Targeting the p110beta Isoform of PI3 Kinase in Pten Null Tumors

靶向 Pten 无效肿瘤中 PI3 激酶的 p110beta 同工型

基本信息

  • 批准号:
    8601056
  • 负责人:
  • 金额:
    $ 40.12万
  • 依托单位:
  • 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:
    2013-01-01 至 2017-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The PI3 Kinase pathway is a leading candidate for targeted tumor therapy at this time. This pathway is frequently activated via mutation in both commonly occurring and rare tumor types. Current PI3K directed therapies are targeted to the catalytic subunits of the so-called Class I enzymes. Of the four Class I isoforms, only p110beta and p110beta are expressed in all tissues. Both the p110beta and p110beta isoforms appear to play distinct roles in oncogenic transformation, and, interestingly, isoform functionality varies according to tumor type. Only p110beta is activated by mutations in human tumors. Experiments with conditional knockout mice and shRNAs in human tumor cell lines have shown that p110beta is the key isoform for signaling from oncogenic receptor tyrosine kinases as well as oncogenes such as ras or polyoma middle T antigen. Surprisingly p110beta has been shown to be key for tumors featuring Pten loss, though mechanistic understanding of this data has been lacking. The roles of the two isoforms in insulin signaling are also quite distinct, with p110beta carrying the larger part of the signal, suggesting that inhibiting individual isoforms could have fewer side-effects than the pan inhibitors now entering the clinic. Thus we are excited that the differences in the roles of the isoforms may be exploited to make safer second-generation drugs for PI3Ks. While pharma has concentrated on p110beta specific inhibitors, we have worked to develop a tool compound, Kin-193, that can be used to treat Pten null tumors in mice via inhibition of p110beta. In this grant we seek to understand the mechanism(s) by which p110beta is specifically activated in Pten null tumors, to characterize Kin-193's effects on human xenograft tumors in mice, and to determine how resistance to p110beta inhibitors may arise.
描述(由申请人提供):PI3激酶途径是目前靶向肿瘤治疗的主要候选途径。在常见和罕见的肿瘤类型中,这一途径经常通过突变被激活。目前的PI3K定向疗法针对的是所谓的I类酶的催化亚基。在四种I类异构体中,只有p110 β和p110 β在所有组织中表达。p110 β和p110 β亚型似乎在癌性转化中发挥着不同的作用,有趣的是,亚型的功能因肿瘤类型而异。在人类肿瘤中,只有p110 β被突变激活。对条件敲除小鼠和人类肿瘤细胞系shrna的实验表明,p110 β是致癌受体酪氨酸激酶以及ras或多瘤中间T抗原等致癌基因信号传导的关键亚型。令人惊讶的是,p110 β已被证明是以Pten缺失为特征的肿瘤的关键,尽管对这一数据的机制理解尚缺乏。这两种异构体在胰岛素信号传导中的作用也非常不同,p110beta携带的信号更大,这表明抑制单个异构体的副作用可能比目前进入临床的pan抑制剂更少。因此,我们很兴奋地发现,这些同工异构体的作用差异可能被用于制造更安全的第二代pi3k药物。虽然制药公司专注于p110 β特异性抑制剂,但我们已经致力于开发一种工具化合物,Kin-193,可通过抑制p110 β用于治疗小鼠Pten无肿瘤。在这项资助中,我们试图了解p110 β在Pten缺失肿瘤中特异性激活的机制,表征Kin-193对小鼠人类异种移植肿瘤的影响,并确定对p110 β抑制剂的耐药性是如何产生的。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(4)

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Jean Zhao其他文献

Jean Zhao的其他文献

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{{ truncateString('Jean Zhao', 18)}}的其他基金

Targeting glioblastoma with CM93, a novel EGFR inhibitor with exceptional brain penetration
使用 CM93 靶向胶质母细胞瘤,这是一种具有出色脑渗透性的新型 EGFR 抑制剂
  • 批准号:
    10697498
  • 财政年份:
    2023
  • 资助金额:
    $ 40.12万
  • 项目类别:
Integrating targeted therapy and immunotherapy to break through cancer
整合靶向治疗和免疫治疗突破癌症
  • 批准号:
    10737039
  • 财政年份:
    2016
  • 资助金额:
    $ 40.12万
  • 项目类别:
Developing novel targeted therapeutics integrated with immunotherapy-based approaches to make breakthroughs in metastatic breast cancer
开发与免疫疗法相结合的新型靶向疗法,以在转移性乳腺癌方面取得突破
  • 批准号:
    9186720
  • 财政年份:
    2016
  • 资助金额:
    $ 40.12万
  • 项目类别:
Developing novel targeted therapeutics integrated with immunotherapy-based approaches to make breakthroughs in metastatic breast cancer
开发与免疫疗法相结合的新型靶向疗法,以在转移性乳腺癌方面取得突破
  • 批准号:
    9763524
  • 财政年份:
    2016
  • 资助金额:
    $ 40.12万
  • 项目类别:
Developing novel targeted therapeutics integrated with immunotherapy-based approaches to make breakthroughs in metastatic breast cancer
开发与免疫疗法相结合的新型靶向疗法,以在转移性乳腺癌方面取得突破
  • 批准号:
    10240658
  • 财政年份:
    2016
  • 资助金额:
    $ 40.12万
  • 项目类别:
Targeting the p110beta Isoform of PI3 Kinase in Pten Null Tumors
靶向 Pten 无效肿瘤中 PI3 激酶的 p110beta 同工型
  • 批准号:
    8419866
  • 财政年份:
    2013
  • 资助金额:
    $ 40.12万
  • 项目类别:
Project 3: Improving therapeutic approaches for breast cancer brain metastases
项目3:改进乳腺癌脑转移的治疗方法
  • 批准号:
    10215415
  • 财政年份:
    2013
  • 资助金额:
    $ 40.12万
  • 项目类别:
Project 3 - Targeting CDK4/6 to modulate immunogenicity in gliomas (Wen/Zhao)
项目3 - 靶向CDK4/6调节胶质瘤的免疫原性(Wen/Zhao)
  • 批准号:
    10019491
  • 财政年份:
    2013
  • 资助金额:
    $ 40.12万
  • 项目类别:
Targeting the p110beta Isoform of PI3 Kinase in Pten Null Tumors
靶向 Pten 无效肿瘤中 PI3 激酶的 p110beta 同工型
  • 批准号:
    8986642
  • 财政年份:
    2013
  • 资助金额:
    $ 40.12万
  • 项目类别:
Project 3 - Targeting CDK4/6 to modulate immunogenicity in gliomas (Wen/Zhao)
项目3 - 靶向CDK4/6调节胶质瘤的免疫原性(Wen/Zhao)
  • 批准号:
    10268490
  • 财政年份:
    2013
  • 资助金额:
    $ 40.12万
  • 项目类别:

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