Publications [#178157] of Gayathri R Devi

Papers Published

1. MA Morse, J Wei, Z Hartman, W Xia, XR Ren, G Lei, WT Barry, T Osada, AC Hobeika, S Peplinski, H Jiang, GR Devi, W Chen, N Spector, A Amalfitano, HK Lyerly, TM Clay, Synergism from combined immunologic and pharmacologic inhibition of HER2 in vivo., International journal of cancer. Journal international du cancer, vol. 126 no. 12 (June, 2010), pp. 2893-903, ISSN 1097-0215 [doi]
   (last updated on 2013/05/13)

   Abstract:
   The monoclonal antibody trastuzumab and the EGFR/HER2 tyrosine kinase inhibitor lapatinib improve the clinical outcome of patients with HER2-overexpressing breast cancer. However, the majority of metastatic cancers will eventually progress, suggesting the need for other therapies. Because HER2 overexpression persists, we hypothesized that the anti-HER2 immune response induced by cancer vaccines would be an effective strategy for treating trastuzumab- and lapatinib-refractory tumors. Furthermore, we hypothesized that the antibody response could synergize with lapatinib to enhance tumor inhibition. We developed a recombinant adenoviral vector expressing a kinase-inactive HER2 (Ad-HER2-ki) to use as a cancer vaccine. Vaccine-induced polyclonal HER2-specific antiserum was analyzed for receptor internalization and signaling effects alone and in combination with lapatinib. Ad-HER2-ki vaccine-induced potent T cell and antibody responses in mice and the vaccine-induced polyclonal HER2-specific antiserum mediated receptor internalization and degradation much more effectively than trastuzumab. Our in vitro studies demonstrated that HER2 vaccine-induced antibodies effectively caused a decrease in HER2 expression, but when combined with lapatinib caused significant inhibition of HER2 signaling, decreased pERK and pAKT levels and reduced breast tumor cell proliferation. In addition, a known mechanism of resistance to lapatinib, induction of survivin, was inhibited. The combination of Ad-HER2-ki plus lapatinib also showed superior antitumor efficacy in vivo. Based on these results, we feel clinical studies using this approach to target HER2-overexpressing breast cancer, including trastuzumab- and lapatinib-resistant tumors is warranted.

   Keywords:
   Adenoviridae • Animals • Blotting, Western • Breast Neoplasms • Cancer Vaccines • Cell Proliferation • Combined Modality Therapy • Drug Synergism • Enzyme-Linked Immunosorbent Assay • Female • Flow Cytometry • Genetic Therapy* • Humans • Mice • Mice, Inbred BALB C • Mice, Inbred C57BL • Protein Kinase Inhibitors • Quinazolines • RNA, Messenger • Receptor, erbB-2 • Reverse Transcriptase Polymerase Chain Reaction • Tumor Cells, Cultured • Xenograft Model Antitumor Assays • genetics • genetics* • immunology* • metabolism • pharmacology* • therapeutic use* • therapy*