CHARACTERIZATION AND TARGETED THERAPY OF T-ALL DEFICIENT FOR PTEN AND INK4A/ARF

PTEN 和 INK4A/ARF T-ALL 缺陷的特征和靶向治疗

• 批准号: 8372961
• 负责人: M. James You
• 金额: $ 30万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8372961
• 关键词: Acute; Acute Lymphocytic Leukemia; Biological Models; Biology; CDKN2A gene; Cells; Clinical Research; Development; Differentiation and Growth; Disease; Drug resistance; Event; Future; Gene Expression; Gene Targeting; Genes; Genetic; Genetically Engineered Mouse; Goals; Histologic; Human; In Vitro; Knowledge; Lead; Light; Malignant Neoplasms; MicroRNAs; Modeling; Molecular; Molecular Target; Mus; Mutation; NOTCH1 gene; Oncogenic; Organism; PTEN gene; Pathogenesis; Pathway interactions; Patients; Play; Pre-Clinical Model; Precursor T-Lymphoblast; Process; Recurrence; Refractory; Regulator Genes; Relative (related person); Role; T-Lymphocyte; Testing; Therapeutic Intervention; Translating; Tumor Suppressor Genes; Tumor Suppressor Proteins; Work; cell growth; chemotherapy; combinatorial; human FRAP1 protein; in vivo; insight; leukemia/lymphoma; leukemogenesis; mTOR Inhibitor; neoplastic; novel; outcome forecast; pre-clinical; prognostic indicator; therapeutic target; tumorigenesis

DESCRIPTION (provided by applicant): T-acute lymphoblastic leukemia/lymphoma (T-ALL) is a very aggressive malignancy. Targetable molecules/pathways of T-ALL are limited because of an insufficient understanding of its genetics and biology. The applicant's long-term goal is to advance the knowledge of the molecular processes for the development, proliferation and survival of T-ALL cells, and to translate the identification of molecular targets into better treatment of T-ALL. Inactivation of PTEN, INK4a and ARF tumor suppressor genes is among the most frequent genetic events in T-ALL. We hypothesized that inactivated Pten and Ink4a/Arf tumor suppressors cooperate in the tumorigenesis of T-ALL. Aberrant molecular pathway/genetic changes in T-ALL, including certain microRNAs, play a role in the pathogenesis of T-ALL, and combined targeted therapy with NOTCH1 and PI3K/mTOR inhibitors, and micorRNAs is effective for T-ALL. Our preliminary studies revealed the mouse T-ALL resembled the human counterparts genetically, histologically and immunophenotypically. In Aim 1, we will determine the impact of INK4a or Arf deficiency on the development of Pten null T-ALL. We plan to evaluate 1) T-ALL biology at the organismal and patho-histologic levels and 2) to determine if the differential tumor suppressor mutational spectrum impacts this effect. In Aim 2, we will characterize Pten and/or Ink4a/Arf deficient T-ALL molecularly. In this aim, we will evaluate (1) the status of known critical genes/pathways involved in the pathogenesis of T-ALL deficient for Pten, Pten and Ink4a/Arf, Ink4a/Arf, Pten and Ink4a, Pten and Arf, Ink4a, and Arf, (2) The expressions levels of miR-150 and -155 in the mouse T-ALL, (3) Functional consequences of expressed miR-150 and -155, and (4) the pertinent targets of miR-150 and -155 in the pathogenesis of T-ALL. In Aim 3, we will evaluate the effects of targeted therapies on Pten and/or Ink4a/Arf deficient T-ALL. We will determine (1) the effects of blocking PI3K/mTOR pathways, (2) the effects of GSI, and (3) the combinatorial effects of PI3K/mTOR inhibitor and GSI on our T-ALL models, (4) the combinatorial effects of PI3K/mTOR inhibitor and GSI on human T-ALL, and (5) the effects of restoring miR-155 and -150 expressions on T-ALL. These studies will likely provide insight into critical genes in the pathogenesis of T-ALL, and provide a platform for effective targeted therapies of T-ALL. PUBLIC HEALTH RELEVANCE: T-acute lymphoblastic leukemia/lymphoma (T-ALL) is a malignant neoplasm of T-lymphoblasts. However, conventional chemotherapy has been far from satisfactory, predominantly due to recurrent/refractory T-ALL. We will look into the role of criticl genes, Pten and Ink4a/Arf, in the pathogenesis of T-ALL, and options for targeted therapy.

描述（由申请人提供）：T-急性淋巴细胞白血病/淋巴瘤（T-ALL）是一种非常侵袭性的恶性肿瘤。由于对其遗传学和生物学的了解不足，T-ALL的靶向分子/途径有限。申请人的长期目标是推进T-ALL细胞发育、增殖和存活的分子过程的知识，并将分子靶标的鉴定转化为T-ALL的更好治疗。PTEN、INK 4a和ARF肿瘤抑制基因的失活是T-ALL中最常见的遗传事件之一。我们假设失活的Pten和Ink 4a/Arf肿瘤抑制因子在T-ALL的肿瘤发生中协同作用。T-ALL中异常的分子通路/遗传学改变，包括某些microRNA，在T-ALL的发病机制中发挥作用，联合使用NOTCH 1和PI 3 K/mTOR抑制剂、microRNA等靶向治疗对T-ALL有效。我们的初步研究表明，小鼠T-ALL在遗传学、组织学和免疫表型上与人类T-ALL相似。在目标1中，我们将确定INK 4a或Arf缺陷对Pten null T-ALL发展的影响。我们计划评估1）T-ALL生物学在有机体和病理组织学水平和2），以确定是否差异肿瘤抑制基因突变谱影响这种效果。在目标2中，我们将从分子上表征Pten和/或Ink 4a/Arf缺陷型T-ALL。为此，我们会 评价（1）参与Pten、Pten和Ink 4a/Arf、Ink 4a/Arf、Pten和Ink 4a、Pten和Arf、Ink 4a和Arf缺陷的T-ALL发病机制的已知关键基因/途径的状态，（2）小鼠T-ALL中miR-150和-155的表达水平，（3）表达的miR-150和-155的功能后果，（4）miR-150和-155在T-ALL发病机制中的相关靶点。在目标3中，我们将评估靶向治疗对Pten和/或Ink 4a/Arf缺陷型T-ALL的影响。我们将确定（1）阻断PI 3 K/mTOR通路的作用，（2）GSI的作用，以及（3）PI 3 K/mTOR抑制剂和GSI对我们的T-ALL模型的组合作用，（4）PI 3 K/mTOR抑制剂和GSI对人T-ALL的组合作用，以及（5）恢复miR-155和-150表达对T-ALL的作用。这些研究可能会提供对T-ALL发病机制中关键基因的深入了解，并提供一个新的研究方向。 T-ALL的有效靶向治疗平台。 公共卫生相关性：T急性淋巴细胞白血病/淋巴瘤（T-ALL）是一种T淋巴母细胞恶性肿瘤。然而，常规化疗远不能令人满意，主要是由于复发性/难治性T-ALL。我们将研究关键基因Pten和Ink 4a/Arf在T-ALL发病机制中的作用，以及靶向治疗的选择。