(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

基本信息

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
项目类别：
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

项目摘要

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高频突变。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 RAS 等位基因编码在癌细胞中稳定表达的功能获得蛋白，但 Ras/GTP 酶激活蛋白 (Ras/GAP) 分子开关的内在特征给开发靶向抑制剂带来了困难，甚至是不可克服的挑战。致癌 Ras/GAP 开关的“不可成药”生化特性代表了癌症治疗中尚未解决的核心问题。激活的 Ras 参与激酶效应级联的复杂网络，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标 (PI3K/Akt/mTOR) 通路与癌症的发生和发生密切相关。维护。在这个项目中，我们将利用 Nf1 突变体和 Kras/Nras“敲入”小鼠品系的可移植原发性骨髓和淋巴白血病，准确地将人类癌症建模为受控进化系统和实验平台，用于询问对小分子抑制剂的反应。特别是，我们将约 40 只原发性白血病移植到小鼠组中，并单独使用 MEK 和 PI3K 抑制剂或联合使用 MEK 和 PI3K 抑制剂治疗这些受体。我们从这些对照临床前试验中分离出了多种独立的耐药性白血病，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和获得性抗性的机制。在这里，我们建议使用这些新型试剂来探究由致癌 Ras 信号驱动的癌症的体内克隆选择，以响应 MEK 和 PI3K 抑制剂的治疗以及响应和耐药机制。该 PQ 提案的具体目标是：（1）研究以 Nf1 失活或致癌 Nras/Kras 突变为特征的原发性 AML 中对 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抑制剂治疗施加的选择压力如何导致体内Ras驱动的癌症克隆进化的生物学原理； (2) 发现赋予靶向抗癌药物耐药性的特定基因和途径； (3) 利用这些数据开发治疗范例，逆转致癌 Ras 的不良生化输出，并可通过人体临床试验进行转化。