Estrogen enhances the efficacy of an oncolytic HSV-1 mutant in the treatment of estrogen receptor-positive breast cancer

Abstract

Abstract. Oncolytic herpes simplex virus-1 (HSV-1) mutants selectively replicate in and lyse tumor cells. Viral replication is dependent on the cellular proliferative mechanism. Estrogen increases cellular proliferation and decreases apoptosis in estrogen receptor-positive (ER + ) human breast cancer cells. We hypothesize that the cellular changes produced by estrogen may enhance oncolytic viral replication and improve the treatment of ER + breast cancer cells. Estrogen increased proliferation and replication of the HSV-1 mutant, NV1066, in ER + breast cancer cells. Additionally, cells grown with estrogen had lower rates of apoptosis and higher bcl-2 levels at baseline and after infection. Estrogen enhanced the oncolytic effect of NV1066, with cell kills of 95% and 97% at MOIs of 0.1 and 0.5, compared to 53 and 87% respectively without estrogen (p<0.001). Therapy of ER + human breast cancer cells with a replication-competent HSV-1 mutant is improved in the presence of estrogen, in contrast to more standard therapies, such as chemotherapy and radiation, which demonstrate decreased efficacy in similar conditions. These data provide the mechanistic basis for the use of oncolytic HSV-1 in patients with hormone receptor-positive breast cancer, particularly if the disease progresses with conventional therapies.

Oncolytic Virotherapy Treatment of Breast Cancer: Barriers and Recent Advances

“…Interestingly, oestrogen may also be combined with oncolytic viruses. In a study by Stiles et al, the addition of oestrogen to the oncolytic HSV-1 NV1066 enhanced the lytic effect of the virus, with an MCF-7 cell death of 95% and 97% in vitro at MOIs of 0.1 and 0.5, respectively, compared to 53% and 87%, respectively, in the absence of estrogen [67]. This finding may be used to target the more immunotherapy-resistant ER+ breast cancers and is worth potential investigation.…”

Role of MAPK in oncolytic herpes viral therapy in triple-negative breast cancer

“…Anthracycline resistance and survival following relapse was significantly worse for patients with higher MAPK score. Other researchers have shown that increased expression of p-MAPK was associated with resistance to anti-EGFR agents such as gefitinib, 32 radiation therapy, 20 or the mTOR inhibitor rapamycin. 35 Normanno et al 33 reported that gefitinib and PD98059 produced synergistic antitumor effect and increased apoptosis compared with singleagent treatment.…”

“…[9][10][11][12][13][14][15] NV1066 is a geneticallyengineered form of HSV-1, which has shown promise as an oncolytic agent against 4110 cell lines, 10 including multiple cancer types, such as mesothelioma, 16 pancreatic cancers, 17,18 melanoma, 19 and breast cancer. 20 Furthermore, NV1066 replicates selectively in cells resistant to apoptosis, and is a derivative of the oncolytic HSV strain NV1020, which has already demonstrated a favorable safety profile in phase I clinical trials. 12,13,21 NV1066 is specifically designed to exploit cells with increased activation of MAPK signaling.…”