Targeting High-Risk Lymphoid Neoplasms

项目总结/摘要 高危淋巴系统恶性肿瘤患者的结局，包括T细胞淋巴瘤、套细胞淋巴瘤、 携带CRLF 2重排的淋巴瘤和急性淋巴母细胞白血病仍然很差。长期 R35计划的目标是在我们的模型、协作、环境和生产力记录的基础上， 反复定义淋巴肿瘤生物学方面，并将这些发现转化为治疗方法 对患者在过去的5年里，我们鉴定了G蛋白β亚基GNB 1和GNB 2的突变， 在一系列不同的癌症，驱动转化和耐药性激酶抑制剂，定义了 一种罕见的滤泡性淋巴瘤亚型的生物学，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，询问单白血病细胞的治疗敏感性，定义了 HMGN 1三倍体、唐氏综合征和ALL之间的关系，有助于确定驱动 男性癌症风险过高，并在中低收入人群中试用下一代淋巴瘤诊断， 收入国家。我的实验室的工作已经导致了目前开放的多个临床试验;每个试验包括 在治疗前、治疗中和疾病进展后进行活检。我领导一个专门的中心， 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 建立并储存了>350例人白血病和淋巴瘤患者来源的异种移植物（PDX）， 个通道好吗我们利用这些模型完全在小鼠中进行II期临床前试验， 和阐明体内获得性抗性的机制。我以黑夜做 通过开源门户网站（www.PRoXe.org）提供PDX和附属数据。我与 与生物工程师和计算生物学家通过NCI癌症系统生物学联盟。我有 获得最先进的基础设施，包括功能增强和功能丧失筛查、下一代 测序、高通量化学生物学、蛋白质组学和代谢物分析。主要重点领域 对于这个R35建议，我目前的R 01奖的基础上，建立创新和忠实的淋巴模型 恶性肿瘤，询问原位微环境和免疫反应，定义治疗机制， 反应和靶适应性体内抗性。凭借精心策划临床前治疗的专业知识，我 学术界和制药公司之间的现有关系，促进快速转化为临床试验的网络，以及 创新发现的跟踪记录，我独特的定位，使变革性的进步，对高， 在接下来的七年甚至更长时间里，淋巴恶性肿瘤的风险。

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.