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Modulation of the Tumor Microenvironment with Trastuzumab Enables Radiosensitization in HER2+ Breast Cancer.
- Source :
-
Cancers [Cancers (Basel)] 2022 Feb 17; Vol. 14 (4). Date of Electronic Publication: 2022 Feb 17. - Publication Year :
- 2022
-
Abstract
- DNA damage repair and tumor hypoxia contribute to intratumoral cellular and molecular heterogeneity and affect radiation response. The goal of this study is to investigate anti-HER2-induced radiosensitization of the tumor microenvironment to enhance fractionated radiotherapy in models of HER2+ breast cancer. This is monitored through in vitro and in vivo studies of phosphorylated γ-H2AX, [ <superscript>18</superscript> F]-fluoromisonidazole (FMISO)-PET, and transcriptomic analysis. In vitro, HER2+ breast cancer cell lines were treated with trastuzumab prior to radiation and DNA double-strand breaks (DSB) were quantified. In vivo, HER2+ human cell line or patient-derived xenograft models were treated with trastuzumab, fractionated radiation, or a combination and monitored longitudinally with [ <superscript>18</superscript> F]-FMISO-PET. In vitro DSB analysis revealed that trastuzumab administered prior to fractionated radiation increased DSB. In vivo, trastuzumab prior to fractionated radiation significantly reduced hypoxia, as detected through decreased [ <superscript>18</superscript> F]-FMISO SUV, synergistically improving long-term tumor response. Significant changes in IL-2, IFN-gamma, and THBS-4 were observed in combination-treated tumors. Trastuzumab prior to fractionated radiation synergistically increases radiotherapy in vitro and in vivo in HER2+ breast cancer which is independent of anti-HER2 response alone. Modulation of the tumor microenvironment, through increased tumor oxygenation and decreased DNA damage response, can be translated to other cancers with first-line radiation therapy.
Details
- Language :
- English
- ISSN :
- 2072-6694
- Volume :
- 14
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Cancers
- Publication Type :
- Academic Journal
- Accession number :
- 35205763
- Full Text :
- https://doi.org/10.3390/cancers14041015