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Synergism from combined immunologic and pharmacologic inhibition of HER2 in vivo.
Morse, Michael A; Wei, Junping; Hartman, Zachary; Xia, Wenle; Ren, Xiu-Rong; Lei, Gangjun; Barry, William T; Osada, Takuya; Hobeika, Amy C; Peplinski, Sharon; Jiang, Haixiang; Devi, Gayathri R; Chen, Wei; Spector, Neil; Amalfitano, Andrea; Lyerly, H Kim; Clay, Timothy M.
Afiliação
  • Morse MA; Division of Medical Oncology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
Int J Cancer ; 126(12): 2893-903, 2010 Jun 15.
Article em En | MEDLINE | ID: mdl-19856307
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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Quinazolinas / Neoplasias da Mama / Terapia Genética / Receptor ErbB-2 / Vacinas Anticâncer / Inibidores de Proteínas Quinases Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2010 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Quinazolinas / Neoplasias da Mama / Terapia Genética / Receptor ErbB-2 / Vacinas Anticâncer / Inibidores de Proteínas Quinases Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2010 Tipo de documento: Article