Therapeutic efficacy of liposomal Grb2 antisense oligodeoxynucleotide (L-Grb2) in preclinical models of ovarian and uterine cancer
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Olivia D. Lara1, Emine Bayraktar1, Paola Amero2, Shaolin Ma1, Cristina Ivan2, Wei Hu1, Ying Wang3, Lingegowda S. Mangala1,4, Prasanta Dutta5, Pratip Bhattacharya5, Ana Tari Ashizawa6, Gabriel Lopez-Berestein2,4,7, Cristian Rodriguez-Aguayo2,4 and Anil K. Sood1,4,7
1 Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2 Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
3 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
4 Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
5 Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
6 Bio-Path Holdings, Inc., Bellaire, TX, USA
7 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
|Anil K. Sood,||email:||[email protected]|
|Cristian Rodriguez-Aguayo,||email:||[email protected]|
Keywords: ovarian cancer; nucleic-acid based therapeutics; therapeutic approaches; uterine cancer
Received: April 02, 2020 Accepted: June 15, 2020 Published: July 21, 2020
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.
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