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.

项目概要/摘要 高危淋巴恶性肿瘤（包括 T 细胞淋巴瘤、套细胞瘤）患者的结果 携带 CRLF2 重排的淋巴瘤和急性淋巴细胞白血病的治疗效果仍然较差。长期来看 该 R35 计划的目标是建立在我们的模型、协作、环境和生产力记录的基础上 迭代地定义淋巴肿瘤生物学的各个方面，并将这些发现转化为治疗方法 对于患者。在过去的 5 年里，我们发现了 G 蛋白 β 亚基 GNB1 和 GNB2 的突变 在一系列不同的癌症中，驱动转化和对激酶抑制剂的耐药性，定义了 滤泡性淋巴瘤罕见亚型的生物学，建立了滤泡性淋巴瘤的临床遗传学预后模型 淋巴瘤，共同开发了一种策略来询问单个白血病细胞的治疗敏感性，定义了 HMGN1 三倍体、唐氏综合症和 ALL 之间的关系，有助于识别驱动的 chr.X 基因 男性癌症风险过高，并在中低收入人群中试点使用下一代淋巴瘤诊断方法 收入国家。我的实验室的工作已经开展了多项临床试验，目前正在进行中；每个试验包括 治疗前、治疗中和疾病进展后进行活检。我领导一个专门中心 研究重点是开发针对 T 细胞淋巴瘤的新策略。我的实验室也有 建立并储存了超过 350 个人类白血病和淋巴瘤患者来源的异种移植物 (PDX) 通道。我们利用这些模型在小鼠中完全安排类似 II 期的临床前试验，定义各个方面 隔室特异性生物学并阐明体内获得性耐药的机制。我们已经做了 PDX 和附属数据可通过开源门户网站 (www.PRoXe.org) 获取。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合作。我有 获得最先进的基础设施，包括功能获得和丧失的筛查、下一代 测序、高通量化学生物学、蛋白质组学和代谢物分析。主要关注领域 这个 R35 提案以我目前的 R01 奖项为基础，构建创新且忠实的淋巴模型 恶性肿瘤，询问原位微环境和免疫反应，定义治疗机制 反应和目标适应性体内抵抗力。凭借协调临床前治疗的专业知识，我的 学术界和制药界的现有关系，一个促进快速转化为临床试验的网络，以及 我拥有创新发现的记录，因此我具有独特的优势，能够在高水平领域取得变革性进展 未来七年及更长时间内罹患淋巴恶性肿瘤的风险。