Targeting ERK5 for Colorectal Cancer Therapy
靶向 ERK5 的结直肠癌治疗
基本信息
- 批准号:10357462
- 负责人:
- 金额:$ 16.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-13 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:BRAF geneCancer CenterCell Differentiation processCell ProliferationCellsClinicClinicalClinical ResearchClinical TrialsColorectal CancerCytokine ReceptorsDataDevelopmentDiagnosisEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorEpithelial CellsFamily memberFeedbackGeneticGrowth FactorHumanIn VitroInvestigational TherapiesKRAS oncogenesisKRAS2 geneLeadMAP Kinase GeneMAP2K1 geneMAPK Signaling Pathway PathwayMAPK phosphataseMAPK3 geneMAPK7 geneMEKsMalignant NeoplasmsMalignant neoplasm of lungMediatingMitogen-Activated Protein Kinase InhibitorMolecularMusMutationNeoplasm MetastasisOrganoidsPathogenesisPathway interactionsPatientsPharmaceutical PreparationsPharmacologyPhosphoric Monoester HydrolasesPlayPublicationsRas/RafReceptor Protein-Tyrosine KinasesResearch Project GrantsResistanceRoleSamplingSignal PathwaySignal TransductionSpecificityTestingTherapeuticTumor stageUp-Regulationadenomabasecancer cellcolon cancer cell linecolon cancer patientscolorectal cancer metastasiscolorectal cancer treatmenteffective therapygain of function mutationin vivoinhibitor/antagonistintestinal epitheliumintestinal homeostasismelanomamortalitymutantnovelpatient derived xenograft modelpatient responsepre-clinicalpreservationpreventresistance mechanismresponsestem cellstargeted agenttargeted treatmenttherapeutic targettherapy resistanttreatment responsetumortumor growthtumor progression
项目摘要
ABSTRACT
Colorectal cancer (CRC) is diagnosed in about 140,000 patients in the US, with a mortality of 50,000 patients
per year. Almost half of these patients have either a RAS or BRAF mutation for which there is currently no
effective therapy. Activated MAPK signaling plays a major role in the pathogenesis of CRC. Pharmacological
inhibitors of mutant BRAFV600E, MEK1/2, and more recently ERK1/2 have been developed for targeted therapy.
Vertical targeting the MAPK pathway, particularly in combination with epidermal growth factor receptor (EGFR)
inhibitors to prevent its feedback activation holds promise for the systemic treatment of CRC. However, primary
or acquired resistance to targeted therapy is a major obstacle, particularly in CRC as compared with other
cancers such as melanoma and lung cancer. Combinations of EGFR/RAF or RAF/MEK inhibitors have been
tested in the lab and clinic, and recently a triple inhibitor cocktail (EGFR/RAF/MEK) has been clinically evaluated
in BRAFV600E mutant CRC. However, in all the studies reactivation of MAPK signaling was identified as a cause
of resistance and low patient response rates. The mechanism of the reactivation of MAPK signaling is poorly
understood. We have found a novel resistance mechanism in intestinal epithelial cells upon genetic deletion of
ERK1/2 in mice in vivo, as well as in response to treatment of human CRC cells with MEK inhibitors in vitro. This
molecular mechanism involves activation of an atypical MAPK family member, ERK5, which provides a by-pass
signaling pathway to the canonical MAPK signaling pathway. Thus the hypothesis upon which the studies are
based is that “therapeutic targeting of ERK5, particularly when either RAS or BRAF is the cancer driver, in
combination with other targeted agents and/or chemotherapeutics will enhance inhibition of CRC proliferation
and metastasis. Pharmacological targeting of ERK5 in combination with EGFR, RAF and/or MEK inhibitors will
be particularly effective in CRC patients with oncogenic KRAS or BRAF mutations, as this approach prevents
acquired resistance via parallel pathways”. The studies we will conduct are to: investigate the molecular
mechanism causing ERK5 upregulation in CRC cells; evaluate of ERK5 signaling in patient-derived CRC
samples with KRAS mutations; and an investigation of treatment of MEK inhibitor-resistant CRC patient derived
xenografts with ERK5 targeted agents. This an exploratory developmental research project to obtain preclinical
data validating a potential new clinical target, ERK5, responsible for tumor progression, invasion and metastasis
of CRC. The information obtained will provide the basis for a clinical trial of the combination of an ERK5 inhibitor,
with an EGFR/RAF/ MEK inhibitor cocktail in CRC patients.
摘要
项目成果
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{{ truncateString('GARTH POWIS', 18)}}的其他基金
Targeting ERK5 for Colorectal Cancer Therapy
靶向 ERK5 的结直肠癌治疗
- 批准号:
10021322 - 财政年份:2020
- 资助金额:
$ 16.95万 - 项目类别:
Inhibiting Multi-Functional ALDOA for Cancer Therapy
抑制多功能 ALDOA 用于癌症治疗
- 批准号:
10357451 - 财政年份:2018
- 资助金额:
$ 16.95万 - 项目类别:
Inhibiting Multi-Functional ALDOA for Cancer Therapy
抑制多功能 ALDOA 用于癌症治疗
- 批准号:
10494262 - 财政年份:2018
- 资助金额:
$ 16.95万 - 项目类别:
PLEKHA7 A Novel Target for Mutant KRAS Therapy
PLEKHA7 突变 KRAS 治疗的新靶点
- 批准号:
8964895 - 财政年份:2015
- 资助金额:
$ 16.95万 - 项目类别:
PLEKHA7 A Novel Target for Mutant KRAS Therapy
PLEKHA7 突变 KRAS 治疗的新靶点
- 批准号:
9301505 - 财政年份:2015
- 资助金额:
$ 16.95万 - 项目类别:
PLEKHA7 A Novel Target for Mutant KRAS Therapy
PLEKHA7 突变 KRAS 治疗的新靶点
- 批准号:
9485728 - 财政年份:2015
- 资助金额:
$ 16.95万 - 项目类别:
PLEKHA7 and beta-catenin interact to regulate mutant KRas
PLEKHA7 和 β-catenin 相互作用调节突变 KRas
- 批准号:
9251596 - 财政年份:2015
- 资助金额:
$ 16.95万 - 项目类别:
Inhibiting oncogenic KRAS for cancer therapy
抑制致癌 KRAS 用于癌症治疗
- 批准号:
8637741 - 财政年份:2013
- 资助金额:
$ 16.95万 - 项目类别:
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