New Paradigms for Targeting Truncal Driver Mutations

针对树干驱动突变的新范例

基本信息

  • 批准号:
    9337392
  • 负责人:
  • 金额:
    $ 98.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-09-01 至 2023-08-31
  • 项目状态:
    已结题

项目摘要

Summary: Solid tumors generate genetically distinct subclones during their evolution and expansion. Deep sequencing followed by quantification of mutant allele frequencies within a given tumor allows one to infer evolutionary trees consisting of shared early driver (“truncal”) mutations and divergent late driver (“branch”) mutations. This knowledge suggests one should therapeutically target truncal mutations, since they are theoretically shared by all of the cells within a tumor, rather than late mutations. Moreover, it is likely that some mutations that occur late during tumor evolution are only advantageous to (or tolerated by) tumor cells because of the mutations that preceded them. In such cases targeting truncal mutations could have therapeutic effects by unmasking deleterious effects to the tumor cell caused by the late mutations. In fact, virtually every successful targeted cancer drug attacks a genetic event that is known or suspected to be truncal. Combining two drugs that inhibit the same truncal lesion in different ways, such as when combining retinoic acid with arsenic trioxide to inhibit the PML-RAR fusion protein in acute promyelocytic leukemia, should enhance efficacy and reduce therapeutic resistance. The Kaelin Lab has had a longstanding interest in pRB and pVHL tumor suppressor proteins and most recently, in IDH oncoproteins. Mutations affecting these proteins occur as early truncal events in specific cancers such as small cell lung cancer (pRB), clear cell renal cancer (pVHL), and acute myelogenous leukemia (IDH1 and IDH2). The Kaelin Lab has played an important role in demonstrating the roles of pRB loss, pVHL loss, and mutant IDH in tumor maintenance and in identifying their pathogenic downstream targets. This proposal seeks to create new paradigms for targeting truncal mutations, including those currently deemed undruggable (for example, loss of function mutations or mutations encoding proteins without druggable pockets). Loss of function mutations will be addressed by exploiting epistatic relationships and synthetic lethal relationships, using both hypothesis-driven and CRISPR-based screening approaches. The Kaelin Lab recently showed that thalidomide-like drugs redirect the cereblon ubiquitin ligase to degrade the IKF1 and IKF3 transcription factors, which play important roles in myeloma. In the course of this work they developed a technology that allows them to screen for proteins that are destabilized (or stabilized) in response to specific chemical or genetic perturbants, as well as to screen for chemical and genetic perturbants that can destabilize (or stabilize) proteins of interest. The former will be used to identify protein-based biomarkers for monitoring molecular pathways of interest and the latter will be used to look for small molecules/targets capable of destabilizing oncoproteins of interest. They also identified a modular degron with IKZF1/3 that can be used to target heterologous proteins for destruction, which will be incorporated into preclinical target validation studies. Finally, CRISPR-based gene editing will be used to rapidly make mouse models of cancer driven by specific truncal mutations and for testing therapeutic and monitoring strategies emerging from these studies.
摘要: 实体瘤在进化和扩张过程中会产生基因上截然不同的亚克隆。深层测序 通过量化给定肿瘤内的突变等位基因频率,可以推断进化 由共享的早期驱动(“主干”)突变和发散的晚期驱动(“分支”)突变组成的树。这 知识表明,一个人应该在治疗上针对躯干突变,因为理论上它们是由 肿瘤内的所有细胞,而不是晚期突变。此外,发生的一些突变很可能 在肿瘤进化的后期,由于突变,只对肿瘤细胞有利(或耐受) 在他们之前。在这种情况下,以躯干突变为靶点可能通过揭开掩蔽而产生治疗效果 晚期突变对肿瘤细胞的有害影响。事实上,几乎每一个成功的靶子 抗癌药物攻击一种已知或怀疑是主干的基因事件。联合两种药物抑制 同一躯干病变有不同的方式,如联合维甲酸和三氧化二砷抑制 PML-RAR融合蛋白在急性早幼粒细胞白血病中的应用 抵抗。凯林实验室长期以来一直对pRb和pVHL肿瘤抑制蛋白和 最近,在IDH癌蛋白中。影响这些蛋白质的突变发生在特定的早期主干事件中 癌症,如小细胞肺癌(PRB)、透明细胞肾癌(PVHL)和急性髓系细胞癌 白血病(IDH1和IDH2)。凯林实验室在展示PRB丢失的作用方面发挥了重要作用, PVHL缺失和突变型IDH在肿瘤维持和识别其致病下游靶点方面的作用。这 一项提案寻求创建针对躯干突变的新范例,包括目前被认为的那些 不可用药(例如,功能丧失突变或编码蛋白质的突变而不能用药 口袋)。功能突变的丧失将通过利用上位关系和合成致死作用来解决 关系,使用假设驱动和基于CRISPR的筛选方法。凯林实验室 最近发现,沙利度胺类药物重定向小脑泛素连接酶以降解IKF1和IKF3 转录因子,在骨髓瘤中发挥重要作用。在这项工作的过程中,他们开发了一种 一种技术,允许他们筛选不稳定(或稳定)的蛋白质,以响应特定的 化学或遗传扰动,以及筛选可能破坏稳定的化学和遗传扰动 (或稳定)目标蛋白质。前者将用于识别以蛋白质为基础的生物标记物进行监测 感兴趣的分子途径,后者将被用来寻找能够 不稳定的感兴趣的癌蛋白。他们还发现了一个带有IKZF1/3的模块化退化基因,可以用来 用于销毁的靶向异源蛋白,将被纳入临床前靶点验证研究。 最后,基于CRISPR的基因编辑将被用来快速制作由特定基因驱动的小鼠癌症模型 用于测试这些研究中出现的治疗和监测策略。

项目成果

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WILLIAM G. KAELIN其他文献

WILLIAM G. KAELIN的其他文献

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{{ truncateString('WILLIAM G. KAELIN', 18)}}的其他基金

New Paradigms for Targeting Truncal Driver Mutations
针对树干驱动突变的新范例
  • 批准号:
    10471191
  • 财政年份:
    2016
  • 资助金额:
    $ 98.25万
  • 项目类别:
New Paradigms for Targeting Truncal Driver Mutations
针对树干驱动突变的新范例
  • 批准号:
    10228726
  • 财政年份:
    2016
  • 资助金额:
    $ 98.25万
  • 项目类别:
New Paradigms for Targeting Truncal Driver Mutations
针对树干驱动突变的新范例
  • 批准号:
    9186766
  • 财政年份:
    2016
  • 资助金额:
    $ 98.25万
  • 项目类别:
New Paradigms for Targeting Truncal Driver Mutations
针对树干驱动突变的新范例
  • 批准号:
    9978002
  • 财政年份:
    2016
  • 资助金额:
    $ 98.25万
  • 项目类别:
The von Hippel-Lindau Tumor Suppressor Gene and Kidney Cancer: Insights into Oxygen Sensing and Treating Cancers Caused by Undruggable Mutations
von Hippel-Lindau 肿瘤抑制基因和肾癌:深入了解氧感应和治疗由不可药物突变引起的癌症
  • 批准号:
    10737695
  • 财政年份:
    2016
  • 资助金额:
    $ 98.25万
  • 项目类别:
New Paradigms for Targeting Truncal Driver Mutations
针对树干驱动突变的新范例
  • 批准号:
    9764295
  • 财政年份:
    2016
  • 资助金额:
    $ 98.25万
  • 项目类别:
Project 2 - Targeting IDH-mutant gliomas (Cahill/Kaelin)
项目 2 - 针对 IDH 突变神经胶质瘤 (Cahill/Kaelin)
  • 批准号:
    10019488
  • 财政年份:
    2013
  • 资助金额:
    $ 98.25万
  • 项目类别:
Targeting the IDH Pathway
靶向 IDH 通路
  • 批准号:
    8588493
  • 财政年份:
    2013
  • 资助金额:
    $ 98.25万
  • 项目类别:
Project 2 - Targeting IDH-mutant gliomas (Cahill/Kaelin)
项目 2 - 针对 IDH 突变神经胶质瘤 (Cahill/Kaelin)
  • 批准号:
    10245086
  • 财政年份:
    2013
  • 资助金额:
    $ 98.25万
  • 项目类别:
P2 - Treament of VHL-/- clear cell renal carcinoma with HIF2a siRNA
P2 - 使用 HIF2a siRNA 治疗 VHL-/- 透明细胞肾癌
  • 批准号:
    8079678
  • 财政年份:
    2010
  • 资助金额:
    $ 98.25万
  • 项目类别:

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Elucidation of the pathophysiology of RARB translocation-positive acute promyelocytic leukemia and development of new target therapy
RARB易位阳性急性早幼粒细胞白血病病理生理学的阐明及新靶向治疗的开发
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ATRA治疗期间急性早幼粒细胞白血病细胞浸润和动员的机制:预防ATRA综合征和额外化疗的新策略。
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