Author of

• 35913

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  P71 - Tumor Biology and Systems Biology - Basic and Translational Science - RTK/VEGF (ID 212)

  • Event: WCLC 2020
  • Type: Posters
  • Track: Tumor Biology and Systems Biology - Basic and Translational Science
  • Presentations: 1
  • Moderators:
  • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall

  • 35915

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    P71.02 - Estrogen Promotes Resistance to Bevacizumab Treatment in Non-Small Cell Lung Cancer (NSCLC) Xenograft Models (ID 3682)

    00:00 - 00:00  |  Presenting Author(s): Sonia A Patel
    • Abstract
    • Slides

    Introduction
    

    Lung cancer is the leading cause of cancer-related deaths with over 130,000 deaths estimated in 2020 alone, and while the rate of lung cancer mortality in the United States has declined among men, it has remained stable in females. In clinical studies, anti-angiogenic therapy (bevacizumab) combined with chemotherapy preferentially benefited male NSCLC (non-small cell lung cancer) patients compared to females, suggesting that estrogen may contribute to lung cancer progression and resistance to anti-angiogenic therapy.

    Methods
    

    Using NSCLC xenograft models, we investigated the impact of estrogen on tumor growth, angiogenesis, and response to bevacizumab. We generated A549 and HCC827 xenograft NSCLC mouse models by subcutaneous injection of these cells into female ovariectomized nude mice with or without estrogen (estradiol 17-β) treatment delivered via continuous release (approximately 80 pg/ml). Animals were randomized to receive vehicle or bevacizumab (10 mg/kg). Tumors were collected after treatment and immunostained to determine pericyte coverage (CD31 and desmin) and myeloid infiltration (CD11b+). Serum levels of angiogenic factors were measured by multiplex bead assay.

    Results
    

    As expected, non-estrogen treated mice showed a reduction of tumor growth with bevacizumab (A549, p = 0.0005, HCC827, p = 0.02) and the efficacy of bevacizumab was diminished when both models were treated with estrogen. We show that estrogen increased pericyte coverage in the tumor vascular network and elevated serum levels of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGFBB), critical regulators of tumor angiogenesis. In addition to an enhanced maturation of tumor-associated blood vessels, we observed that estrogen induced the recruitment of tumor-infiltrating myeloid cells mediated by increased secretion of granulocyte colony-stimulating factor (G-CSF) and chemokine ligand 1 (CXCL1). Blockade of estrogen receptor signaling using fulvestrant re-sensitized tumors to VEGF targeting as evidenced by reduced tumor vasculature and an increase in overall survival in NSCLC xenograft models.

    Conclusion
    

    Taken together, our preclinical data indicate that estrogen receptor signaling indeed promotes resistance to anti-angiogenic agents and that inhibition of this pathway can enhance the efficacy of VEGF blockade. These data have important clinical implications for female NSCLC patients and support the future clinical testing of estrogen receptor blockade in combination with anti-angiogenic regimens.

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