(PQD1) Response and Resistance to Inhibitors of Ras Effectors in Blood Cancers

(PQD1) 血癌中 Ras 效应物抑制剂的反应和耐药性

• 批准号: 9112921
• 负责人: KEVIN M. SHANNON
• 金额: $ 32.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-17 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9112921
• 关键词: Acute Lymphocytic Leukemia; Acute Myelocytic Leukemia; Acute T Cell Leukemia; Address; Advanced Malignant Neoplasm; Aftercare; Alleles; Antineoplastic Agents; Architecture; Area; Biochemical; Cancer Burden; Cells; Characteristics; Clinical; Clinical Trials; Clonal Evolution; Complex; Data; Development; Disease; Disease remission; Drug resistance; Drug-sensitive; Evolution; FRAP1 gene; Frequencies; Genes; Genetic; Genetic Variation; Goals; Growth; HRAS gene; Health; Hematopoietic Neoplasms; Human; Insertional Mutagenesis; Investigation; Knock-in Mouse; Lymphoblastic Leukemia; MAP3K1 gene; MEKs; Maintenance; Malignant Neoplasms; Methods; Modeling; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Myeloid Leukemia; NF1 gene; NF1 mutation; Oncogenic; Output; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phosphatidylinositols; Phosphotransferases; Property; Proteins; Proto-Oncogenes; Ras Inhibitor; Reagent; Relapse; Resistance; Resources; Signal Transduction; System; Testing; Therapeutic; Time; Translating; Transplantation; Tumor Suppressor Proteins; Wild Type Mouse; base; cancer cell; cancer initiation; cell growth; cohort; drug discovery; fitness; gain of function; genome-wide analysis; in vivo; inhibitor/antagonist; kinase inhibitor; leukemia; mutant; novel; preclinical trial; pressure; ras GTPase-Activating Proteins; research study; resistance mechanism; response; small molecule inhibitor; targeted treatment; therapeutic target; treatment response

DESCRIPTION (provided by applicant): RAS proto-oncogenes are mutated at high frequency in many different malignancies. Thus, developing effective therapeutic strategies for reversing the biochemical consequences of oncogenic Ras is a fundamental obstacle to reducing the worldwide burden of cancer. Although oncogenic RAS alleles encode gain-of-function proteins that are robustly expressed in cancer cells, intrinsic characteristics of the Ras/GTPase activating protein (Ras/GAP) molecular switch pose difficult, if not insurmountable, challenges to developing targeted inhibitors. The "undruggable" biochemical properties of the oncogenic Ras/GAP switch represent a central unsolved problem in cancer therapeutics. Activated Ras engages a complex network of kinase effector cascades of which the Raf/MEK/ERK and phosphoinositide-3-OH kinase (PI3K), Akt, mammalian Target of Rapamycin (PI3K/Akt/mTOR) pathways are strongly implicated in cancer initiation and maintenance. In this project, we will exploit transplantable primary myeloid and lymphoid leukemias from strains of Nf1 mutant and Kras/Nras "knock in" mice that accurately model human cancers as a controlled evolutionary system and experimental platform for interrogating responses to small-molecule inhibitors. In particular, we have transplanted ~40 primary leukemias into cohorts of mice, and have treated these recipients with MEK and PI3K inhibitors alone and in combination. We have isolated multiple, independent drug resistant leukemias from these controlled preclinical trials, and have shown that acquired resistance follows distinct evolutionary trajectories. These data recapitulate, with remarkable fidelity, the initial response and ultimate relapse of advanced human cancers treated with targeted inhibitors. This general approach has the additional advantage of providing a tractable forward genetic system for discovering and validating mechanisms of de novo and acquired resistance. Here we propose to use these novel reagents to interrogate in vivo clonal selection of cancers driven by oncogenic Ras signaling in response to treatment with MEK and PI3K inhibitors as well as mechanisms of response and resistance. The specific aims of this PQ proposal are: (1) to investigate the evolution of acquired resistance to MEK inhibitors in primary AML characterized by Nf1 inactivation or by oncogenic Nras/Kras mutations; and (2) to elucidate the clonal architecture, evolution, and drug responses in T-ALLs from wild-type and Kras mutant mice. Our overall goals are: (1) to reveal biologic principles underlying how the selective pressure imposed by MEK and/or PI3K inhibitor treatment leads to clonal evolution of Ras-driven cancers in vivo; (2) to discover specific genes and pathways that confer resistance to targeted anti-cancer agents; and, (3) to use these data to develop therapeutic paradigms for reversing the adverse biochemical outputs of oncogenic Ras that can be translated through human clinical trials.

描述(申请人提供)：RAS原癌基因在许多不同的恶性肿瘤中发生高频突变。因此，制定有效的治疗策略来逆转致癌RAS的生化后果是减轻全球癌症负担的根本障碍。虽然致癌的RAS等位基因编码在癌细胞中大量表达的功能获得蛋白，但RAS/GTP酶激活蛋白(RAS/GAP)分子开关的内在特性给开发靶向抑制剂带来了困难，如果不是不可逾越的挑战。致癌的RAS/GAP开关的“不能用药”的生化特性是癌症治疗中一个尚未解决的中心问题。激活的RAS参与了一个复杂的激酶效应级联网络，其中Raf/MEK/ERK和磷脂酰肌醇-3-羟基激酶(PI3K)、Akt、哺乳动物雷帕霉素靶标(PI3K/Akt/mTOR)通路与肿瘤的发生和维持密切相关。在这个项目中，我们将开发可移植的初级髓系和淋巴细胞性白血病，这些白血病来自Nf1突变株和Kras/NRAS“敲入”小鼠，这些小鼠准确地模拟人类癌症，作为一个受控的进化系统和询问对小分子抑制剂的反应的实验平台。特别是，我们已经将大约40例原发白血病移植到小鼠队列中，并用MEK和PI3K抑制剂单独和联合治疗这些受体。我们从这些对照的临床前试验中分离出多个独立的耐药白血病，并表明获得性耐药遵循不同的进化轨迹。这些数据以惊人的保真度概括了使用靶向抑制剂治疗的晚期人类癌症的初始反应和最终复发。这一通用方法的另一个优点是提供了一个易于处理的正向遗传系统，用于发现和验证从头耐药和获得性耐药的机制。在这里，我们建议使用这些新的试剂来询问体内由癌基因RAS信号驱动的癌症克隆选择对MEK和PI3K抑制剂治疗的反应，以及反应和耐药的机制。该PQ方案的具体目的是：(1)研究以NF1失活或致癌基因NRAS/Kras突变为特征的原发AML对MEK抑制剂获得性耐药性的演变；(2)阐明野生型和Kras突变小鼠T-ALL的克隆结构、进化和药物反应。我们的总体目标是：(1)揭示MEK和/或PI3K抑制剂治疗施加的选择性压力如何导致体内RAS驱动的癌症克隆进化的生物学原理；(2)发现赋予靶向抗癌剂耐药性的特定基因和途径；以及(3)利用这些数据开发可通过人体临床试验翻译的逆转致癌RAS不利生化输出的治疗范例。