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Dual HER2 Targeting with Trastuzumab and Liposomal-Encapsulated Doxorubicin (MM-302) Demonstrates Synergistic Antitumor Activity in Breast and Gastric Cancer.
Espelin, Christopher W; Leonard, Shannon C; Geretti, Elena; Wickham, Thomas J; Hendriks, Bart S.
Afiliação
  • Espelin CW; Merrimack Pharmaceuticals, One Kendall Square, Cambridge, Massachusetts. cespelin@merrimack.com.
  • Leonard SC; Merrimack Pharmaceuticals, One Kendall Square, Cambridge, Massachusetts.
  • Geretti E; Merrimack Pharmaceuticals, One Kendall Square, Cambridge, Massachusetts.
  • Wickham TJ; Merrimack Pharmaceuticals, One Kendall Square, Cambridge, Massachusetts.
  • Hendriks BS; Merrimack Pharmaceuticals, One Kendall Square, Cambridge, Massachusetts.
Cancer Res ; 76(6): 1517-27, 2016 Mar 15.
Article em En | MEDLINE | ID: mdl-26759238
ABSTRACT
Trastuzumab is the standard of care for HER2-positive breast cancer patients, markedly improving disease-free and overall survival. Combined with chemotherapy, it enhances patient outcomes, but cardiotoxicity due to the trastuzumab treatment poses a serious adverse effect. MM-302 is a HER2-targeted PEGylated liposome that encapsulates doxorubicin to facilitate its delivery to HER2-overexpressing tumor cells while limiting exposure to nontarget tissues, including the heart. In this study, we evaluated the feasibility and preclinical activity of combining MM-302 with trastuzumab. MM-302 and trastuzumab target different domains of the HER2 receptor and thus could simultaneously bind HER2-overexpressing tumor cells in vitro and in vivo. Furthermore, trastuzumab did not disrupt the mechanism of action of MM-302 in delivering doxorubicin to the n0ucleus and inducing DNA damage. Reciprocally, MM-302 did not interfere with the ability of trastuzumab to block prosurvival p-Akt signaling. Interestingly, coadministration of the two agents acutely increased the deposition of MM-302 in human xenograft tumors and subsequently increased the expression of the DNA damage marker p-p53. Finally, the combination of MM-302 and trastuzumab induced synergistic antitumor activity in HER2-overexpressing xenograft models of breast and gastric cancer. Collectively, our findings highlight a novel combination therapy that efficiently targets HER2-overexpressing cells through multiple mechanisms and support the ongoing investigation of combined MM-302/trastuzumab therapy for HER2-positive metastatic breast cancer in a randomized phase II clinical trial.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Gástricas / Neoplasias da Mama / Protocolos de Quimioterapia Combinada Antineoplásica / Receptor ErbB-2 Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Female / Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Neoplasias Gástricas / Neoplasias da Mama / Protocolos de Quimioterapia Combinada Antineoplásica / Receptor ErbB-2 Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Female / Humans Idioma: En Ano de publicação: 2016 Tipo de documento: Article