GnRH-R–Targeted Lytic Peptide SensitizesBRCAWild-type Ovarian Cancer to PARP Inhibition

Abstract

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 AE 0.13 g) than those treated with a vehicle (1.19 AE 1.09 g), EP-100 alone (0.62 AE 0.78 g), or olaparib alone (0.50 AE 0.63 g). Our findings indicate that combining EP-100 with olaparib is a promising therapeutic strategy for ovarian cancer.

A novel dopamine receptor D2 antagonist (ONC206) potentiates the effects of olaparib in endometrial cancer

“…In this study, we found that the combination of olaparib and ONC206 showed significant effects on the AKT/mTOR/S6 pathway compared to ONC206 or olaparib alone. The finding of increased inhibition of the PI3K/AKT/mTOR pathway with the combination therapy is consistent with prior studies evaluating this treatment strategy 15 , 45 , 51 , 57 .…”

“…This pathway exerts a profound impact on downregulation of BRCA1 and BRCA2, the process of DNA damage repair, and the maintenance of genome stability. Activation of the PI3K/AKT pathway is associated with acquired resistance to PARP inhibitor treatment and may compromise the efficacy of PARP inhibitors 19 , 51 , 52 . PTEN-deficient tumors present an enhanced sensitivity to the combination of PI3K and PARP inhibition in EC cells and in a PTEN-deficient mouse model of EC 19 , 53 .…”

Role of Gonadotropin-Releasing Hormone (GnRH) in Ovarian Cancer

“…EP-100 a fusion peptide in which 18-amino-acid cationic α-helical lytic peptide (CLIP-71) is covalently linked to GnRH, was created to deliver lytic peptides to GnRH receptor-positive cancer cells [ 155 ] ( Table 2 ). It was recently shown, that EP-100 in combination with PARP inhibitor olaparib is a promising strategy for the therapy of ovarian cancer [ 156 ].…”

XGBG: A Novel Method for Identifying Ovarian Carcinoma Susceptible Genes Based on Deep Learning

“…Studies have indicated that KNG1 is highly related to the gonadotropin-releasing hormone (GnRH) ( 22 ), which is a hypothalamic neuropeptide that plays an important role in the reproductive system. Investigators have made a great effort to develop GnRH agonists and antagonists for the treatment of tumors such as ovarian cancers ( 23 ). Coagulation factor II (F2) is found to be overexpressed in various epithelial neoplasms including ovarian cancer ( 24 ); F2 receptor, also known as PAR1, has been provided to be differentially expressed in ovarian cancer tissue ( 25 ).…”