Mechanism-based targeting of unique survival signaling in residual tumors
Mechanism-based targeting of unique survival signaling in residual tumors
批准号:
10442812
负责人:
Kris Wood
金额:
$35.45万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-03-22 至 2027-02-28
关键词:
ATM activationAcute Myelocytic LeukemiaAnimal ModelAreaAutomobile DrivingBRAF geneBiologicalBiological ProcessBiologyCASP3 geneCASP7 geneCancer ModelCancer PatientCaspaseCell DeathCell SurvivalCell modelCellsClinicalCombined Modality TherapyCredentialingDNA DamageDNA Double Strand BreakDNA RepairDNA-dependent protein kinaseDependenceDisease ResistanceDouble Strand Break RepairERBB2 geneEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorExhibitsFDA approvedFGFR2 geneFoundationsGenesGenetically Engineered MouseGenomicsGlobal ChangeLinkLogisticsLung AdenocarcinomaLung NeoplasmsMolecularNon-Small-Cell Lung CarcinomaOncogenesOutcomePIK3CA genePathway interactionsPatientsPhosphotransferasesPopulationProgression-Free SurvivalsProgressive DiseaseProteomicsRegulationResidual CancersResidual TumorsResidual stateSamplingSignal TransductionSpecimenTherapeuticTissuesTumor BiologyUp-RegulationWorkataxia telangiectasia mutated proteinbasecancer cellcancer subtypescancer typecaspase-activated deoxyribonucleasefitnessinhibitorinhibitor therapyinterestloss of function mutationmelanomamutantneoplastic cellpatient derived xenograft modelpatient subsetsrepairedresponsetargeted cancer therapytargeted treatmenttherapeutic targettranslational potentialtreatment responsetumor
中文摘要
项目总结/文摘
英文摘要
Project Summary/Abstract
The clinical activities of oncogene targeted therapies are limited by the fact that a subset of residual cancer
cells often survive treatment, eventually giving rise to progressive, resistant disease that is very difficult to treat.
To date, relatively little is known about residual disease cells, in part because obtaining and analyzing tumor
specimens at this stage has been logistically challenging. We recently discovered that residual cells surviving
treatment with diverse, oncogene-matched targeted therapies exhibit DNA double strand breaks (DSBs) and
consequent, ATM-dependent DSB repair. In mechanistic studies performed in EGFR mutant non-small cell
lung cancer (NSCLC), this DNA damage was observed to be driven by the counterintuitive “sublethal”
activation of executioner caspases 3 and 7, which drive DNA damage through their direct activation of
caspase-activated DNase (CAD). As a consequence, residual cancer cells that survive upfront EGFR inhibitor
treatment require ATM activity to resolve DSBs, and combining EGFR inhibitors with ATM inhibitors eradicates
residual cells, leading to highly penetrant and durable therapeutic responses in cellular and animal models.
These findings are further supported by our clinical observations that residual EGFR mutant lung tumors
display marked upregulation of ATM activity and that rare NSCLC patients whose tumors harbor loss-of-
function mutations in ATM exhibit increased progression-free survival on EGFR inhibitor therapy. In this
proposal, we describe studies to define the mechanisms driving sublethal caspase activation in residual tumor
cells and their consequent, ATM-dependent survival. Further, we propose to define the broad, functional
implications of sublethal caspase and ATM activation in residual tumor cells, revealing consequent mechanistic
vulnerabilities of residual tumors. Finally, we describe studies that integrate cellular, patient-derived xenograft,
and genetically engineered mouse models with highly credentialed, longitudinally sampled clinical specimens
to evaluate the therapeutic targeting of residual tumor cell survival. Together, these studies will define key,
distinguishing features of residual tumor cells, advancing our basic understanding of this critically important but
poorly understood aspect of tumor biology while defining a new class of mechanism-based strategies with the
potential to minimize residual disease.
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专著(0)
科研奖励(0)
会议论文
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批准号:10595677
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负责人:Kris Wood
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依托单位:
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依托单位:
海外基金