Exploiting WEE1/p53 synthetic lethality as a novel therapy in head and neck cancer
利用 WEE1/p53 合成致死作用作为头颈癌的新型疗法
基本信息
- 批准号:10171805
- 负责人:
- 金额:$ 16.67万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-06-14 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAftercareBiologyBiopsyCDC2 geneCDK2 geneCell Culture TechniquesCell LineCellsCisplatinClinicClinicalClinical ManagementClinical TrialsCombined Modality TherapyDNA DamageDNA RepairDNA replication forkDataDevelopmentEngineeringG1 ArrestG2/M ArrestG2/M Checkpoint PathwayGene SilencingGenesGenomeGenome StabilityGenomic InstabilityGoalsGrowthHead and Neck CancerHead and Neck Squamous Cell CarcinomaHistologicHumanHuman PapillomavirusHuman papilloma virus infectionHypersensitivityIn VitroKnowledgeLeadLinkMalignant Epithelial CellMediatingMitosisModelingMusMutateMutationNatureNeoadjuvant TherapyNormal CellOncogenicOutcomePapillomavirus Transforming Protein E6Pathway interactionsPatientsPharmaceutical PreparationsPhasePhase I Clinical TrialsPhase II Clinical TrialsPhosphorylationPhosphotransferasesPoint MutationPre-Clinical ModelPrognosisPublishingRiskS PhaseSamplingSmall Interfering RNASolidSolid NeoplasmSpecificitySuppressor MutationsSurveysTP53 geneTestingTherapeuticTimeTranslatingTreatment FailureTreatment ProtocolsTumor Suppressor GenesTumor Suppressor ProteinsWorkXenograft procedurebasebench to bedsidecancer cellcell killingchemotherapeutic agentchemotherapyclinical efficacyclinically relevantco-clinical trialcombinatorialcytotoxicitydocetaxelgene repairgenotoxicityhigh riskimprovedin vivoindividualized medicineinhibitor/antagonistknock-downmalignant phenotypemutantneoplastic cellnew therapeutic targetnovelnovel therapeuticspatient derived xenograft modelphase I trialpreclinical studyprematurepreventreplication stressresponseresponse biomarkersuccesstargeted cancer therapytargeted treatmenttreatment optimizationtumortumor growth
项目摘要
This proposal addresses one of the most urgent needs in the clinical management of head and neck squamous
cell carcinoma (HNSCC), the development of targeted and less toxic therapies. Recent studies have shown that
50-60% of HNSCC tumors harbor mutations in the TP53 tumor suppressor gene with other studies
demonstrating that disruptive mutations in TP53 are associated with worse prognosis and survival. Additional
studies have linked HPV infection as a second pathway to p53 inactivation in HNSCC. Despite overwhelming
evidence implicating p53 functional derangement in the biology and clinical outcome of HNSCC, there are no
targeted therapies that capitalize on this knowledge. Towards this goal, we hypothesized that the driver
oncogenic/tumor suppressor mutations (i.e., TP53 loss) that confer dominant malignant phenotypes in cancer
cells also engender unique, exploitable vulnerabilities. Since p53 mutant HNSCCs are aggressive tumors
incapable of G1 arrest and with higher levels of genomic instability, these tumors rely on a functional G2/M cell
cycle checkpoint to repair the DNA damage that might occur as a result of this instability or through genotoxic
therapy. In support of this hypothesis, we identified p53 synthetic lethal interactions with several G2/M checkpoint
regulators using high throughput arrayed siRNA gene silencing against human kinases in p53-mutated HNSCC.
Moreover, treatment with AZD1775, a specific WEE1 inhibitor, blocked tumor growth as a single agent and
caused tumor regression when used in combination with cisplatin in p53 mutant HNSCC xenografts. To translate
these findings to the clinic, we opened a phase I clinical trial with AZD1775 in combination with neoadjuvant
weekly cisplatin and docetaxel in previously untreated, metastatic HNSCC patients. Building on these successes,
this proposal will provide needed mechanistic understanding on the biology of p53 alterations and G2/M reliance
in HNSCC, while providing translational data to advance WEE1 inhibition with AZD1775 as a novel therapy for
HNSCC. Therefore, in Aim 1 we will determine the mechanism(s) of growth arrest upon WEE1 inhibition in
HNSCC and determine how p53 inactivation affects this response. In Aim 2 we will identify novel sensitizers to
the WEE1 inhibitor AZD1775 to unveil novel synergistic and less toxic partners for combinatorial therapy. Lastly,
in Aim 3, we will leverage our ongoing phase I clinical trial to functionally evaluate the effects of AZD1775 on
tumor biopsies and relevant preclinical models established from patient biopsies before and after treatment to
correlate markers of WEE1 inhibition to p53 status and clinical efficacy for the first time in HNSCC. This new
knowledge will help inform which HNSCC might benefit most from this line of therapy and help advance AZD1775
into phase II clinical trials.
该建议解决了头颈部鳞状细胞癌临床管理中最迫切的需求之一,
细胞癌(HNSCC),靶向和毒性较小的治疗方法的发展。最近的研究表明
50-60%的HNSCC肿瘤在TP 53肿瘤抑制基因中具有突变,
这表明TP 53的破坏性突变与更差的预后和生存相关。额外
研究已经将HPV感染作为HNSCC中p53失活的第二途径联系起来。尽管有压倒性
有证据表明p53功能紊乱与HNSCC的生物学和临床结局有关,目前还没有
利用这些知识的靶向治疗。为了实现这个目标,我们假设司机
致癌/肿瘤抑制突变(即,TP 53缺失),其赋予癌症中的显性恶性表型
细胞还产生独特的、可利用的脆弱性。由于p53突变型HNSCC是侵袭性肿瘤,
这些肿瘤不能发生G1期阻滞,基因组不稳定性更高,依赖于功能性G2/M细胞
循环检查点,以修复可能由于这种不稳定性或通过遗传毒性而发生的DNA损伤
疗法为了支持这一假设,我们鉴定了p53与几个G2/M检查点的合成致死相互作用,
在p53突变的HNSCC中使用针对人激酶的高通量阵列siRNA基因沉默调节剂。
此外,AZD 1775(一种特异性WEE 1抑制剂)单药治疗可阻断肿瘤生长,
在p53突变型HNSCC异种移植物中与顺铂联合使用时引起肿瘤消退。翻译
为了将这些发现应用于临床,我们启动了一项AZD 1775联合新辅助化疗的I期临床试验,
在既往未接受治疗的转移性HNSCC患者中,每周给予顺铂和多西他赛。在这些成功的基础上,
这一建议将提供对p53改变和G2/M依赖的生物学机制的理解
在HNSCC中,虽然提供了翻译数据,以促进AZD 1775作为一种新的治疗方法对WEE 1的抑制,
HNSCC。因此,在目标1中,我们将确定在WEE 1抑制后生长停滞的机制,
HNSCC,并确定p53失活如何影响这种反应。在目标2中,我们将确定新的致敏剂,
WEE 1抑制剂AZD 1775,以揭示用于组合治疗的新型协同和毒性较小的合作伙伴。最后,
在目标3中,我们将利用我们正在进行的I期临床试验,在功能上评估AZD 1775对
肿瘤活检和从治疗前后的患者活检建立的相关临床前模型,
在HNSCC中首次将WEE 1抑制标记物与p53状态和临床疗效相关联。这个新
这些知识将有助于告知哪种HNSCC可能从该治疗中获益最多,并有助于推进AZD 1775
进入II期临床试验
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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Bruce E Clurman其他文献
Cyclin E in normal and neoplastic cell cycles
正常和肿瘤细胞周期中的细胞周期蛋白 E
- DOI:
10.1038/sj.onc.1208613 - 发表时间:
2005-04-18 - 期刊:
- 影响因子:7.300
- 作者:
Harry C Hwang;Bruce E Clurman - 通讯作者:
Bruce E Clurman
Bruce E Clurman的其他文献
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{{ truncateString('Bruce E Clurman', 18)}}的其他基金
The Fbw7 ubiquitin ligase network: normal and neoplastic functions
Fbw7 泛素连接酶网络:正常和肿瘤功能
- 批准号:
10639893 - 财政年份:2023
- 资助金额:
$ 16.67万 - 项目类别:
Exploiting WEE1/p53 synthetic lethality as a novel therapy in head and neck cancer
利用 WEE1/p53 合成致死作用作为头颈癌的新型疗法
- 批准号:
10603076 - 财政年份:2017
- 资助金额:
$ 16.67万 - 项目类别:
Exploiting WEE1/p53 synthetic lethality as a novel therapy in head and neck cancer
利用 WEE1/p53 合成致死作用作为头颈癌的新型疗法
- 批准号:
9398810 - 财政年份:2017
- 资助金额:
$ 16.67万 - 项目类别:
Identifying CDK4 and CDK6 substrates in cancers and cancer therapy
鉴定癌症和癌症治疗中的 CDK4 和 CDK6 底物
- 批准号:
8958740 - 财政年份:2015
- 资助金额:
$ 16.67万 - 项目类别:
Developing Ubiquitin Ligase Agonists as Cancer Therapeutics
开发泛素连接酶激动剂作为癌症治疗药物
- 批准号:
8562191 - 财政年份:2013
- 资助金额:
$ 16.67万 - 项目类别:
Cell Proliferation and Differentiation By the Fbw 7 Tumor Suppressor
Fbw 7 肿瘤抑制因子促进细胞增殖和分化
- 批准号:
7226081 - 财政年份:2006
- 资助金额:
$ 16.67万 - 项目类别:
Normal and Neoplastic Regulation of Cyclin E
细胞周期蛋白 E 的正常和肿瘤调节
- 批准号:
6916340 - 财政年份:2003
- 资助金额:
$ 16.67万 - 项目类别:
Normal and Neoplastic Regulation of Cyclin E
细胞周期蛋白 E 的正常和肿瘤调节
- 批准号:
7253916 - 财政年份:2003
- 资助金额:
$ 16.67万 - 项目类别:
Normal and Neoplastic Regulation of Cyclin E
细胞周期蛋白 E 的正常和肿瘤调节
- 批准号:
7997178 - 财政年份:2003
- 资助金额:
$ 16.67万 - 项目类别:
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