@article{4c03141607fa4beabf396521a3359aba,
title = "Estrogen Promotes Resistance to Bevacizumab in Murine Models of NSCLC",
abstract = "Introduction: Subgroup analyses from clinical studies have suggested that among patients with metastatic NSCLC receiving chemotherapy, females may derive less benefit from the addition of the vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (BV) than males. This has raised the question of whether estrogen may affect the response to antiangiogenic therapy. Methods: To address this, we investigated the effects of estrogen on tumor growth, angiogenesis, and the response to BV in human xenograft models of NSCLC. Results: We observed that estrogen induced marked resistance to BV, which was accompanied by a 2.3-fold increase in tumor vascular pericyte coverage (p = 0.01) and an up-regulation of proangiogenic factors, VEGF and platelet-derived growth factor-BB. We also investigated the role of infiltrating myeloid cells, a population that has been associated with resistance to anti-VEGF therapies. We observed that estrogen induced a greater than twofold increase (p = 0.001) in the recruitment of tumor-infiltrating myeloid cells and concomitant increases in the myeloid recruitment factors, G-CSF and CXCL1. Blockade of the estrogen receptor pathway using fulvestrant resensitized tumors to VEGF targeting as evidenced by reduced tumor vasculature and an increase in overall survival in our NSCLC xenograft models. Conclusions: Collectively, these data provide evidence that estrogen may promote resistance to VEGF-targeted therapies, potentially by enhancing pericyte coverage and myeloid recruitment, and suggest that estrogen receptor blockade merits further investigation as an approach to enhance the effects of antiangiogenic therapy.",
keywords = "Bevacizumab, Estrogen, Fulvestrant, Non–small cell lung cancer, Pericytes, Tumor endothelium",
author = "Patel, {Sonia A.} and Herynk, {Matthew H.} and Tina Cascone and Babita Saigal and Nilsson, {Monique B.} and Hai Tran and Sumankalai Ramachandran and Lixia Diao and Jing Wang and Xiuning Le and John Minna and Wistuba, {Ignacio I.} and Heymach, {John V.}",
note = "Funding Information: This research was supported by the Joan{\textquoteright}s Legacy award and the Flight Attendant{\textquoteright}s Medical Research Institute . Dr. Heymach is a Damon Runyon-Lilly Clinical Investigator supported in part by Damon Runyon Cancer Research Foundation grant CI 24-04. This work was also supported by The University of Texas Southwestern Medical Center , MD Anderson Cancer Center Lung SPORE National Institutes of Health grant P50 CA070907, the David Bruton Jr. Endowment, the Rexanna Foundation for Fighting Lung Cancer, National Institutes of Health P30 CA016672-44, 1R01 CA190628, Lung Cancer Moon Shot Program, the Hallman Fund, the Richardson fund, and the Kopelman Foundation and the Margot Johnson Cancer Research Fund. Funding Information: Disclosure: Cascone reports receiving speaker's fees from the Society for Immunotherapy of Cancer (SITC) and Bristol-Myers Squibb, consulting fees from MedImmune/AstraZeneca and Bristol-Myers Squibb, and advisory role fees from EMD Serono and Bristol-Myers Squibb and clinical research funding to MD Anderson Cancer Center from Boehringer Ingelheim, MedImmune/AstraZeneca, EMD Serono, and Bristol-Myers Squibb. Tran reports receiving research funding from Bayer-AS, Bristol-Myers Squibb, Ziopharm, and Guardant Health. Le reports receiving consulting/advisory fees from EMD Serono (Merck KGaA), AstraZeneca, Spectrum Pharmaceutics, Eli Lilly, Boehringer Ingelheim, and Daiichi Sanko and research funding from Eli Lilly and Boehringer Ingelheim. Wistuba reports receiving grants and personal fees from Genentech/Roche, Bayer, Bristol-Myers Squibb, AstraZeneca/Medimmune, Pfizer, HTG Molecular, Asuragen, Guardant Health, and Merck, outside the submitted work; personal fees from GlaxoSmithKline, Oncocyte, and Merck Sharp & Dohme; and grants from Oncoplex, DepArray, Adaptive, Adaptimmune, EMD Serono, Takeda, Amgen, Karus, Johnson & Johnson, Iovance, 4D, Novartis, and Akoya. Minna reports receiving licensing fees for tumor cell lines from the National Institutes of Health and the University of Texas Southwestern Medical Center. Nilsson and Heymach have filed a patent for the use of poziotinib for treating EGFR- and HER2-mutant cancers, licensed the technology to Spectrum Pharmaceuticals, and receive royalties and licensing fees. Dr. Heymach reports receiving grant or research support from AstraZeneca, Boehringer Ingelheim, Spectrum Pharmaceuticals, and GlaxoSmithKline and has served on advisory committees for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Catalyst, EMD Serono, Foundation Medicine, Hengrui Therapeutics, Genentech, GlaxoSmithKline, Guardant Health, Eli Lilly, Merck, Novartis, Pfizer, Roche, Sanofi, Seattle Genetics, Spectrum, and Takeda. The remaining authors declare no conflict of interest.This research was supported by the Joan's Legacy award and the Flight Attendant's Medical Research Institute. Dr. Heymach is a Damon Runyon-Lilly Clinical Investigator supported in part by Damon Runyon Cancer Research Foundation grant CI 24-04. This work was also supported by The University of Texas Southwestern Medical Center, MD Anderson Cancer Center Lung SPORE National Institutes of Health grant P50 CA070907, the David Bruton Jr. Endowment, the Rexanna Foundation for Fighting Lung Cancer, National Institutes of Health P30 CA016672-44, 1R01 CA190628, Lung Cancer Moon Shot Program, the Hallman Fund, the Richardson fund, and the Kopelman Foundation and the Margot Johnson Cancer Research Fund. Publisher Copyright: {\textcopyright} 2021",
year = "2021",
month = dec,
doi = "10.1016/j.jtho.2021.07.007",
language = "English (US)",
volume = "16",
pages = "2051--2064",
journal = "Journal of Thoracic Oncology",
issn = "1556-0864",
publisher = "International Association for the Study of Lung Cancer",
number = "12",
}