Jupiter microtubule-associated homolog 1 (JPT1): A predictive and pharmacodynamic biomarker of metformin response in endometrial cancers.,Cancer Medicine

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Jupiter microtubule-associated homolog 1 (JPT1): A predictive and pharmacodynamic biomarker of metformin response in endometrial cancers.
Cancer Medicine ( IF 2.9 ) Pub Date : 2019-12-06 , DOI: 10.1002/cam4.2729
Nicholas W Bateman _{1,

2,

3} , Pang-Ning Teng _{1,

3} , Erica Hope ₁ , Brian L Hood _{1,

3} , Julie Oliver _{1,

3} , Wei Ao _{1,

3} , Ming Zhou ₄ , Guisong Wang _{1,

3} , Domenic Tommarello _{1,

3} , Katlin Wilson _{1,

3} , Tracy Litzy _{1,

3} , Kelly A Conrads _{1,

3} , Chad A Hamilton _{1,

2} , Kathleen M Darcy _{1,

2,

3} , Yovanni Casablanca _{1,

2} , George Larry Maxwell _{1,

2,

4} , Victoria Bae-Jump ₅ , Thomas P Conrads _{1,

2,

4}

Affiliation

Preoperative use of metformin in obese women with endometrioid endometrial cancer (EEC) reduces tumor proliferation and inhibits the mammalian target of rapamycin pathway, though is only effective in select cases. This study sought to identify a predictive and/or pharmacodynamic proteomic signature of metformin response to tailor its pharmacologic use. Matched pre- and post-metformin-treated tumor tissues from a recently completed preoperative window trial of metformin in EEC patients (ClinicalTrials.gov: NCT01911247) were analyzed by mass spectrometry (MS)-based proteomic and immunohistochemical analyses. Jupiter microtubule-associated homolog 1 (JPT1) was significantly elevated in metformin responders (n = 13) vs nonresponders (n = 7), and found to decrease in abundance in metformin responders following treatment; observations that were verified by immunohistochemical staining for JPT1. Metformin response and loss of JPT1 were assessed in RL95-2 and ACI-181 endometrial cancer (EC) cell lines. We further identified that silencing of JPT1 abundance does not alter cellular response to metformin or basal cell proliferation, but that JPT1 abundance does decrease in response to metformin treatment in RL95-2 and ACI-181 EC cell lines. These data suggest that JPT1 represents a predictive and pharmacodynamic biomarker of metformin response that, if validated in larger patient populations, may enable preoperative EEC patient stratification to metformin treatment and the ability to monitor patient response.

中文翻译：

Jupiter microtubule-associated homolog 1 （JPT1）：子宫内膜癌中二甲双胍反应的预测和药效学生物标志物。

患有子宫内膜样子宫内膜癌（EEC）的肥胖女性术前使用二甲双胍可减少肿瘤增殖并抑制哺乳动物雷帕霉素途径的靶标，但仅在特定病例中有效。本研究旨在确定二甲双胍反应的预测和/或药效学蛋白质组学特征，以调整其药理学用途。通过基于质谱（MS）的蛋白质组学和免疫组织化学分析分析来自最近完成的 EEC 患者二甲双胍术前窗口试验（ClinicalTrials.gov： NCT01911247）的匹配二甲双胍治疗前后肿瘤组织。二甲双胍反应者（n = 13）与无反应者（n = 7）相比，木星微管相关同源物 1 （JPT1）显着升高，并且发现治疗后二甲双胍反应者的丰度降低;通过 JPT1 的免疫组织化学染色验证的观察结果。在 RL95-2 和 ACI-181 子宫内膜癌（EC）细胞系中评估二甲双胍反应和 JPT1 丢失。我们进一步确定，JPT1 丰度的沉默不会改变细胞对二甲双胍或基底细胞增殖的反应，但在 RL95-2 和 ACI-181 EC 细胞系中，JPT1 丰度确实会响应二甲双胍处理而降低。这些数据表明，JPT1 代表了二甲双胍反应的预测和药效学生物标志物，如果在更大的患者群体中得到验证，则可能使术前 EEC 患者分层至二甲双胍治疗，并能够监测患者反应。

更新日期：2019-12-06

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