TY - JOUR
T1 - Therapeutic efficacy of liposomal Grb2 antisense oligodeoxynucleotide (L-Grb2) in preclinical models of ovarian and uterine cancer
AU - Lara, Olivia D.
AU - Bayraktar, Emine
AU - Amero, Paola
AU - Ma, Shaolin
AU - Ivan, Cristina
AU - Hu, Wei
AU - Wang, Ying
AU - Mangala, Lingegowda S.
AU - Dutta, Prasanta
AU - Bhattacharya, Pratip
AU - Ashizawa, Ana Tari
AU - Lopez-Berestein, Gabriel
AU - Rodriguez-Aguayo, Cristian
AU - Sood, Anil K.
N1 - Funding Information:
O.D. Lara was supported by a National Institutes of Health institutional training grant (5T32CA009599). C. Rodriguez-Aguayo was supported by the NIH through the Ovarian Spore Career Enhancement Program, and the NCI grant FP00000019. This work was also supported, in part, by BioPath (W. Hu). This work was supported in part by other National Institutes of Health grants (P30CA016672, CA213759, P50CA217685, P50CA098258, CA177909, and R35CA209904), the Blanton-Davis Ovarian Cancer Research Program, the American Cancer Society Research Professor Award, and the Frank T. McGraw Memorial Chair in Cancer Research (to A.K. Sood).
Funding Information:
A.K. Sood is an advisor for KIYATEC and Merck, is a Bio-Path Holdings, Inc., stockholder, and has received research funding from MTrap.
Publisher Copyright:
© Lara et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2020/7/21
Y1 - 2020/7/21
N2 - 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.
AB - 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.
KW - Nucleic-acid based therapeutics
KW - Ovarian cancer
KW - Therapeutic approaches
KW - Uterine cancer
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UR - http://www.scopus.com/inward/citedby.url?scp=85089628262&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.27667
DO - 10.18632/oncotarget.27667
M3 - Article
C2 - 32754300
AN - SCOPUS:85089628262
SN - 1949-2553
VL - 11
SP - 2819
EP - 2833
JO - Oncotarget
JF - Oncotarget
IS - 29
ER -