Phosphorylation-dependent regulation of GLI transcription factors
GLI 转录因子的磷酸化依赖性调节
基本信息
- 批准号:9913480
- 负责人:
- 金额:$ 31.69万
- 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:2019-04-11 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAllograftingAlternative TherapiesAngerAntibodiesBasal cell carcinomaBiochemistryBiological AssayBrainCarcinomaCatalogsCell LineCellular biologyCessation of lifeClinicalCyclic AMP-Dependent Protein KinasesDataDatabasesDevelopmentDiseaseDrug resistanceErinaceidaeExhibitsFDA approvedGLI geneGLI2 geneGenesGeneticGenetic TechniquesGenetic TranscriptionGoalsGrowthHealthHematopoietic NeoplasmsHumanHuman DevelopmentIn VitroMalignant Bone NeoplasmMalignant NeoplasmsMalignant neoplasm of brainMalignant neoplasm of prostateMolecular BiologyMutationOncogenicOutcomePancreasPathway interactionsPatientsPhosphorylationPhosphotransferasesProstateRecurrenceRegulationResistanceResistance developmentSignal PathwaySkin CancerSomatic MutationStainsTestingTranscription CoactivatorTranscriptional ActivationUnited StatesWorkZinc Fingersatypical protein kinase Ccancer typecell growthcomparativeinhibitor/antagonistloss of functionlung small cell carcinomamalignant breast neoplasmmalignant stomach neoplasmmortalitymutantnew therapeutic targetoverexpressionprotein kinase C iotareceptorscreeningsmoothened signaling pathwaytargeted treatmenttherapeutic targettherapy developmenttranscription factortumortumor growth
项目摘要
Project Summary
Basal cell carcinomas (BCCs) are locally invasive epithelial cancers that affect over 4 million patients a year in
the United States and are solely driven by activating mutations in the Hedgehog (HH) pathway. Inappropriate
HH pathway activation also drives growth of a variety of cancers including brain, pancreatic, prostate, and
small cell lung cancer that account for up to 25% of all human cancer deaths. HH antagonists such as
vismodegib are FDA-approved to treat advanced and metastatic BCCs, however, nearly 60% of advanced
tumors display inherent vismodegib resistance and 20% of tumors that do respond acquire drug resistance
every year. This is a highly relevant issue as advanced BCC cases are estimated to approach 400,000 patients
each year, illustrating a critical need to identify therapeutic targets downstream of SMO to suppress HH
pathway activity. The consequence of not meeting this need will likely be the inability to treat patients who are
resistant to current approved therapies, leading to an increase in mortality for patients inflicted with BCC and
other HH-dependent cancers.
Our long-term objective is to identify and develop targeted therapeutics to treat drug-resistant HH-driven
cancers. The overall objective of this application is to define how GLI is oncogenically activated in HH-driven
cancer. Our central hypothesis is that GLI phosphorylation drives transcriptional activation and SMO
antagonist-resistant BCC growth, and targeting the signaling pathways that activate GLI will suppress tumor
growth. My two specific aims will define 1) how GLI zinc finger phosphorylation and 2) how clinically recurrent
GLI mutations promote transcriptional activity, tumor growth, and drug resistance. Defining how GLI is
activated in cancer may reveal novel therapeutic targets to treat patients with HH-driven cancers.
To achieve these aims, we will use BCC cell lines and allografts that overexpress clinically observed and
recurrent GLI mutants to assay for tumor growth in the presence or absence of HH antagonists. We will use
the GLI mutants that show increased transcriptional activity to define how GLI is activated in cancer using
standard molecular biology, biochemistry, cell biology, and genetic techniques. Our preliminary data has
already identified three kinases that regulate GLI activity, and we plan to generate phospho-specific mutants to
define when, where, and how each kinase acts on GLI. We will immunofluorescently stain human tumors with
appropriate antibodies to verify these pathways operate in humans, and we will perform standard gain- and
loss-of-function studies to analyze the pathways involved over the lifetime of the tumor.
项目概要
基底细胞癌 (BCC) 是局部侵袭性上皮癌,每年影响超过 400 万患者
美国,仅由激活 Hedgehog (HH) 通路中的突变驱动。不当
HH 通路激活还会促进多种癌症的生长,包括脑癌、胰腺癌、前列腺癌和
小细胞肺癌占所有人类癌症死亡人数的 25%。 HH 拮抗剂如
vismodegib 已获得 FDA 批准用于治疗晚期和转移性 BCC,然而,近 60% 的晚期和转移性 BCC
肿瘤表现出固有的 vismodegib 耐药性,并且 20% 确实有反应的肿瘤获得了耐药性
每年。这是一个高度相关的问题,因为晚期 BCC 病例估计接近 400,000 名患者
每年,这都表明迫切需要确定 SMO 下游的治疗靶点以抑制 HH
途径活动。不满足这一需求的后果可能是无法治疗患有以下疾病的患者:
对目前批准的治疗有耐药性,导致患有 BCC 的患者死亡率增加
其他 HH 依赖性癌症。
我们的长期目标是确定和开发靶向疗法来治疗耐药性 HH 驱动的
癌症。该应用的总体目标是定义 GLI 在 HH 驱动的致癌性中如何被激活
癌症。我们的中心假设是 GLI 磷酸化驱动转录激活和 SMO
拮抗剂耐药的 BCC 生长,并靶向激活 GLI 的信号通路将抑制肿瘤
生长。我的两个具体目标将定义 1) GLI 锌指磷酸化和 2) 临床复发情况
GLI 突变促进转录活性、肿瘤生长和耐药性。定义 GLI 的含义
在癌症中被激活可能会揭示治疗 HH 驱动的癌症患者的新治疗靶点。
为了实现这些目标,我们将使用过度表达临床观察到的和
复发性 GLI 突变体可在 HH 拮抗剂存在或不存在的情况下测定肿瘤生长。我们将使用
GLI 突变体表现出增加的转录活性,以定义 GLI 如何在癌症中被激活
标准分子生物学、生物化学、细胞生物学和遗传技术。我们的初步数据有
已经鉴定出三种调节 GLI 活性的激酶,我们计划生成磷酸化特异性突变体
定义每种激酶作用于 GLI 的时间、地点和方式。我们将对人类肿瘤进行免疫荧光染色
适当的抗体来验证这些途径在人类中的运作,我们将执行标准增益和
功能丧失研究,以分析肿瘤生命周期中涉及的途径。
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(0)
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Scott Atwood其他文献
Scott Atwood的其他文献
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{{ truncateString('Scott Atwood', 18)}}的其他基金
Phosphorylation-dependent regulation of GLI transcription factors
GLI 转录因子的磷酸化依赖性调节
- 批准号:
10362740 - 财政年份:2019
- 资助金额:
$ 31.69万 - 项目类别:
Phosphorylation-dependent regulation of GLI transcription factors
GLI 转录因子的磷酸化依赖性调节
- 批准号:
10586028 - 财政年份:2019
- 资助金额:
$ 31.69万 - 项目类别:
aPKC function in Hedgehog signaling and basal cell carcinoma
aPKC 在 Hedgehog 信号传导和基底细胞癌中的功能
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9034140 - 财政年份:2014
- 资助金额:
$ 31.69万 - 项目类别:
aPKC function in Hedgehog signaling and basal cell carcinoma
aPKC 在 Hedgehog 信号传导和基底细胞癌中的功能
- 批准号:
8804247 - 财政年份:2014
- 资助金额:
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aPKC function in Hedgehog signaling and basal cell carcinoma
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aPKC function in Hedgehog signaling and basal cell carcinoma
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MIM regulates Shh target gene expression in tumors
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