Improving response to immunotherapy by genistein and antiestrogens
改善金雀异黄素和抗雌激素免疫疗法的反应
基本信息
- 批准号:10112524
- 负责人:
- 金额:$ 40.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-02 至 2023-03-31
- 项目状态:已结题
- 来源:
- 关键词:4T1AffectAgonistBacteriaBindingBiologicalBreastBreast Cancer PatientC57BL/6 MouseCarbohydratesCarcinogensCellsChemical StructureClinical TrialsConsumptionDietESR1 geneESR2 geneEffectivenessEstradiolEstrogen AntagonistsEstrogen Receptor alphaEstrogen Receptor betaEstrogen ReceptorsEstrogen receptor positiveEstrogensExperimental DesignsFatty acid glycerol estersFiberFulvestrantGenisteinGerm-FreeGlioblastomaGrowthHealthImmuneImmunityImmunomodulatorsImmunosuppressionImmunotherapyImpairmentInflammationIntestinesIsoflavonesKnockout MiceLaboratoriesLinkMalignant NeoplasmsMammary NeoplasmsMediatingMetastatic breast cancerModificationMonoclonal Antibody TherapyMusMyeloid-derived suppressor cellsNeoplasm MetastasisOutcomePD-1/PD-L1PDL1 inhibitorsPilot ProjectsPlayProteinsRattusRecurrenceReportingRodentRoleSignal TransductionSoybeansSupplementationTNFRSF1B geneTamoxifenTranslatingTransplantationTumor ImmunityUp-Regulationadvanced breast canceradvanced diseaseaggressive breast canceranti-PD-1anti-PD1 antibodiesanti-PD1 therapybreast cancer progressioncancer immunotherapyconditional knockoutdaidzeindietarydimethylbenzanthraceneestrogenicfecal transplantationfight againstgut dysbiosisgut microbiomeimmune checkpointimmune checkpoint blockersimprovedin vivomalignant breast neoplasmmelanomanano-stringneoplastic cellpreclinical studyprogrammed cell death protein 1responsesoytumortumor microenvironment
项目摘要
Cancer immunotherapies have been remarkably successful in treating many previously incurable cancers.
However, their utility in advanced breast cancer has been limited. For example, immune checkpoint blockers
(ICBs) show little to no efficacy as monotherapies in recurrent or metastatic breast cancer. High estrogen levels
in the breast tumor microenvironment (TME) may impair the response to ICBs, as 17β-estradiol (E2), by
activating estrogen receptor α (ERα/ESR1), activates immunosuppressive myeloid derived suppressor cells
(MDSCs) which impair response to ICBs. There also is a growing evidence showing that the gut microbiome,
modified by diet, plays a critical role in the response to ICB. In our pilot study, growth of allografted ESR1 negative
E0771 murine mammary tumors was significantly inhibited by anti-PD1 ICB therapy when mice also were treated
with ESR1 inhibiting antiestrogen tamoxifen. This effect, however, was strongly dependent on the diet fed to
mice. The effect was seen only in mice which consumed 5058 rodent laboratory diet, but not in mice fed 5V5M
or AIN93G rodent diet. The key difference between 5058 and 5V5M diets is that only 5058 contains soybeans
which are high in isoflavone genistein (GEN). 5V5M diet contains low levels of isoflavones, and AIN93G does
not contain any GEN. Although GEN has a chemical structure similar to that of E2, it preferentially binds to the
other estrogen receptor: ERβ/ESR2. ERβ has opposite effects from ERα and its activation augments immunity
and inhibits inflammation, including in the gut. Since GEN modifies the gut microbiome, we will investigate here
if the diet-dependent effects of anti-PD1+antiestrogen in promoting elimination of mammary tumors are caused
by GEN’s effect on the gut microbiome. This will be done by transplanting fecal microbiome from GEN fed donor
mice to germ-free recipient mice, and determining if the recipient mice kept on GEN-free diet will respond equally
well to anti-PD1 + fulvestrant as mice also fed GEN. We will then study if GEN’s effects on the gut microbiome
are mediated by GEN binding and activating ERβ/ESR2 in the gut by using conditional knockout mice which do
not express ESR2 in the intestine. Finally, we will compare the effects of GEN to that of ESR2 agonist LY500307,
currently in clinical trials, in modifying response to PD1 blockage and fulvestrant. If we show the potential for
supplementation with GEN or LY500307 to increase responsiveness of mammary tumors to anti-PD1 therapy
with antiestrogen treatment, this might allow breast cancer patients with advanced disease to harness the power
of immunotherapy.
癌症免疫疗法在治疗许多以前无法治愈的癌症方面非常成功。
然而,它们在晚期乳腺癌中的效用有限。例如,免疫检查点阻断剂
在复发性或转移性乳腺癌中,ICB作为单一疗法显示出很少或没有功效。高雌激素水平
在乳腺肿瘤微环境(TME)中,可能通过以下方式损害对ICBs的反应,如17β-雌二醇(E2),
激活雌激素受体α(ERα/ESR 1),激活免疫抑制性髓源性抑制细胞
(MDSC)损害对ICB的反应。还有越来越多的证据表明,肠道微生物组,
通过饮食改变,在对ICB的反应中起关键作用。在我们的初步研究中,同种异体移植的ESR 1阴性
E0771小鼠乳腺肿瘤被抗PD 1 ICB治疗显著抑制,当小鼠也被治疗时
与ESR 1抑制抗雌激素他莫昔芬。然而,这种效果强烈依赖于喂食的饮食,
小鼠仅在食用5058啮齿动物实验室饮食的小鼠中观察到该效果,但在喂食5V5 M的小鼠中未观察到该效果
或AIN 93 G啮齿动物饮食。5058和5V5 M日粮之间的关键区别在于,只有5058含有大豆
其中高含量的染料木黄酮(GEN)。5V5 M饮食含有低水平的咖啡酮,而AIN 93 G含有
虽然GEN具有与E2类似的化学结构,但它优先结合E2。
其他雌激素受体:ERβ/ESR 2。ERβ具有与ERα相反的作用,其激活增强免疫
并抑制炎症,包括肠道炎症。由于GEN改变了肠道微生物组,我们将在这里进行研究。
如果抗PD 1+抗雌激素在促进乳腺肿瘤消除方面的饮食依赖性作用
GEN对肠道微生物组的影响。这将通过移植来自GEN喂养供体的粪便微生物组来完成
小鼠到无菌受体小鼠,并确定保持无GEN饮食的受体小鼠是否会同样响应
我们将研究GEN对肠道微生物组的影响
通过GEN结合和激活肠道中的ERβ/ESR 2介导,
在肠道中不表达ESR 2。最后,我们将比较GEN与ESR 2激动剂LY 500307的作用,
目前在临床试验中,用于改变对PD 1阻断和氟维司群的反应。如果我们展示出
补充GEN或LY 500307以增加乳腺肿瘤对抗PD 1治疗的反应性
通过抗雌激素治疗,这可能使晚期乳腺癌患者能够利用这种力量,
免疫疗法。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Maternal obesity and resistance to breast cancer treatments among offspring: Link to gut dysbiosis.
- DOI:10.1002/cnr2.1752
- 发表时间:2022-12
- 期刊:
- 影响因子:1.7
- 作者:Andrade, Fabia de Oliveira;Verma, Vivek;Hilakivi-Clarke, Leena
- 通讯作者:Hilakivi-Clarke, Leena
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LEENA A. HILAKIVI-CLARKE其他文献
LEENA A. HILAKIVI-CLARKE的其他文献
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{{ truncateString('LEENA A. HILAKIVI-CLARKE', 18)}}的其他基金
Effect of maternal obesity on breast cancer among offspring: role of the gut microbiota
母亲肥胖对后代乳腺癌的影响:肠道微生物群的作用
- 批准号:
10734892 - 财政年份:2023
- 资助金额:
$ 40.77万 - 项目类别:
Transgenerational effects of maternal high fat diet during pregnancy on breast ca
孕期母亲高脂肪饮食对乳腺癌的跨代影响
- 批准号:
8543663 - 财政年份:2012
- 资助金额:
$ 40.77万 - 项目类别:
Transgenerational effects of maternal high fat diet during pregnancy on breast ca
孕期母亲高脂肪饮食对乳腺癌的跨代影响
- 批准号:
8321741 - 财政年份:2012
- 资助金额:
$ 40.77万 - 项目类别:
Transgenerational effects of maternal high fat diet during pregnancy on breast ca
孕期母亲高脂肪饮食对乳腺癌的跨代影响
- 批准号:
8706830 - 财政年份:2012
- 资助金额:
$ 40.77万 - 项目类别:
Early Life Estrogenicity and Mammary Cancer Risk
生命早期雌激素和乳腺癌风险
- 批准号:
8180999 - 财政年份:2010
- 资助金额:
$ 40.77万 - 项目类别:
Genome wide methylation arrays for detecting markers of increased susceptibility
用于检测易感性增加标记物的全基因组甲基化阵列
- 批准号:
7934998 - 财政年份:2009
- 资助金额:
$ 40.77万 - 项目类别:
In utero dietary exposure to endocrine disruptors
子宫内饮食接触内分泌干扰物
- 批准号:
7192451 - 财政年份:2005
- 资助金额:
$ 40.77万 - 项目类别:
In utero dietary exposure to endocrine disruptors and l*
在子宫内饮食中接触内分泌干扰物和 l*
- 批准号:
7060414 - 财政年份:2005
- 资助金额:
$ 40.77万 - 项目类别:
In utero dietary exposure to endocrine disruptors
子宫内饮食接触内分泌干扰物
- 批准号:
6940954 - 财政年份:2005
- 资助金额:
$ 40.77万 - 项目类别:
Timing of dietary exposure and breast cancer risk
饮食暴露时间与乳腺癌风险
- 批准号:
6802869 - 财政年份:2003
- 资助金额:
$ 40.77万 - 项目类别:
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