment; Follicular Lymphoma; GNB1 gene; GTP-Binding Protein beta Subunits; Genes; Goals; HMGN1 gene; Human; Immune response; In Situ; Infrastructure; Laboratories; Lead; Leukemic Cell; Lymphoma; Lymphoma cell; Malignant Neoplasms; Malignant lymphoid neoplasm; Mantle Cell Lymphoma; Modeling; Mus; Mutation; Patient-Focused Outcomes; Patients; Phase; Positioning Attribute; Productivity; Proteomics; Research; Resistance; Serial Passage; Specialized Center; Systems Biology; T-Cell Lymphoma; Therapeutic; Translating; Translations; Tumor Biology; Work; cancer risk; high risk; in vivo; innovation; kinase inhibitor; leukemia/lymphoma; loss of function; low and middle-income countries; lymphoid neoplasm; male; next generation; next generation sequencing; open source; patient derived xenograft model; pre-clinical; preclinical trial; prognostic model; programs; screening; therapeutic target; treatment response; web portal

Project Summary/Abstract The outcomes for patients with high-risk lymphoid malignancies, including T-cell lymphomas, mantle cell lymphoma and acute lymphoblastic leukemia that harbor CRLF2 rearrangements, remain poor. The long-term goal of this R35 program is to build on our models, collaborations, environment and record of productivity to iteratively define aspects of lymphoid tumor biology and translate these discoveries into therapeutic approaches for patients. Over the previous 5 years, we identified mutations of the G protein beta subunits GNB1 and GNB2 across a range of different cancers that drive transformation and resistance to kinase inhibitors, defined the biology of a rare subtype of follicular lymphoma, established a clinicogenetic prognostic model for follicular lymphoma, co-developed a strategy to interrogate therapeutic sensitivity of single leukemia cells, defined the relationship between HMGN1 triplication, Down Syndrome and ALL, helped identify chr.X genes that drive excess cancer risk in males and piloted the use of next-generation lymphoma diagnostics in lower- and middle- income countries. Work from my lab has led to multiple clinical trials that are currently open; each trial includes biopsies prior to treatment, on treatment and after progression of disease. I lead a Specialized Center for Research that is focused on developing new strategies to target T-cell lymphomas. My laboratory has also established and banked >350 human leukemia and lymphoma patient-derived xenografts (PDXs) that serially passage. We utilize these models to orchestrate phase II-like pre-clinical trials completely in mice, define aspects of compartment-specific biology and elucidate mechanisms of in vivo acquired resistance. We have made the PDXs and affiliated data available through an open source web portal (www.PRoXe.org). I collaborate closely with bioengineers and computational biologists through an NCI Cancer Systems Biology Consortium. I have access to state-of-the-art infrastructure, including gain- and loss-of-function screening, next-generation sequencing, high-throughput chemical biology, proteomics and metabolite profiling. The major areas of focus for this R35 proposal build on my current R01 awards to build innovative and faithful models of lymphoid malignancies, interrogate in situ microenvironmental and immune responses, define mechanisms of therapeutic response and target adaptive in vivo resistance. With the expertise to orchestrate preclinical therapeutics, my existing relationships within academia and Pharma, a network to facilitate rapid translation into clinical trials, and a track-record for innovative discovery, I am uniquely positioned to make transformative advances against high- risk lymphoid malignancies over the next seven years and beyond.

项目总结/文摘

项目成果

Low-cost transcriptional diagnostic to accurately categorize lymphomas in low- and middle-income countries.

• DOI: 10.1182/bloodadvances.2021004347
• 发表时间: 2021-05
• 期刊: Blood advances
• 影响因子: 7.5
• 作者: F. Valvert;Oscar Silva;E. Solórzano-Ortíz;M. Puligandla;Marcos Mauricio Siliézar Tala;Timothy Guyon;Samuel L. Dixon;Nelly López;Francisco López;César Camilo Carías Alvarado;R. Terbrueggen;K. Stevenson;Y. Natkunam;D. Weinstock;Edward L Briercheck

The molecular ontogeny of follicular lymphoma: gene mutations succeeding the BCL2 translocation define common precursor cells.

滤泡性淋巴瘤的分子个体发育：BCL2 易位后的基因突变定义了常见的前体细胞。

• DOI: 10.1111/bjh.17990
• 发表时间: 2022
• 期刊: British journal of haematology
• 影响因子: 6.5
• 作者: Haebe,Sarah;Keay,William;Alig,Stefan;Mohr,Anne-Wiebe;Martin,LarissaK;Heide,Michael;Secci,Ramona;Krebs,Stefan;Blum,Helmut;Moosmann,Andreas;LouissaintJr,Abner;Weinstock,DavidM;Thoene,Silvia;vonBergwelt-Baildon,Michael;Ruland,
• 通讯作者: Ruland,

Genomic landscape of young ATLL patients identifies frequent targetable CD28 fusions

• DOI: 10.1182/blood.2019001815
• 发表时间: 2020-04-23
• 期刊: BLOOD
• 影响因子: 20.3
• 作者: Yoshida，Noriaki;Shigemori，Kay;Weinstock，David M.
• 通讯作者: Weinstock，David M.