Discovering mechanisms of sensitivity and resistance to triple combination targeted therapy in HR+/HER2+ breast cancer
发现HR/HER2乳腺癌三联联合靶向治疗的敏感性和耐药机制
基本信息
- 批准号:10460233
- 负责人:
- 金额:$ 23.18万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAdhesionsAnimal ModelApoptoticAromatase InhibitorsBAG1 geneBCL2 geneBiological AssayBiological MarkersBiopsyBreastCD47 geneCDK4 geneCell LineCell ProliferationCessation of lifeChromosomal RearrangementClinicalClinical ResearchClinical TrialsComplexCopy Number PolymorphismCyclin D1DataDiseaseDrug CombinationsDrug TargetingDrug resistanceERBB2 geneEnrollmentEvaluationFYN geneFibroblast Growth Factor ReceptorsGenesGoalsHormone ReceptorIGF1R geneIn VitroInheritedJAK2 geneLYN geneLaboratoriesLetrozoleMalignant NeoplasmsMammary NeoplasmsMediatingMetastatic breast cancerMulti-Institutional Clinical TrialMusMutationNeoplasm Circulating CellsOncogenesOralPathway interactionsPatientsPhasePhase III Clinical TrialsProteinsQuality of lifeReceptor SignalingRecurrenceRegimenResearch PersonnelResistanceResistance developmentRiskSTAT3 geneSafetySamplingSignal TransductionSingle Nucleotide PolymorphismTimeTumor Cell LineUp-RegulationXenograft Modelbasebiomarker developmentbiomarker panelbiomarker validationbreast cancer genomicscancer cellcancer subtypescareer developmentchemotherapydesigndisorder controldrug metabolismexperimental studyimprovedin vivoinhibitorinsightknock-downliquid biopsymRNA ExpressionmRNA sequencingmalignant breast neoplasmmortalitynon-invasive monitornoveloverexpressionpatient derived xenograft modelpatient populationpatient stratificationpersonalized medicinepotential biomarkerpre-clinicalpredictive markerpredictive panelpreventprotein biomarkersprotein expressionresistance generesistance mechanismresponseresponse biomarkerside effectskillssmall molecule inhibitorstandard of caretargeted agenttargeted treatmenttherapy resistanttooltreatment responsetreatment stratificationtumoryoung woman
项目摘要
Project summary / abstract
Breast cancers overexpressing both the HER2 oncogene and hormone receptors (HR) are common among
young women, comprising up to 20% of all breast cancer cases and significantly contributing to mortality in this
patient population. These cancers represent a unique challenge because of a cross-talk between the HER2
and HR pathways, leading to targeted therapy resistance commonly mediated by activation of the cyclin D1 /
CDK4/6 complex downstream of HER2 and HR signalling cascades. At present, the vast majority of patients
with metastatic HR+/HER2+ breast cancer are treated with chemotherapy associated with multiple side effects,
because several standard of care targeted drug combinations failed to improve overall survival in phase III
clinical trials. Based on a strong signalling rationale and preliminary data obtained in our laboratory, I proposed a
triple combination of targeted agents - HER2 small molecule inhibitor tucatinib, aromatase inhibitor letrozole, and
CDK4/6 inhibitor palbociclib - as a novel targeted approach for treatment of HR+/HER2+ disease. After
demonstrating high activity of this combination in preclinical experiments, I opened an investigator-initiated
multicenter clinical trial of tucatinib, palbociclib and letrozole for patients with HR+/HER2+ metastatic breast
cancer. This trial was opened in November 2017 and has already shown a favourable safety and efficacy profile:
as
longest
of the October 1 st 2018 data cut off, with 18 out of 40 patients enrolled, clinical benefit rate was 75%, with the
duration of response of 8 months and ongoing.Triple combination targeted therapy has high potential to
challenge current standard of care front line chemotherapy approach for patients with HR+/HER2+ metastatic
disease. Therefore, it is critically important to develop a biomarker to allow stratification of patients into those
who will ultimately need chemotherapy, and those who will respond to front line triple targeted combination,
and may have long term disease control and improved quality of life with an oral targeted regimen. In this
application, I propose a comprehensive approach to identify pathways of intrinsic sensitivity and acquired
resistance to triple combination targeted therapy with the ultimate goal of developing a biomarker of response
to this therapy. I have already identified several potential drivers of acquired resistance via sequencing of drug
resistant tumor cell lines. These potential biomarkers will be validated in cell line based functional assays and
animal models. Additionally, patient tumor samples from the tucatinib, palbociclib and letrozole clinical trial will
be analyzed by total mRNA sequencing to identify the pathways and genes of intrinsic sensitivity to therapy,
and these pathways will be validated in vitro and in vivo. Moreover, using a liquid biopsy approach, I will
develop a predictive panel of biomarkers in circulating tumor cells, to allow a non-invasive monitoring of
biomarkers on therapy. Collectively, the proposed
studies
may
deliver
clinically
valuable
tools
allowing
for
stratification
of
treatment
for
patients
with
HR+/
HER2+
metastatic
breast
cancer
and
offering a personalized
medicine approach currently non-existent for this patient population.
项目摘要/摘要
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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Elena Shagisultanova其他文献
Elena Shagisultanova的其他文献
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{{ truncateString('Elena Shagisultanova', 18)}}的其他基金
Discovering mechanisms of sensitivity and resistance to triple combination targeted therapy in HR+/HER2+ breast cancer
发现HR/HER2乳腺癌三联联合靶向治疗的敏感性和耐药机制
- 批准号:
10223242 - 财政年份:2019
- 资助金额:
$ 23.18万 - 项目类别:
Discovering mechanisms of sensitivity and resistance to triple combination targeted therapy in HR+/HER2+ breast cancer
发现HR/HER2乳腺癌三联联合靶向治疗的敏感性和耐药机制
- 批准号:
9805695 - 财政年份:2019
- 资助金额:
$ 23.18万 - 项目类别:
Discovering mechanisms of sensitivity and resistance to triple combination targeted therapy in HR+/HER2+ breast cancer
发现HR/HER2乳腺癌三联联合靶向治疗的敏感性和耐药机制
- 批准号:
10678935 - 财政年份:2019
- 资助金额:
$ 23.18万 - 项目类别:
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