THE RNA HELICASE EIF4A IS A THERAPEUTIC VULNERABILITY IN TRIPLE-NEGATIVE BREAST CANCER
RNA解旋酶EIF4A是三阴性乳腺癌的治疗漏洞
基本信息
- 批准号:10582328
- 负责人:
- 金额:$ 20万
- 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
- 起止时间:2022-07-01 至 2023-06-30
- 项目状态:已结题
- 来源:
- 关键词:5&apos Untranslated RegionsAfrican American populationBiological MarkersBlack AmericanBreast Cancer ModelCOVID-19Cancer EtiologyCancer cell lineCarboplatinCessation of lifeChemicalsClinicalClinical TrialsCollaborationsCombined Modality TherapyDiseaseEssential GenesEukaryotic Initiation Factor-4FFutureGenetic EngineeringGrowth FactorInfiltrationLaboratoriesMalignant NeoplasmsMessenger RNAModelingMusMyelogenousMyeloid CellsOncogenesPatient-derived xenograft models of breast cancerPatientsPharmaceutical PreparationsPhase I Clinical TrialsPhenotypePremenopausePropertyProteinsRNA HelicaseSeriesSolidSolid NeoplasmStructureTherapeuticTimeTranslation InitiationTranslational RegulationTranslationsTumor-associated macrophagesUnderserved PopulationWomancancer subtypeschemotherapydesigndocetaxelethnic diversityimprovedinhibitorinterestmalignant breast neoplasmmouse modelneutrophilpatient derived xenograft modelpreclinical studypredicting responseprotein expressionracial diversityresponsestandard of caretriple-negative invasive breast carcinomatumortumor-immune system interactions
项目摘要
1 This application is being submitted in response to the Notice of Special Interest (NOSI)
2 identified as NOT-CA-22-039. Triple negative breast cancer (TNBC) is a biologically
3 heterogeneous and clinically important breast cancer subtype because if it were considered a
4 distinct disease, TNBC would rank as the 5th leading cause of cancer deaths in women. TNBC
5 also is more prevalent in younger premenopausal women especially Black or African Americans.
6 Protein translational regulation has been demonstrated to be a potential vulnerability in cancer
7 including TNBC. The eIF4A RNA helicase is a key regulator of translation initiation as part of the
8 eIF4F translation initiation complex. Interestingly, eIF4A selectively inhibits the translation of many
9 oncogene and growth factor mRNAs with highly structured 5’UTRs and is an essential gene in
10 many cancer cell lines. eFFECTOR Therapeutics has developed an improved eIF4A inhibitor,
11 Zotatifin (eFT226), that is currently being evaluated in a Phase I clinical trial (NCT04092673) in
12 patients with advanced solid tumor malignancies. In collaboration with eFFECTOR, we have
13 performed studies to determine the efficacy of Zotatifin in syngeneic genetically engineered
14 mouse (GEM) TNBC models developed in our laboratory. In these models a marked improvement
15 in tumor regression and time to end point was observed following combination treatment of
16 Zotatifin with standard-of-care either carboplatin or docetaxel. We now propose to expand these
17 studies to a series of racially and ethnically diverse TNBC PDX models with a special focus on
18 those derived from underserved populations in order to better identify which patients might benefit
19 from combination therapy in future clinical trials. Analysis of eIF4A protein expression across
20 TNBC PDX models has identified models with markedly different levels of Zotatifin target
21 expression. We now propose to optimize and elucidate mechanisms of single agent and
22 combination therapy with Zotatifin and chemotherapy across several high and low eIF4A PDX
23 models and to develop biomarkers to predict response. Our previous studies in GEM models
24 identified changes in the myeloid immune microenvironment including decreased infiltration of
25 neutrophils and repolarization of tumor associated macrophages to a less immunosuppressive
26 and more tumor inhibitory phenotype. Thus, we will also study effects of Zotatifin and
27 chemotherapy on circulating and tumor associated myeloid cells in these PDX models. In
28 summary, these preclinical studies may help provide key information to inform the design of future
29 clinical trials. Although these studies are initially focused on TNBC they may have a broader
30 application to other solid cancers.
本申请是根据特别利益通知(NOSI)提交的。
项目成果
期刊论文数量(0)
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会议论文数量(0)
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Nicholas Mitsiades其他文献
Nicholas Mitsiades的其他文献
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{{ truncateString('Nicholas Mitsiades', 18)}}的其他基金
Combating Highly Aggressive Prostate Cancer: Development of Novel Patient Derived Xenograft Models and Application in Preclinical Studies of Novel Selective Androgen Receptor Degraders
对抗高度侵袭性前列腺癌:新型患者异种移植模型的开发及其在新型选择性雄激素受体降解剂临床前研究中的应用
- 批准号:
10435884 - 财政年份:2021
- 资助金额:
$ 20万 - 项目类别:
REGULATION OF UVEAL MELANOMA CELL FATE BY THE PKC PATHWAY VIA MITF
PKC 途径通过 MITF 调节葡萄膜黑色素瘤细胞的命运
- 批准号:
9749971 - 财政年份:2015
- 资助金额:
$ 20万 - 项目类别:
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