A novel metabolic reprograming strategy for the treatment of diabetes-associated breast cancer
一种治疗糖尿病相关乳腺癌的新型代谢重编程策略
基本信息
- 批准号:10409714
- 负责人:
- 金额:$ 35.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-06-01 至 2024-04-30
- 项目状态:已结题
- 来源:
- 关键词:Adverse effectsAffectAfrican AmericanAnimal ModelAnimalsAntineoplastic AgentsBiological MarkersBiologyBlood GlucoseBreast Cancer CellBreast Cancer PatientBreast Cancer Risk FactorBreast Cancer TreatmentBreast Cancer cell lineCancer BurdenCancer PatientCancer PrognosisCell DeathCell ProliferationCellsCessation of lifeCitric Acid CycleCombined Modality TherapyComplexDataDevelopmentDiabetes MellitusDiabetic mouseDoseDrug TargetingGlucoseGlycolysisGlycolysis InhibitionGoalsHispanicHumanHyperglycemiaIn VitroLatinaLeadLegal patentLightLongitudinal StudiesMalignant NeoplasmsMetabolicMetabolic PathwayMetabolismMetforminMethodsMinorNormal CellOutcomePatient-derived xenograft models of breast cancerPatientsPharmacologic SubstancePharmacologyPlayPoisonProductionPublic HealthRegimenResearchResistanceRoleSafetySignal TransductionTestingTherapeuticTimeUp-RegulationWeight GainWomanXenograft procedureaerobic glycolysisanticancer activitybasebreast cancer progressioncancer cellcancer health disparitycancer therapycell growthcytotoxicdiabeticeffectiveness testingglucose metabolismhealth disparityin vivoinhibitormalignant breast neoplasmmortalitymouse modelneoplastic cellnew therapeutic targetnovelpatient derived xenograft modelpersonalized medicinepre-clinicalresponse biomarkerside effectsmall moleculetargeted cancer therapytherapeutically effectivetreatment strategytriple-negative invasive breast carcinomatumortumor growthtumor metabolism
项目摘要
PROJECT SUMMARY/ABSTRACT
Diabetes increases the risk of breast cancer (BC) in women and mortality in patients with cancer. African-
American (AA) women are disproportionately affected by diabetes and its complications. Concurrently, these
women have worst outcome from BC. In addition, many women gain weight after BC treatment and end up with
diabetes. AA and Hispanic/Latina women are even more affected by this. There exist some important distinctions
between the BC patients with and without diabetes in the regimen selection and outcomes of cancer therapy.
Currently there are no specific treatments to target diabetes-associated BC. Our long-term goals are to
understand the fundamental mechanisms of diabetes-induced BC progression, and to develop personalized
treatments for diabetes-associated BC. Based on the metabolic differences between normal and cancer cells,
we for the first time propose this safe and effective therapeutic strategy targeting cancer metabolism to “poison”
BC cells, with relatively non-toxicity to normal cells. The present project focuses on targeting lactate metabolism
and transport to induce BC cell death. The central hypothesis of this strategy is that pharmaceutical induction of
glucose import and glycolysis to even higher levels while blocking the products of glycolysis from entering the
tricarboxylic acid (TCA) cycle, results in production of high amounts of lactate. Meanwhile, blocking the export
of excessive lactate by inhibiting monocarboxylate transporter 4 (MCT4) leads to a metabolic crisis and
acidification within the cancer cells, causing their death. Our preliminary in vitro results indicate that this metabolic
reprogramming strategy (MRS) can successfully block cancer cells proliferation. Moreover, we have identified
CB-2 as a novel small molecule MCT4 inhibitor (Patent Application Number: 62/662,637). CB-2 has shown a
significantly inhibitory effect on lactate secretion and striking cytotoxic activity against triple-negative breast
cancer (TNBC) cells, which have a high glycolytic rate/MCT4 expression. Guided by strong preliminary data,
we propose to pursue three Specific Aims to test this hypothesis: (1) To investigate the effect of MRS on
energy metabolic pathways of different BC cell lines and the possible reasons for sensitivity or resistance to this
approach. (2) To confirm the mechanism of action and anticancer activity of CB-2. (3) To test the effectiveness,
safety, and potential side effects of this MRS in diabetic mouse models bearing human BC xenografts.
Collectively, these studies will allow us to gain a more in-depth understanding of cancer cell metabolism and
may in the long term reveal an effective therapeutic strategy for diabetes-associated BC and TNBCs. The
complex biology that contributes to the unequal cancer burdens needs to be investigated to increase our basic
understanding of cancer health disparities. Hence, investigating glucose metabolism features in tumor cells
would be a significant step in shedding light on this health disparity. Moreover, searching new drug targets and
developing new treatment methods in diabetes-associated BC contribute to decreasing cancer health disparities.
项目总结/文摘
项目成果
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{{ truncateString('Yong Wu', 18)}}的其他基金
A novel metabolic reprograming strategy for the treatment of diabetes-associated breast cancer
一种治疗糖尿病相关乳腺癌的新型代谢重编程策略
- 批准号:
10615233 - 财政年份:2020
- 资助金额:
$ 35.88万 - 项目类别:
Mechanisms behind hyperglycemia-associated breast cancer risk and progression
高血糖相关乳腺癌风险和进展背后的机制
- 批准号:
9113516 - 财政年份:2015
- 资助金额:
$ 35.88万 - 项目类别:
Mechanisms behind hyperglycemia-associated breast cancer risk and progression
高血糖相关乳腺癌风险和进展背后的机制
- 批准号:
8856136 - 财政年份:2015
- 资助金额:
$ 35.88万 - 项目类别:
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