(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

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):在许多不同的恶性肿瘤中,Ras原始基因在高频中被突变。因此,制定有效的治疗策略来扭转致癌性RAS的生化后果是减轻全球癌症负担的根本障碍。尽管致癌性RAS等位基因编码在癌细胞中强烈表达的功能获得的蛋白质,但RAS/GTPase激活蛋白(RAS/GAP)分子开关的内在特征会带来困难,即使不是不可逾越的挑战,它会对产生靶向抑制剂产生挑战。致癌性RAS/GAP开关的“不可能”的生化特性代表了癌症治疗中的一个未解决的问题。激活的RA与激酶效应器级联反应的复杂网络,其中Raf/MEK/ERK和磷酸肌辅助3-OH激酶(PI3K),Akt,Akt,Rapamycin(PI3K/AKT/MTOR)途径的哺乳动物靶标强烈涉及癌症的起始和维持癌症。在这个项目中,我们将利用NF1突变体和KRAS/NRAS“敲击”小鼠的菌株中的可移植原代髓样和淋巴性白血病,这些小鼠将人类癌症准确地模拟为受控的进化系统和实验平台,以询问对小分子抑制剂的反应。特别是,我们已经将〜40个原发性白血病移植到小鼠队列中,并与MEK和PI3K抑制剂一起治疗了这些受体。我们已经从这些受控的临床前试验中分离出多种独立的耐药性白血病,并表明获得的抗性遵循不同的进化轨迹。这些数据以显着的保真度概括了用靶向抑制剂治疗的晚期人类癌的初始反应和最终复发。这种通用方法具有附加优势,即提供可探索的前向遗传系统,以发现和验证从头和获得的抗药性的机制。在这里,我们建议使用这些新型试剂来询问由致癌性RAS信号传导驱动的癌症的体内克隆选择,以响应MEK和PI3K抑制剂的治疗以及反应和抗性的机制。该PQ提案的具体目的是:(1)研究以NF1失活或致癌NRAS/KRAS突变为特征的原代AML中获得的MEK抑制剂的演变; (2)阐明了来自野生型和KRAS突变小鼠的T-Alls中的克隆结构,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驱动的癌症的克隆进化; (2)发现赋予靶向抗癌药的耐药性的特定基因和途径; (3)使用这些数据来开发治疗范例来逆转可以通过人类临床试验来翻译的致癌RA的不良生化输出。

项目成果

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KEVIN M. SHANNON其他文献

KEVIN M. SHANNON的其他文献

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{{ truncateString('KEVIN M. SHANNON', 18)}}的其他基金

In Vivo Functional Analysis of Chromosome 7q22 Deletions in Myeloid Malignancies
骨髓恶性肿瘤中染色体 7q22 缺失的体内功能分析
  • 批准号:
    9924474
  • 财政年份:
    2017
  • 资助金额:
    $ 32.89万
  • 项目类别:
Selectively Targeting Oncogenic NRAS in Cancer
选择性靶向癌症中的致癌 NRAS
  • 批准号:
    10372214
  • 财政年份:
    2015
  • 资助金额:
    $ 32.89万
  • 项目类别:
Project 3: Efficacy of MEK Inhibition in Juvenile Myelomonocytic Leukemia
项目3:MEK抑制对幼年粒单核细胞白血病的疗效
  • 批准号:
    8932164
  • 财政年份:
    2015
  • 资助金额:
    $ 32.89万
  • 项目类别:
Selectively Targeting Oncogenic NRAS in Cancer
选择性靶向癌症中的致癌 NRAS
  • 批准号:
    10209682
  • 财政年份:
    2015
  • 资助金额:
    $ 32.89万
  • 项目类别:
Developmental Research Program
发展研究计划
  • 批准号:
    8932166
  • 财政年份:
    2015
  • 资助金额:
    $ 32.89万
  • 项目类别:
Selectively Targeting Oncogenic NRAS in Cancer
选择性靶向癌症中的致癌 NRAS
  • 批准号:
    9040123
  • 财政年份:
    2015
  • 资助金额:
    $ 32.89万
  • 项目类别:
Selectively Targeting Oncogenic NRAS in Cancer
选择性靶向癌症中的致癌 NRAS
  • 批准号:
    10610346
  • 财政年份:
    2015
  • 资助金额:
    $ 32.89万
  • 项目类别:
Career Enhancement Program
职业提升计划
  • 批准号:
    10494113
  • 财政年份:
    2015
  • 资助金额:
    $ 32.89万
  • 项目类别:
Developmental Research Program
发展研究计划
  • 批准号:
    10494111
  • 财政年份:
    2015
  • 资助金额:
    $ 32.89万
  • 项目类别:
Career Development Program
职业发展计划
  • 批准号:
    8932167
  • 财政年份:
    2015
  • 资助金额:
    $ 32.89万
  • 项目类别:

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Alternatively spliced cell surface proteins as drivers of leukemogenesis and targets for immunotherapy
选择性剪接的细胞表面蛋白作为白血病发生的驱动因素和免疫治疗的靶点
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    2023
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Targeting CD83 to reduce leukemia relapse and GVHD after allogeneic hematopoietic cell transplantation
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    10573570
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Chimeric antigen receptor-modified iNKT cell therapy for CD7+ malignancies
嵌合抗原受体修饰的 iNKT 细胞治疗 CD7 恶性肿瘤
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