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.
项目概要/摘要
糖尿病会增加女性患乳腺癌 (BC) 的风险和非洲癌症患者的死亡率。
美国 (AA) 女性受糖尿病及其并发症的影响尤为严重。
女性接受 BC 治疗后的结果最差。此外,许多女性在 BC 治疗后体重增加,最终患上 BC 病。
AA 和西班牙裔/拉丁裔女性受此影响更大,存在一些重要的区别。
患有和不患有糖尿病的 BC 患者在治疗方案选择和癌症治疗结果方面的差异。
目前还没有针对糖尿病相关 BC 的具体治疗方法。
了解糖尿病引起的 BC 进展的基本机制,并制定个性化的治疗方案
糖尿病相关 BC 的治疗基于正常细胞和癌细胞之间的代谢差异,
我们首次提出这种安全有效的针对癌症代谢“毒”的治疗策略
BC细胞,对正常细胞相对无毒性,目前的项目重点针对乳酸代谢。
和运输诱导 BC 细胞死亡 该策略的中心假设是药物诱导 BC 细胞死亡。
葡萄糖输入和糖酵解达到更高水平,同时阻止糖酵解产物进入
三羧酸(TCA)循环会产生大量乳酸,同时阻碍出口。
通过抑制单羧酸转运蛋白 4 (MCT4) 来消除过量乳酸会导致代谢危机
癌细胞内的酸化,导致其死亡。我们的初步体外结果表明,这种代谢。
此外,我们还发现重编程策略(MRS)可以成功阻止癌细胞增殖。
CB-2作为一种新型小分子MCT4抑制剂(专利申请号:62/662,637)已显示出
对乳酸分泌具有显着的抑制作用,对三阴性乳腺具有显着的细胞毒活性
癌症(TNBC)细胞,具有高糖酵解率/MCT4表达,以强有力的初步数据为指导,
我们建议追求三个具体目标来检验这一假设:(1) 研究 MRS 对
不同BC细胞系的能量代谢途径以及对此敏感或抵抗的可能原因
(2) 确认CB-2的作用机制和抗癌活性。 (3) 测试有效性。
该 MRS 在携带人类 BC 异种移植物的糖尿病小鼠模型中的安全性和潜在副作用。
总的来说,这些研究将使我们能够更深入地了解癌细胞的代谢和
从长远来看,可能会揭示糖尿病相关 BC 和 TNBC 的有效治疗策略。
需要对造成癌症负担不平等的复杂生物学进行研究,以提高我们的基本能力
了解癌症健康差异因此,研究肿瘤细胞中的葡萄糖代谢特征。
此外,寻找新的药物靶点和方法将是揭示这种健康差异的重要一步。
开发糖尿病相关 BC 的新治疗方法有助于减少癌症健康差异。
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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Yong Wu其他文献
Effects of Decabrominated Diphenyl Ether (PBDE209) on Voltage-Gated Sodium Channels in Primary Cultured Rat Hippocampal Neurons
十溴二苯醚 (PBDE209) 对原代培养大鼠海马神经元电压门控钠通道的影响
- DOI:
- 发表时间:
- 期刊:
- 影响因子:4.5
- 作者:
Chen Liang;Chen Ju-Tao;Xing Tairan;Wang Ming;Ruan Di-Yun;Tang Ming-Liang;Yong Wu - 通讯作者:
Yong Wu
Yong Wu的其他文献
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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:
8856136 - 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:
9113516 - 财政年份:2015
- 资助金额:
$ 35.88万 - 项目类别:
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