Maximizing the Effectiveness of PI3K Inhibitors in the Treatment of Pten null Cancers
最大化 PI3K 抑制剂治疗 Pten 无效癌症的有效性
基本信息
- 批准号:10705059
- 负责人:
- 金额:$ 102.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:Adaptor Signaling ProteinBCAR1 geneBinding ProteinsCRKL geneCRKL proteinCellsClinicClinicalCombined Modality TherapyDataDefectDependenceDrug TargetingEffectivenessEventFamilyFamily memberFeedbackGrantGrowth Factor ReceptorsGuanosine Triphosphate PhosphohydrolasesIn VitroMalignant NeoplasmsMembrane MicrodomainsMolecularOncogenesPIK3CG genePTEN genePharmaceutical PreparationsPhosphatidylinositide 3-Kinase InhibitorPhosphatidylinositolsProtein IsoformsProteinsResistanceSignal TransductionTestingTumor Suppressor ProteinsWorkimmune checkpointimmune checkpoint blockadein vivoinhibitornovel drug combinationresponsesynergismtumor
项目摘要
Project Summary/Abstract
In studying the PI3 Kinase isoform dependence of different tumor types, we made an extremely surprising
finding that now turns out to have considerable clinical importance. This finding forms the basis for this OIA
application. We discovered that tumors driven by the loss of the PTEN tumor suppressor are uniquely
dependent on the p110β isoform of PI3 Kinase. This finding likely explains why PI3K inhibitors first tested on
PTEN null tumors failed in the clinic, as they were poor p110β inhibitors. New p110b specific compounds are
now showing clinical promise. In attempting to understand the molecular mechanisms that uniquely couple
PTEN loss to p110β activation, we have uncovered a set of molecular mechanisms, which not only explains
how p110β is activated in response to PTEN loss but also suggests why the same tumors might quickly
become partially or even totally resistant to PI3K inhibition. Notably the same mechanisms clearly suggest
other drug targets, which can and should be attacked in combination with PI3K in PTEN null tumors. Our very
recent data identify 2 proteins that uniquely interact with p110β, and not with p110α, form a positive feedback
loop in the absence of PTEN. One of these proteins is the small ras family GTPase known as Rac, which
interacts with p110β but not p110α. We have recently shown that Rac localizes p110b to the lipid rafts where it
is activated. Thus Rac is an upstream activator of p110β. However Rac family members are unique in that
their activators, the Rac GEFs, are activated by the phosphoinositide products of PI3Ks. Thus Rac is also a
downstream effector of p110β. The interactions of Rac and p110β constitute the very definition of a positive
feedback loop. However, this leaves open how the Rac/p110β feedback loop is initiated- what activates
p110β/Rac in the first place. We have found that the activation event is dependent the small adapter protein
CRKL which is also a p110β specific binding protein. Activation of CRKL occurs via a SRC/p130Cas signaling
cascade that is also activated by PTEN loss. Notably SRC signaling renders cells resistant to PI3K inhibition.
Finally and most exciting we have found that p110b inhibitors synergize with immune checkpoint blockade. We
have generated data already showing the inhibitors of SRC RAC PAK (another downstream target of RAC)
lipid raft formation and immune checkpoints can all combine well with p110b inhibitors in vitro, and in some
cases, in vivo. This grant will focus more rigorous testing of new drug combinations on the one hand and on
the other hand, further refining our mechanistic understanding of the effects of PTEN loss to generate even
better combination therapy.
项目摘要/摘要
在研究不同肿瘤类型的PI3Kinase亚型依赖关系时,我们取得了一个非常令人惊讶的结果
这一发现现在被证明具有相当大的临床重要性。这一发现构成了内审办的基础
申请。我们发现,由PTEN抑癌基因缺失所驱动的肿瘤是独一无二的
依赖于PI3Kinase的p110β亚型。这一发现可能解释了为什么PI3K抑制剂首先在
PTEN缺失的肿瘤在临床上失败了,因为它们是很差的p110β抑制剂。新的p110b特定化合物是
现在显示出临床前景。在试图理解独一无二的耦合的分子机制
P110β的失活,我们揭示了一套分子机制,这不仅解释了
P110β是如何被激活的,但也暗示了为什么相同的肿瘤可能很快
部分甚至完全抵抗PI3K抑制。值得注意的是,同样的机制清楚地表明
其他药物靶点,可以也应该与PI3K联合攻击PTEN缺失肿瘤。我们的非常
最近的数据确定了两种与p110β唯一相互作用而不是与p110α相互作用的蛋白质形成正反馈
在没有PTEN的情况下循环。其中一种蛋白质是被称为rac的小ras家族gtp酶,它
与p110β相互作用,但不与p110α相互作用。我们最近发现RAC将p110b定位在脂筏上,在那里它
已被激活。因此,rac是p110β的上游激活剂。然而,RAC家族成员的独特之处在于
它们的激活剂RAC GEF被PI3K的磷脂酰肌醇产物激活。因此,RAC也是一个
P110β下游效应子。Rac和p110β的相互作用构成了阳性的定义
反馈环路。然而,这使得rac/p110β反馈环路如何启动-什么被激活
P110β/rac放在首位。我们已经发现,激活事件依赖于小接头蛋白
CRK1也是一种p110β特异性结合蛋白。CRKL的激活通过SRC/p130Cas信号发生
也被PTEN缺失激活的级联反应。值得注意的是,SRC信号使细胞对PI3K抑制产生抵抗。
最后,也是最令人兴奋的是,我们发现p110b抑制剂与免疫检查点阻断具有协同作用。我们
已经生成了显示SRC RAC PAK(RAC的另一个下游目标)的抑制剂的数据
脂筏形成和免疫检查点在体外都能与p110b抑制剂很好地结合,在某些情况下
病例,活体内。这笔拨款一方面将集中在对新药组合的更严格测试上,另一方面将集中在
另一方面,进一步细化我们对PTEN丢失的影响的机械性理解,以产生甚至
更好的联合疗法。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
More than one route to render tumors resistant to cGAS/STING activation.
使肿瘤抵抗 cGAS/STING 激活的途径不止一种。
- DOI:10.1016/j.tips.2022.11.002
- 发表时间:2023
- 期刊:
- 影响因子:13.8
- 作者:Manokaran,Cherubin;Roberts,ThomasM;Wang,Yubao
- 通讯作者:Wang,Yubao
The Mediator captures CDK7, an attractive transcriptional target in cancer.
Mediator 捕获 CDK7,这是癌症中一个有吸引力的转录靶标。
- DOI:10.1016/j.ccell.2021.07.021
- 发表时间:2021
- 期刊:
- 影响因子:50.3
- 作者:Wang,Yubao;Manokaran,Cherubin;Wu,Su;Roberts,ThomasM
- 通讯作者:Roberts,ThomasM
Statin-mediated inhibition of RAS prenylation activates ER stress to enhance the immunogenicity of KRAS mutant cancer.
- DOI:10.1136/jitc-2021-002474
- 发表时间:2021-07
- 期刊:
- 影响因子:10.9
- 作者:Nam GH;Kwon M;Jung H;Ko E;Kim SA;Choi Y;Song SJ;Kim S;Lee Y;Kim GB;Han J;Woo J;Cho Y;Jeong C;Park SY;Roberts TM;Cho YB;Kim IS
- 通讯作者:Kim IS
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THOMAS M ROBERTS其他文献
THOMAS M ROBERTS的其他文献
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{{ truncateString('THOMAS M ROBERTS', 18)}}的其他基金
Maximizing the Effectiveness of PI3K Inhibitors in the Treatment of Pten null Cancers
最大化 PI3K 抑制剂治疗 Pten 无效癌症的有效性
- 批准号:
9816457 - 财政年份:2019
- 资助金额:
$ 102.88万 - 项目类别:
Maximizing the Effectiveness of PI3K Inhibitors in the Treatment of Pten null Cancers
最大化 PI3K 抑制剂治疗 Pten 无效癌症的有效性
- 批准号:
10238853 - 财政年份:2019
- 资助金额:
$ 102.88万 - 项目类别:
Maximizing the Effectiveness of PI3K Inhibitors in the Treatment of Pten null Cancers
最大化 PI3K 抑制剂治疗 Pten 无效癌症的有效性
- 批准号:
9978752 - 财政年份:2019
- 资助金额:
$ 102.88万 - 项目类别:
Maximizing the Effectiveness of PI3K Inhibitors in the Treatment of Pten null Cancers
最大化 PI3K 抑制剂治疗 Pten 无效癌症的有效性
- 批准号:
10468110 - 财政年份:2019
- 资助金额:
$ 102.88万 - 项目类别:
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项目 2:通过 PP2A/YAP/Hippo 途径进行致癌转化
- 批准号:
10227783 - 财政年份:2017
- 资助金额:
$ 102.88万 - 项目类别:
PROJECT 2: Oncogenic Transformation via the PP2A/YAP/Hippo pathway
项目 2:通过 PP2A/YAP/Hippo 途径进行致癌转化
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9981671 - 财政年份:2017
- 资助金额:
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