Regulation of Tumor Oxygenation by BACH1 in Breast Cancer
BACH1 在乳腺癌中对肿瘤氧合的调节
基本信息
- 批准号:10693966
- 负责人:
- 金额:$ 39.83万
- 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:2022-09-01 至 2027-08-31
- 项目状态:未结题
- 来源:
- 关键词:Angiogenic FactorAntioxidantsBACH1 geneBlood flowBreast Cancer CellBreast Cancer PatientBreast cancer metastasisCancer EtiologyCancer PatientCatabolismCell HypoxiaCessation of lifeClinicalClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsComplexCytotoxic ChemotherapyDataDiseaseDrug Delivery SystemsERBB2 geneEndothelial CellsEpigenetic ProcessFDA approvedGene ExpressionGenesGenetic TranscriptionGoalsHemeHeminHormone ReceptorHypoxiaHypoxia Inducible FactorImmunotherapyLocalized Malignant NeoplasmMediatingMetabolicMusOxygenOxygen Therapy CarePatientsPharmaceutical PreparationsPhenotypePlayProductionPublishingRadiationRadiation therapyRefractoryRegulationResistanceRoleSchemeSignal TransductionSpecificityStressSurvival RateTestingTherapeuticTranscriptional RegulationTreatment EfficacyTumor OxygenationUbiquitinWomanWorkXenograft procedureaggressive breast cancerangiogenesisbiological adaptation to stresscancer cellcancer subtypeschemotherapycytotoxicgene repressionimprovedinhibitormalignant breast neoplasmmigrationmortalitymouse modelmulticatalytic endopeptidase complexmutantneoplastic cellnovelnovel therapeutic interventionoverexpressionoxidationprognosticprogramspublic health relevanceradiation resistanceresponsesmall hairpin RNAstandard of caretranscription factortreatment strategytriple-negative invasive breast carcinomatumortumor hypoxiatumor microenvironment
项目摘要
Triple negative breast cancer (TNBC), the most aggressive and metastatic subtype of breast cancer, is one
of the major causes of cancer death in women. TNBC also has lower survival rates for primarily local
cancers. Loss of hormone receptors and the lack of HER2 overexpression in TNBC limit treatments to
cytotoxic therapies such as radiation, a key clinical strategy for 10-15% of breast cancer patients. Hypoxia
is a major cause of resistance to radiotherapy, chemotherapy and even immunotherapy. Thus, identifying
mechanisms to suppress the hypoxia stress response and increase the sensitivity of TNBC tumors to
therapy remains a top clinical priority. Upon hypoxic stress, cancer cells initiate a transcriptional program that
enables them to survive and migrate from an inhospitable microenvironment. While hypoxia-inducible factors
(HIFs) are generally considered the main effectors, growing evidence suggests the hypoxia cellular response is
much more complex and requires coordinated signaling with other stress response factors. One promising
candidate is BACH1, a transcription factor that is induced by hypoxia and represses transcription of genes
involved in heme oxidation and anti-oxidant production. Based on preliminary results, we now hypothesize that
BACH1 is stabilized by hypoxia and functions as a key inducer of the cellular hypoxia response in TNBC
cells leading to abnormal leaky vasculature that contributes to intratumoral hypoxia and radiation
resistance. Specifically, we plan to: 1. Determine whether BACH1 is regulated by oxygen and induces a
transcriptional hypoxic stress response in TNBC cells; 2. Determine whether BACH1 promotes angiogenesis,
leaky vasculature and hypoxia in TNBC tumors; and 3. Determine whether BACH1 depletion sensitizes TNBC
tumors to radiation. We propose that targeting BACH1 represents a unique strategy for increasing tumor
oxygenation to improve the efficacy of cytotoxic, standard-of-care therapies such as radiation. Normalizing
vasculature to suppress leakiness should also facilitate drug delivery to tumors. Since BACH1 can be targeted
by an FDA approved drug either alone or in combination with HIF inhibitors, the proposed work could lead to a
clinical trial in breast cancer and other cancer patients whose treatment involves radiation therapy.
三阴性乳腺癌(TNBC)是一种最具侵袭性和转移性的乳腺癌亚型
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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MARSHA R ROSNER其他文献
MARSHA R ROSNER的其他文献
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{{ truncateString('MARSHA R ROSNER', 18)}}的其他基金
Tumor-stromal interactions as targets of tumor metastasis suppressors
肿瘤-基质相互作用作为肿瘤转移抑制因子的靶点
- 批准号:
8817963 - 财政年份:2015
- 资助金额:
$ 39.83万 - 项目类别:
Tumor-stromal interactions as targets of tumor metastasis suppressors
肿瘤-基质相互作用作为肿瘤转移抑制因子的靶点
- 批准号:
9223680 - 财政年份:2015
- 资助金额:
$ 39.83万 - 项目类别:
Modulation of Head and Neck Cancer by Protein Kinase C
蛋白激酶 C 对头颈癌的调节
- 批准号:
7104272 - 财政年份:2004
- 资助金额:
$ 39.83万 - 项目类别:
Modulation of Head and Neck Cancer by Protein Kinase C
蛋白激酶 C 对头颈癌的调节
- 批准号:
7232269 - 财政年份:2004
- 资助金额:
$ 39.83万 - 项目类别:
Role of Raf Kinase Inhibitory Protein in Prostate Cancer
Raf 激酶抑制蛋白在前列腺癌中的作用
- 批准号:
6990554 - 财政年份:2004
- 资助金额:
$ 39.83万 - 项目类别:
Role of Raf Kinase Inhibitory Protein in Prostate Cancer
Raf 激酶抑制蛋白在前列腺癌中的作用
- 批准号:
7154753 - 财政年份:2004
- 资助金额:
$ 39.83万 - 项目类别:
Role of Raf Kinase Inhibitory Protein in Prostate Cancer
Raf 激酶抑制蛋白在前列腺癌中的作用
- 批准号:
7533439 - 财政年份:2004
- 资助金额:
$ 39.83万 - 项目类别:
Role of Raf Kinase Inhibitory Protein in Prostate Cancer
Raf 激酶抑制蛋白在前列腺癌中的作用
- 批准号:
7322528 - 财政年份:2004
- 资助金额:
$ 39.83万 - 项目类别:
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