Notch and GATA-3 as novel therapeutic targets in T-cell lymphomas

项目摘要 疾病进展迅速和对化疗耐药的疾病是最常见的 常见的T细胞淋巴瘤(TCL)，这些患者中的大多数最终会屈从于进行性 在确诊后三年内患病。只有一小部分(≤10%)的患者将获得持久缓解 对于新药，由于促进TCL进展和化疗耐药的机制较差 对克服它们的理解和治疗策略没有定义。我们最近已经证明了T- 细胞转录因子GATA-3识别分子、遗传和临床上不同的TCL亚群 对化疗有很强的抗药性。我们还证明了Notch激活在TCL中普遍存在， Notch阻断可抑制TCL增殖和Notch靶基因GATA-3的表达 学习。遗传学和药理学的功能丧失(和功能获得)策略在 遗传多样性的TCL细胞，随后证明GATA-3直接赋予对 以细胞自主的方式进行化疗。此外，淋巴瘤相关巨噬细胞(LAM)在 肿瘤微环境促进化疗耐药，依赖GATA-3的细胞因子调节 它们的功能极化，突出了GATA-3依赖的另一种非细胞自主机制 化疗耐药。因此，迫切需要确定调控GATA-3表达的因素和 在这些咄咄逼人的TCL中发挥作用。在缺乏这样的知识的情况下，治疗的发展 削弱GATA-3依赖的转录调控并改善这些TCL结果的策略 仍然难以捉摸。我们的长期目标是了解推动TCL的基本机制 并促进他们对目前可用的治疗方法的抵抗力。通过这样做，我们希望发展 合理设计的治疗策略，将克服化疗耐药性的挑战和 改善患有这些TCL的患者的预后。我们在此应用程序中的总体目标是评估 Notch信号在T细胞淋巴瘤发生中的作用及确定最佳GATA-3的要求 DNA结合和转录调控。这些将通过解决我们的核心假设来实现 Noch和GATA-3促进TCL进展和化疗耐药。除了身体健康外- 基于我们自己的初步数据，我们的中心假设与我们目前的情况完全一致 了解TCL的遗传格局和分子发病机制，具有重要的治疗意义 这意味着什么。

Project Abstract Rapid disease progression and chemotherapy resistant disease are frequently observed among the most common T-cell lymphomas (TCL) and the majority of these patients will ultimately succumb to progressive disease within three years of diagnosis. Only a minority (≤10%) of patients will achieve a durable remission with novel agents, as the mechanisms promoting TCL progression and chemotherapy resistance are poorly understood and therapeutic strategies to overcome them are not defined. We have recently shown that the T- cell transcription factor GATA-3 identifies a molecularly, genetically, and clinically distinct subset of TCL that are highly resistant to chemotherapy. We have also demonstrated that Notch activation is prevalent in the TCL, and Notch blockade inhibits both TCL proliferation and GATA-3 expression, a Notch target gene, in preliminary studies. Genetic and pharmacologic loss-of-function (and gain-of-function) strategies were performed in genetically diverse TCL cells and subsequently demonstrated that GATA-3 directly confers resistance to chemotherapy in a cell-autonomous fashion. In addition, lymphoma-associated macrophages (LAM) within the tumor microenvironment (TME) promote chemotherapy resistance, and GATA-3 dependent cytokines regulate their functional polarization, highlighting an additional non-cell-autonomous mechanism for GATA-3-dependent chemotherapy resistance. Thus, there is a critical need to identify factors regulating GATA-3 expression and function in these aggressive TCL. In the absence of such knowledge, the development of therapeutic strategies that impair GATA-3-dependent transcriptional regulation and improve outcomes among these TCL will remain elusive. Our long-term goals are to understand the fundamental mechanisms that drive TCL pathogenesis and promote their resistance to currently available therapies. In doing so, we hope to develop rationally designed therapeutic strategies that will overcome the challenge of chemotherapy resistance and improve outcomes for patients afflicted with these TCL. Our overall objectives in this application are to evaluate the role of Notch signaling in T-cell lymphomagenesis and to identify the requirements for optimal GATA-3 DNA binding and transcriptional regulation. These will be achieved by addressing our central hypothesis that Notch and GATA-3 promote TCL progression and resistance to chemotherapy. In addition to being well- grounded in our own preliminary data, our central hypothesis is entirely consistent with our current understanding of the genetic landscape and molecular pathogenesis of the TCL and has significant therapeutic implications.