Project 2: Targeting RTK Co-Dependencies in Triple-Negative Breast Cancer
项目 2:针对三阴性乳腺癌的 RTK 相互依赖性
基本信息
- 批准号:10460215
- 负责人:
- 金额:$ 33.71万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-09-19 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:Adjuvant TherapyAnimal ModelBreast Cancer PatientCancer and Leukemia Group BCell CompartmentationChronicClinical DataClinical ResearchDataDependenceDiseaseERBB2 geneEnzymesEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorEquilibriumEvaluationExhibitsFamilyFeedbackGenomeGenomicsGoalsHumanHyperactivityHypersensitivityImmuneImmune checkpoint inhibitorImmune systemImmunocompetentIn VitroKnowledgeMalignant NeoplasmsMitoticModelingMolecularMutateMutationNormal tissue morphologyOncogenicPDGFRB genePTPN12 genePaclitaxelPathogenesisPathway interactionsPatient-derived xenograft models of breast cancerPatientsPlatelet-Derived Growth Factor alpha ReceptorPlayPre-Clinical ModelProtein Tyrosine PhosphataseProteinsProteomeProxyReagentReceptor ActivationReceptor Protein-Tyrosine KinasesResistanceRoleSignal TransductionTherapeuticTissue MicroarrayTranslatingTranslational ResearchTumor Suppressor ProteinsTumor TissueTyrosineTyrosine Kinase InhibitorTyrosine PhosphorylationWorkantagonistanti-tumor immune responsebasebreast cancer progressioncheckpoint therapyefficacy evaluationinhibitorinnovationinorganic phosphateinsightkinase inhibitormalignant breast neoplasmmemberneoplastic cellnext generationnovel therapeutic interventionpatient derived xenograft modelphase II trialpre-clinicalpreclinical studypreclinical trialpredictive markerrandomized trialreceptor bindingreceptor functionresponsestandard of caretaxanetherapeutic targettriple-negative invasive breast carcinomatumor
项目摘要
PROJECT SUMMARY
Despite extensive efforts to characterize the genomes and proteomes of triple-negative breast cancer
(TNBC), no dominantly-acting mutated RTK has emerged as therapeutic target in TNBC. Instead, TNBCs exhibit
broad, rather than selective, hyper-activation of RTK signaling, with several proto-oncogenic RTKs hyper-active
in the same tumor. Recent discoveries have revealed that the coordinate activation of RTKs observed in TNBC
is a result of inactivation of the protein tyrosine phosphatase PTPN12. In the current proposal, we aim to translate
our new knowledge of how RTKs are aberrantly activated and drive TNBC progression into a new therapeutic
approach for TNBC patients.
Data from our team and confirmed by others indicates that PTPN12 functions as a tumor suppressor by
restraining the activity of a select set of proto-oncogenic RTKs, including MET and PDGFR?, binding these
receptors and suppressing downstream signaling. PTPN12 is compromised in 45-55% of TNBCs, and we have
shown in in vitro and pre-clinical models of TNBC that inactivation of PTPN12 leads to hyper-activation of MET,
PDGFR?, and a small subset of other RTKs. Importantly, this provokes the therapeutic hypothesis that
PTPN12-deficient TNBCs can be treated by combined targeting of RTKs like MET, PDGFR, and potentially
other RTKs that are locked in the chronically active state. To translate these pre-clinical findings into a new
therapeutic approach, we will evaluate the efficacy of the well-tolerated MET/PDGFR inhibitor sitravatinib as
monotherapy in metastatic TNBC patients, develop rational strategies to combine sitravitinib with standard of
care therapies, and explore new ways to capitalize on the anti-tumoral and pro-immune effects of sitravatinib in
the context of immune checkpoint therapies.
Herein, our mechanistic, pre-clinical, and clinical studies will evaluate the proof-of-concept for the use of
sitravatinib to treat PTPN12-deficient TNBC and lay the groundwork for the next generation of combination
approaches for TNBC and other RTK-dependent cancers.
项目总结
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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Thomas Westbrook其他文献
Thomas Westbrook的其他文献
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{{ truncateString('Thomas Westbrook', 18)}}的其他基金
Therapeutic Targeting of RNA Splicing in Triple-Negative Breast Cancer
RNA 剪接在三阴性乳腺癌中的治疗靶向
- 批准号:
10660649 - 财政年份:2018
- 资助金额:
$ 33.71万 - 项目类别:
New Vulnerabilities in MYC-Driven Breast Cancer
MYC 驱动的乳腺癌中的新漏洞
- 批准号:
10333228 - 财政年份:2018
- 资助金额:
$ 33.71万 - 项目类别:
Identifying and targeting oncogenic Myc enhancer control in pediatric tumors
识别和靶向儿童肿瘤中的致癌 Myc 增强子控制
- 批准号:
9891027 - 财政年份:2017
- 资助金额:
$ 33.71万 - 项目类别:
Project 2: Targeting RTK Co-Dependencies in Triple-Negative Breast Cancer
项目 2:针对三阴性乳腺癌的 RTK 相互依赖性
- 批准号:
10219970 - 财政年份:2014
- 资助金额:
$ 33.71万 - 项目类别:
Project 2: Targeting RTK Co-Dependencies in Triple-Negative Breast Cancer
项目 2:针对三阴性乳腺癌的 RTK 相互依赖性
- 批准号:
10704539 - 财政年份:2014
- 资助金额:
$ 33.71万 - 项目类别:
Discovering genetic networks of triple-negative breast cancer
发现三阴性乳腺癌的遗传网络
- 批准号:
8685919 - 财政年份:2013
- 资助金额:
$ 33.71万 - 项目类别:
Discovering genetic networks of triple-negative breast cancer
发现三阴性乳腺癌的遗传网络
- 批准号:
9265420 - 财政年份:2013
- 资助金额:
$ 33.71万 - 项目类别:
Discovering genetic networks of triple-negative breast cancer
发现三阴性乳腺癌的遗传网络
- 批准号:
8560337 - 财政年份:2013
- 资助金额:
$ 33.71万 - 项目类别:
Discovering genetic networks of triple-negative breast cancer
发现三阴性乳腺癌的遗传网络
- 批准号:
8847687 - 财政年份:2013
- 资助金额:
$ 33.71万 - 项目类别:
Discovering genetic networks of triple-negative breast cancer
发现三阴性乳腺癌的遗传网络
- 批准号:
9040908 - 财政年份:2013
- 资助金额:
$ 33.71万 - 项目类别:
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