Exploiting synthetic-lethal interactions to target triple-negative breast cancers
Exploiting synthetic-lethal interactions to target triple-negative breast cancers
批准号:
9269527
负责人:
Dai Horiuchi
金额:
$23.94万
依托单位国家:
美国
项目类别:
财政年份:
2015
资助国家:
美国
项目状态:
已结题
起止时间:
2015-04-01 至 2018-03-31
关键词:
Alpha CellApoptosisApoptoticAutomobile DrivingBCL1 OncogeneBCL2 geneBCL2L11 geneBiologicalBiologyBreast Cancer CellBreast Cancer cell lineBreast Epithelial CellsCancer cell lineCell Culture TechniquesCell CycleCell DeathCell LineCellsClinicalClinical ResearchClinical TrialsCollaborationsComplementCyclin-Dependent Kinase InhibitorCyclin-Dependent KinasesDiversity LibraryEpidermal Growth Factor ReceptorEstrogen ReceptorsFamily memberGeneticHumanKnowledgeLeadLymphomaMalignant NeoplasmsMalignant neoplasm of prostateMammary NeoplasmsMammary glandMentorsMessenger RNAMitochondriaMitoticModelingMolecularMusOncogenicOncoproteinsPathway interactionsPatientsPhasePhenotypePhosphotransferasesPlayProgesterone ReceptorsProtein-Serine-Threonine KinasesProteinsProto-Oncogene Proteins c-mycRNA InterferenceReportingResearchRoleSignal PathwaySignal TransductionTestingTherapeuticTherapeutic InterventionTumorigenicityUp-Regulationbasecancer subtypescellular engineeringchemical geneticsclinically relevantcombinatorialdesigneffective therapyexperimental studygenetic approachhigh throughput screeninginhibitor/antagonistinsightkillingsmalignant breast neoplasmmembermouse modelnovelnovel therapeuticsoutcome forecastoverexpressionreceptorsmall hairpin RNAsmall moleculesmall molecule inhibitortargeted treatmenttooltranscription factortreatment strategytriple-negative invasive breast carcinomatumortumor xenografttumorigenic
中文摘要
项目总结/文摘
英文摘要
PROJECT SUMMARY/ABSTRACT
No targeted therapeutic strategies are currently available against triple-negative (TN) breast cancer,
the most difficult-to-treat form of breast cancer, which does not overexpress human epidermal growth factor
receptor 2 (HER2) and lacks the expression of the estrogen and progesterone receptors. Thus, there is an
urgent need in deepening our understanding of this aggressive breast cancer subtype and identifying
clinically relevant targets for therapeutic intervention. We have recently discovered that an oncogenic
transcription factor MYC as well as the MYC-dependent signaling pathways are significantly up-regulated in
primary human triple-negative breast tumors. In addition, we found that MYC activation is associated with
patientsʼ poor prognosis suggesting that the MYC pathways may play a fundamental role in driving the
formation of these aggressive tumors.
How can we kill MYC-driven TN tumors? Because MYC is a transcription factor, rationally designed
small molecule inhibitors that can directly inhibit its activity are not available for clinical use. An alternative
approach in selectively killing MYC-driven tumors is to exploit the existence of “synthetic-lethal” interactions.
Our group previously took a cell cycle-biased approach and discovered that inhibition of the mitotic kinase
cyclin-dependent kinase (CDK) 1 resulted in apoptosis in cells engineered to overexpress MYC. The
mechanism of such cell death involved an up-regulation of a pro-apoptotic BCL-2 family member BIM. We
subsequently used this approach to treat TN cell lines and xenograft tumors with elevated MYC expression.
These observations suggest that MYC-dependent synthetic-lethal interactions exist, and importantly, can be
targeted to selectively kill MYC-driven tumors.
Aim 1 of this proposed research will further study the clinical potential of small molecule CDK
inhibition against MYC-driven TN cancers particularly in combination with clinical inhibitors of anti-apoptotic
BCL-2 members. This is based on our novel hypothesis that, because CDK inhibition up-regulates BIM and
activates mitochondrial intrinsic pathway, the combined use of the inhibitors for CDK and anti-apoptotic
BCL-2 family members may significantly enhance the rate of cell death. Aim 2 will characterize a newly
discovered synthetic-lethal interaction between MYC activation and inhibition of Pim1, a non-essential,
kinase previously shown to genetically interact with MYC. Aim 3 will conduct a high-throughout small
molecule screen to identify potential lead molecules capable of inducing MYC-dependent synthetic lethality
in mammary cells. We will carry out these experiments using a combination of model human mammary
epithelial cells, genetically defined cancer cell lines, and a panel of novel human-in-mouse orthotopic tumor
grafts models. If successful, the proposed research will not only expand our knowledge on MYC biology but
will also provide novel therapeutic concepts to be tested again patients with TN tumors.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.18632/oncotarget.26468
发表时间:
2018-12-18
期刊:
Oncotarget
影响因子:
--
作者:
[Brisard, Daphne, Eckerdt, Frank, Platanias, Leonidas C]
通讯作者:
Platanias, Leonidas C
Investigating Rational Combination Therapies for Triple-Negative Breast Cancer
-
批准号:10367060
-
项目类别:
-
资助金额:$34.35万
-
财政年份:2022
-
负责人:Dai Horiuchi
-
依托单位:
Investigating Rational Combination Therapies for Triple-Negative Breast Cancer
-
批准号:10543989
-
项目类别:
-
资助金额:$33.66万
-
财政年份:2022
-
负责人:Dai Horiuchi
-
依托单位:
Exploiting synthetic-lethal interactions to target triple-negative breast cancers
-
批准号:9070742
-
项目类别:
-
资助金额:$24.43万
-
财政年份:2015
-
负责人:Dai Horiuchi
-
依托单位:
Exploiting synthetic-lethal interactions to target triple-negative breast cancers
-
批准号:8487128
-
项目类别:
-
资助金额:$11.65万
-
财政年份:2013
-
负责人:Dai Horiuchi
-
依托单位:
Exploiting synthetic-lethal interactions to target triple-negative breast cancers
-
批准号:8639510
-
项目类别:
-
资助金额:$11.65万
-
财政年份:2013
-
负责人:Dai Horiuchi
-
依托单位:
国内基金
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