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

Authors
  • Bateman, Nicholas W1, 2, 3
  • Teng, Pang-Ning1, 3
  • Hope, Erica1
  • Hood, Brian L1, 3
  • Oliver, Julie1, 3
  • Ao, Wei1, 3
  • Zhou, Ming4
  • Wang, Guisong1, 3
  • Tommarello, Domenic1, 3
  • Wilson, Katlin1, 3
  • Litzy, Tracy1, 3
  • Conrads, Kelly A1, 3
  • Hamilton, Chad A1, 2
  • Darcy, Kathleen M1, 2, 3
  • Casablanca, Yovanni1, 2
  • Maxwell, George Larry1, 2, 4
  • Bae-Jump, Victoria5
  • Conrads, Thomas P1, 2, 4
  • 1 Gynecologic Cancer Center of Excellence, Department of Obstetrics and Gynecology, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, MD, USA.
  • 2 The John P. Murtha Cancer Center, Uniformed Services University and Walter Reed National Military Medical Center, Bethesda, MD, USA.
  • 3 Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., Bethesda, MD, USA.
  • 4 Department of Obstetrics and Gynecology, Inova Fairfax Medical Campus, Falls Church, VA, USA.
  • 5 University of North Carolina at Chapel Hill, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Chapel Hill, NC, USA.
Type
Published Article
Journal
Cancer Medicine
Publisher
Wiley
Publication Date
Dec 06, 2019
Identifiers
DOI: 10.1002/cam4.2729
PMID: 31808620
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. © 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.

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