(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: 8895286
• 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 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8895286
• 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; Frequencies; Genes; Genetic; Genetic Variation; Goals; Growth; HRAS gene; Hematopoietic Neoplasms; Human; Insertional Mutagenesis; Investigation; Knock-in Mouse; Lymphoblastic Leukemia; MEKs; Maintenance; Malignant Neoplasms; Methods; Modeling; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Myeloid Leukemia; NF1 gene; Oncogenic; Output; Pathway interactions; Pharmaceutical Preparations; Phosphatidylinositols; Phosphotransferases; Property; Proteins; Proto-Oncogenes; Ras Inhibitor; Reagent; Relapse; Relative (related person); 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; human MAP3K1 protein; in vivo; inhibitor/antagonist; kinase inhibitor; leukemia; mTOR protein; mutant; novel; preclinical study; pressure; public health relevance; ras GTPase-Activating Proteins; research study; resistance mechanism; response; small molecule; therapeutic target

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（由申请人提供）：RAS原癌基因在许多不同的恶性肿瘤中发生高频率突变。因此，开发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。尽管致癌基因RAS等位基因编码的功能获得蛋白在癌细胞中大量表达，但RAS /GTPase激活蛋白（RAS /GAP）分子开关的内在特征给开发靶向抑制剂带来了困难，如果不是不可克服的挑战。致癌Ras/GAP开关的“不可药物”生化特性代表了癌症治疗中尚未解决的核心问题。活化的Ras参与一个复杂的激酶效应级联网络，其中Raf/MEK/ERK和磷酸肌醇-3- oh激酶（PI3K）、Akt、哺乳动物雷帕霉素靶蛋白（PI3K/Akt/mTOR）通路与癌症的发生和维持密切相关。在这个项目中，我们将利用来自Nf1突变株和Kras/Nras敲入小鼠的可移植原发性髓系和淋巴系白血病，准确地模拟人类癌症，作为一个受控的进化系统和实验平台，来研究对小分子抑制剂的反应。特别是，我们已经将约40例原发性白血病移植到小鼠队列中，并使用MEK和PI3K抑制剂单独或联合治疗这些受体。我们已经从这些对照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。这种一般的方法有一个额外的优点，即为发现和验证新生和获得性耐药性的机制提供了一个可处理的正向遗传系统。在这里，我们建议使用这些新试剂来询问由致癌Ras信号驱动的癌症对MEK和PI3K抑制剂治疗的体内克隆选择，以及反应和耐药机制。该PQ提案的具体目的是：(1)研究以Nf1失活或致癌Nras/Kras突变为特征的原发性AML中MEK抑制剂获得性耐药的演变；(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抑制剂治疗所施加的选择压力如何导致体内ras驱动癌症的克隆进化的生物学原理；(2)发现对靶向抗癌药物产生耐药性的特定基因和途径；(3)利用这些数据开发治疗范例，逆转可通过人体临床试验翻译的致癌Ras的不利生化输出。