Targeting High-Risk Lymphoid Neoplasms

针对高风险淋巴肿瘤

• 批准号: 9816293
• 负责人: David Marc Weinstock
• 金额: $ 79.87万
• 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 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9816293
• 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; 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; Xenograft procedure; 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; pre-clinical; preclinical trial; predictive modeling; 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.

项目摘要/摘要 高风险淋巴恶性肿瘤的患者的结局，包括T细胞淋巴瘤，地幔细胞 具有CRLF2重排的淋巴瘤和急性淋巴细胞白血病仍然很差。长期 该R35计划的目标是建立我们的模型，协作，环境和生产力记录 迭代地定义淋巴样肿瘤生物学的各个方面，并将这些发现转化为治疗方法 适用于患者。在过去的5年中，我们确定了G蛋白β亚基GNB1和GNB2的突变 跨越驱动激酶抑制剂转化和抗性的不同癌症，定义了 卵泡淋巴瘤罕见亚型的生物学，建立了卵泡的临床遗传预后模型 淋巴瘤共同开发了一种审查单个白血病细胞治疗敏感性的策略，定义了 HMGN1三重三分之一，唐氏综合症和所有人之间的关系有助于识别驱动的CHR.X基因 男性过多的癌症风险，并试图在下层和中期使用下一代淋巴瘤诊断 收入国家。我实验室的工作导致了目前开放的多次临床试验。每个试验包括 在治疗之前，治疗和疾病进展后的活检。我领导一个专门的中心 研究重点是制定针对T细胞淋巴瘤的新策略。我的实验室也有 建立和储存> 350人白血病和淋巴瘤患者衍生的异种移植物（PDXS） 通道。我们利用这些模型在小鼠中完全策划了类似II期的临床前试验，并定义方面 隔室特异性生物学和阐明体内获得的抗性的机制。我们做了 PDX和关联数据可通过开源Web门户（www.proxe.org）获得。我密切合作 通过NCI癌症系统生物学联盟与生物工程师和计算生物学家。我有 访问最先进的基础设施，包括获得功能丧失筛查，下一代 测序，高通量化学生物学，蛋白质组学和代谢物分析。重点的主要领域 对于我目前的R01奖项建立的R35提案，以建立创新和忠实的淋巴模型 恶性肿瘤，原位微环境和免疫反应，定义治疗机制 反应和靶向自适应体内抗性。凭借精心策划临床前治疗剂的专业知识，我 学术界和制药中的现有关系，这是一个促进快速转化为临床试验的网络， 我是创新发现的田径记录，我独一无二地取得了变革性的进步 在未来七年及以后的情况下，风险淋巴恶性肿瘤。