Abstract
Background: Adaptor proteins such as growth factor receptor-bound protein-2 (Grb2) play important roles in cancer cell signaling. In the present study, we examined the biological effects of liposomal antisense oligodeoxynucleotide that blocks Grb2 expression (L-Grb2) in gynecologic cancer models.Materials and Methods: Murine orthotopic models of ovarian (OVCAR5 and SKOV3ip1) and uterine (Hec1a) cancer were used to study the biological effects of L-Grb2 on tumor growth. In vitro experiments (cell viability assay, Western blot analysis, siRNA transfection, and reverse phase protein array) were carried out to elucidate the mechanisms and potential predictors of tumor response to L-Grb2.Findings: Treatment with L-Grb2 decreased tumor growth and metastasis in orthotopic models of ovarian cancer (OVCAR5, SKOV3ip1) by reducing angiogenesis and increasing apoptosis at a dose of 15 mg/kg with no effect on mouse body weight. Treatment with L-Grb2 and paclitaxel led to the greatest decrease in tumor weight (mean ± SEM, 0.17 g ± 0.10 g) compared with that in control mice (0.99 g ± 0.35 g). We also observed a reduction in tumor burden after treatment with L-Grb2 and the anti-VEGF antibody B-20 (86% decrease in tumor weight compared with that in controls). Ovarian cancer cells with ErbB2 amplification (OVCAR8 and SKOV3ip1) were the most sensitive to Grb2 downregulation. Reverse phase protein array analysis identified significant dysregulation of metabolites (LDHA, GAPDH, and TCA intermediates) in ovarian cancer cells after Grb2 downregulation.Interpretation: L-Grb2 has therapeutic efficacy in preclinical models of ovarian and uterine cancer. These findings support further clinical development of L-Grb2.
Highlights
Adaptor proteins are essential for signal propagation after receptor tyrosine kinase (RTK) activation [1]
We observed a reduction in tumor growth at 15 mg/kg, but there was no additive benefit of increasing the L-growth factor receptor-bound protein-2 (Grb2) dose
We first performed a series of experiments to characterize the therapeutic efficacy of liposomal antisense oligodeoxynucleotide that blocks Grb2 expression (L-Grb2) in combination with paclitaxel
Summary
Adaptor proteins are essential for signal propagation after receptor tyrosine kinase (RTK) activation [1]. Growth factor receptor-bound protein-2 (Grb2) is a 25-kDa adaptor protein that uses its SH2 domain to bind to phosphotyrosine residues in RTKs (EGFR, ErbB2, and VEGF) and its SH3 domains to bind to proline-rich motifs, such as those in the guanine nucleotide exchange factor Son of Sevenless [4,5,6,7]. This cascade leads to activation of RAS/RAF/mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signaling pathways critical to tumorigenesis [8, 9]. We examined the biological effects of liposomal antisense oligodeoxynucleotide that blocks Grb expression (L-Grb2) in gynecologic cancer models
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