Targeting High-Risk Lymphoid Neoplasms

项目摘要/摘要 高危淋巴系统恶性肿瘤患者的预后，包括T细胞淋巴瘤、套细胞 含有CRLF2重排的淋巴瘤和急性淋巴细胞性白血病的发病率仍然很低。长期的 此R35计划的目标是建立在我们的模型、协作、环境和工作效率记录的基础上，以 反复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 对病人来说。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 一种罕见的滤泡性淋巴瘤的生物学，建立了滤泡性预后的临床发生模型 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、唐氏综合征和ALL之间的关系有助于确定驱动CHR.X基因 在男性癌症风险过高的情况下，并在中低位男性中试点使用下一代淋巴瘤诊断技术 收入国家。我的实验室的工作已经导致了多项临床试验，这些试验目前正在进行中；每项试验包括 治疗前、治疗时和病情进展后进行活组织检查。我领导着一个专门的中心 专注于开发针对T细胞淋巴瘤的新策略的研究。我的实验室也有 建立并储存了350例白血病和淋巴瘤患者来源的连续异种移植(PDX) 通过。我们利用这些模型在小鼠身上完全协调类似II期的临床前试验，定义Aspects 并阐明体内获得性耐药的机制。我们已经做出了 PDX及其附属数据可通过开放源码门户网站(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合作。我有过 访问最先进的基础设施，包括增减功能筛选、下一代 测序、高通量化学生物学、蛋白质组学和代谢物分析。重点关注的领域 对于这份R35计划，建立在我目前的R01奖的基础上，建立了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，确定治疗机制 反应和靶点适应性体内抵抗。有了协调临床前治疗的专业知识，我的 学术界和Pharma内部现有的关系，一个促进快速转化为临床试验的网络，以及 作为创新发现的记录，我处于独特的地位，能够在对抗高- 在接下来的七年和更长时间内有患淋巴系统恶性肿瘤的风险。

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.