Targeting eEF2 with the protein translation elongation inhibitor SVC112 in head and neck squamous cancer
使用蛋白质翻译延伸抑制剂 SVC112 靶向 eEF2 治疗头颈鳞状细胞癌
基本信息
- 批准号:10704601
- 负责人:
- 金额:$ 32.82万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectBiological AssayBiological MarkersCancer ModelCancer PatientCancer PrognosisCancer cell lineCell CommunicationCell CycleCell modelCellsClinical TrialsColoradoCompanionsComplexCyclin D1DataDiseaseDoseDrug KineticsDrug resistanceEvaluationFDA approvedFRAP1 geneFailureGenesGoalsGrowthHead and Neck CancerHead and Neck Squamous Cell CarcinomaHead and neck structureHomeHumanHuman PapillomavirusHypoxiaImmuneImmune EvasionImmune TargetingImmunityImmunologic Deficiency SyndromesImmunologic SurveillanceImmunotherapyIn VitroInternal Ribosome Entry SiteInvadedLigandsMalignant NeoplasmsMeasuresMediatingMessenger RNAMinorityModalityModelingMolecular TargetMusMutationOncogenicOncoproteinsOutcomePIK3CG genePapillomavirus Transforming Protein E6Pathway interactionsPatientsPharmaceutical PreparationsPredictive Value of TestsPredispositionProductionPropertyProtein BiosynthesisProtein Synthesis InhibitionProteinsProteomeProteomicsProto-Oncogene Proteins c-mycRadiation therapyRelapseReportingResistanceRestRibosomesSamplingSignal TransductionStressT-LymphocyteTestingTherapeuticTherapeutic IndexTissue BanksTissuesToxic effectTranslationsTreatment EfficacyTreatment FailureTumor BankTumor-infiltrating immune cellsWorkcancer cellcancer infiltrating T cellscancer therapyefficacy testingfitnessgene producthumanized mousein vivoin vivo Modelinhibitormouse modelnovel therapeuticspatient derived xenograft modelpembrolizumabpharmacologicpredictive markerprogrammed cell death ligand 1programmed cell death protein 1protein expressionribosome profilingsmall moleculestemnesssynergismtooltranscription factortumortumor growthtumor microenvironmenttumor progression
项目摘要
SUMMARY. Radiation therapy (RT) and immunotherapy with PD-1 inhibitors are used in early and relapsed
head and neck squamous cell cancers (HNSCC), respectively; RT failures are common, and most patients do
not respond to PD-1 inhibition. Both impact the tumor microenvironment (TME), but studying the TME is limited
by the availability of models with human immune cells. PI3K/mTOR signaling regulates protein synthesis through
transcription factors such as Myc or SOX2, that dictate growth, invasion, and drug resistance in HNSCC. SVC112
is a fully synthetic small molecule that inhibits protein synthesis at the elongation step by inhibiting eEF2. SVC112
had greater effect on cancer over non-cancer cells, and was more potent and selective than homoharringtonin
(HHT), an FDA-approved translation elongation inhibitor. Cancer cells had higher eEF2 than non-cancer cells,
and the most susceptible strain had the highest eEF2 expression. SVC112 depleted SOX2, Myc, and Cyclin D1
in HNSCC cells at concentrations that had minimal effect on the rest of the proteome. SVC112 decreased
spheres in vitro, reduced tumor growth in vivo in patient-derived xenografts (PDX), and induced tumor regression
when given with RT in three out of four PDX models. SVC112 also reduced the E6 oncoprotein in human
papillomavirus-driven cells. Lastly, SVC112 decreased PD-1 ligand (PD-L1) resulting in decreased PD-L1:PD-1
interactions leading to increased sphere T cell invasion, while having no effect on T cell fitness or function. Thus,
SVC112 can target multiple key pathways (SOX2, Myc, PD-L1), and can influence the TME to reverse immune
evasion. To test SVC112’s therapeutic potential in HNSCC, several unique tools will be used including 1) spheres
containing cancer cells and T cells (iSpheres) that enable studying TME interactions and immunotherapy in vitro,
2) syngeneic mouse models of HNSCC, and 3) humanized mouse (HM) models, developed by the PI, that enable
studying TME interactions and immunotherapy in vivo. The hypothesis that SVC112’s discriminating effect is
due to selective depletion of key proteins will be tested by ribosome profiling (to identify mRNA targets) and
proteomics analysis (to identify proteins targets). Then, we will test the mechanism of SVC112 synergy with RT,
and if the modulation of the TME by SVC112 will further enhance RT efficacy. Lastly, the hypothesis that
reduction of PD-L1 by SVC112 in HNSCC will alter the tumor-immune interaction will be tested by defining the
effect of SVC112 on the expression of proteins critical for the TME, T cell tumor infiltration, and cancer-immune
crosstalk. The effect of SVC112 on T cell fitness and function will be examined, aiding SVC112 translation. We
will assess SVC112 and PD-1 inhibition in iSphere and HM models, and explore their efficacy when both are
combined. Lastly, we will test the predictive value of eEF2 in SVC112 susceptibility, and we will assess eEF2
expression in human tumors, to enable identifying a companion biomarker to SVC112, using a HNSCC tissue
bank with 1,250 patient cases. This project will propel the translation of SVC112, a drug discovered in Colorado,
by dissecting the basis for its effect, studying its toxicity, and testing predictive biomarkers to aid clinical trials.
总结。放射治疗(RT)和PD-1抑制剂免疫治疗用于早期和复发
项目成果
期刊论文数量(0)
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Antonio Jimeno其他文献
Antonio Jimeno的其他文献
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{{ truncateString('Antonio Jimeno', 18)}}的其他基金
Targeting eEF2 with the protein translation elongation inhibitor SVC112 in head and neck squamous cancer
使用蛋白质翻译延伸抑制剂 SVC112 靶向治疗头颈鳞状细胞癌中的 eEF2
- 批准号:
10477463 - 财政年份:2021
- 资助金额:
$ 32.82万 - 项目类别:
Targeting eEF2 with the protein translation elongation inhibitor SVC112 in head and neck squamous cancer
使用蛋白质翻译延伸抑制剂 SVC112 靶向治疗头颈鳞状细胞癌中的 eEF2
- 批准号:
10268847 - 财政年份:2021
- 资助金额:
$ 32.82万 - 项目类别:
Targeting oncogenic Myb fusions in salivary gland cancer with the elongation inhibitor SVC112
使用延伸抑制剂 SVC112 靶向唾液腺癌中的致癌 Myb 融合
- 批准号:
10368161 - 财政年份:2021
- 资助金额:
$ 32.82万 - 项目类别:
Targeting oncogenic Myb fusions in salivary gland cancer with the elongation inhibitor SVC112
使用延伸抑制剂 SVC112 靶向唾液腺癌中的致癌 Myb 融合
- 批准号:
10592292 - 财政年份:2021
- 资助金额:
$ 32.82万 - 项目类别:
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