TY - JOUR
T1 - GnRH-R-Targeted lytic peptide sensitizes BRCA wild-type ovarian cancer to PARP inhibition
AU - Ma, Shaolin
AU - Pradeep, Sunila
AU - Villar-Prados, Alejandro
AU - Wen, Yunfei
AU - Bayraktar, Emine
AU - Mangala, Lingegowda S.
AU - Kim, Mark Seungwook
AU - Wu, Sherry Y.
AU - Hu, Wei
AU - Rodriguez-Aguayo, Cristian
AU - Leuschner, Carola
AU - Liang, Xiaoyan
AU - Ram, Prahlad T.
AU - Schlacher, Katharina
AU - Coleman, Robert L.
AU - Sood, Anil K.
N1 - Funding Information:
STR DNA fingerprinting was done by the CCSG-funded Characterized Cell Line Core, NCI # CA016672. RPPA was performed by the RPPA Core Facility, The University of MD Anderson Cancer Center, NCI CA16672. We thank Dr. Walter Hittelman for support on multiphoton confocal microscopy. We thank the Department of Scientific Publications at MD Anderson for reviewing this manuscript. This work was supported, in part, by the NIH grants (CA016672, UH3TR000943, P50 CA217685, R35 CA209904), Ovarian Cancer Research Fund, Inc. (Program Project Development Grant), The Judi A. Rees Ovarian Cancer Research Fund, The Blanton-Davis Ovarian Cancer Research Program, the American Cancer Society Research Professor Award, and the Frank McGraw Memorial Chair in Cancer Research. Y. Wen was supported, in part, by the NIH 5 P50 SPORE CDP Award CA116199, the Marsha Rivkin Center for Ovarian Cancer, and the National Comprehensive Cancer Network. S.Y. Wu was supported by the CPRIT Research Training Program (RP101502, RP140106, and RP170067).
Funding Information:
C. Leuschner is the vice president of Research and Development and has ownership interest (including stock, patents, etc.) in Esperance Pharmaceuticals. R.L. Coleman reports receiving a commercial research grant from Esperance Pharmaceuticals, AstraZeneca, and Clovis, reports receiving other commercial research support from Merck, Genmab, Roche, is a consultant/advisory board member for AstraZeneca, Clovis, Genentech, Genmab, Gamamab, Aravive, and Tesaro. A.K. Sood reports receiving a commercial research grant from M-Trap, has ownership interest (including stock, patents, etc.) in Biopath, and is a consultant/advisory board member for Kiyatec and Merck. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - EP-100 is a synthetic lytic peptide that specifically targets the gonadotropin-releasing hormone receptor on cancer cells. To extend the utility of EP-100, we aimed to identify effective combination therapies with EP-100 for ovarian cancer and explore potential mechanisms of this combination. A series of in vitro (MTT assay, immunoblot analysis, reverse-phase protein array, comet assay, and immunofluorescence staining) and in vivo experiments were carried out to determine the biological effects of EP-100 alone and in combination with standard-of-care drugs. EP-100 decreased the viability of ovarian cancer cells and reduced tumor growth in orthotopic mouse models. Of five standard drugs tested (cisplatin, paclitaxel, doxorubicin, topotecan, and olaparib), we found that the combination of EP-100 and olaparib was synergistic in ovarian cancer cell lines. Further experiments revealed that combined treatment of EP-100 and olaparib significantly increased the number of nuclear foci of phosphorylated histone H2AX. In addition, the extent of DNA damage was significantly increased after treatment with EP-100 and olaparib in comet assay. We performed reverse-phase protein array analyses and identified that the PI3K/AKT pathway was inhibited by EP-100, which we validated with in vitro experiments. In vivo experiment using the HeyA8 mouse model demonstrated that mice treated with EP-100 and olaparib had lower tumor weights (0.06 ± 0.13 g) than those treated with a vehicle (1.19 ± 1.09 g), EP-100 alone (0.62 ± 0.78 g), or olaparib alone (0.50 ± 0.63 g). Our findings indicate that combining EP-100 with olaparib is a promising therapeutic strategy for ovarian cancer.
AB - EP-100 is a synthetic lytic peptide that specifically targets the gonadotropin-releasing hormone receptor on cancer cells. To extend the utility of EP-100, we aimed to identify effective combination therapies with EP-100 for ovarian cancer and explore potential mechanisms of this combination. A series of in vitro (MTT assay, immunoblot analysis, reverse-phase protein array, comet assay, and immunofluorescence staining) and in vivo experiments were carried out to determine the biological effects of EP-100 alone and in combination with standard-of-care drugs. EP-100 decreased the viability of ovarian cancer cells and reduced tumor growth in orthotopic mouse models. Of five standard drugs tested (cisplatin, paclitaxel, doxorubicin, topotecan, and olaparib), we found that the combination of EP-100 and olaparib was synergistic in ovarian cancer cell lines. Further experiments revealed that combined treatment of EP-100 and olaparib significantly increased the number of nuclear foci of phosphorylated histone H2AX. In addition, the extent of DNA damage was significantly increased after treatment with EP-100 and olaparib in comet assay. We performed reverse-phase protein array analyses and identified that the PI3K/AKT pathway was inhibited by EP-100, which we validated with in vitro experiments. In vivo experiment using the HeyA8 mouse model demonstrated that mice treated with EP-100 and olaparib had lower tumor weights (0.06 ± 0.13 g) than those treated with a vehicle (1.19 ± 1.09 g), EP-100 alone (0.62 ± 0.78 g), or olaparib alone (0.50 ± 0.63 g). Our findings indicate that combining EP-100 with olaparib is a promising therapeutic strategy for ovarian cancer.
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U2 - 10.1158/1535-7163.MCT-18-0770
DO - 10.1158/1535-7163.MCT-18-0770
M3 - Article
C2 - 30926640
AN - SCOPUS:85065508642
SN - 1535-7163
VL - 18
SP - 969
EP - 979
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 5
ER -