Abstract
Tumor-specific replication-selective oncolytic virotherapy is a promising antitumor therapy for induction of cell death in tumor cells but not of normal cells. We previously developed an oncolytic adenovirus, OBP-301, that kills human epithelial malignant cells in a telomerase-dependent manner. Recent evidence suggests that nonepithelial malignant cells, which have low telomerase activity, maintain telomere length through alternative lengthening of telomeres (ALT). However, it remains unclear whether OBP-301 is cytopathic for nonepithelial malignant cells. Here, we evaluated the antitumor effect of OBP-301 on human bone and soft tissue sarcoma cells. The cytopathic activity of OBP-301, coxsackie and adenovirus receptor (CAR) expression, and telomerase activity were examined in 10 bone (OST, U2OS, HOS, HuO9, MNNG/HOS, SaOS-2, NOS-2, NOS-10, NDCS-1, and OUMS-27) and in 4 soft tissue (CCS, NMS-2, SYO-1, and NMFH-1) sarcoma cell lines. OBP-301 antitumor effects were assessed using orthotopic tumor xenograft models. The fiber-modified OBP-301 (termed OBP-405) was used to confirm an antitumor effect on OBP-301-resistant sarcomas. OBP-301 was cytopathic for 12 sarcoma cell lines but not for the non-CAR-expressing OUMS-27 and NMFH-1 cells. Sensitivity to OBP-301 was dependent on CAR expression and not on telomerase activity. ALT-type sarcomas were also sensitive to OBP-301 because of upregulation of human telomerase reverse transcriptase (hTERT) mRNA following virus infection. Intratumoral injection of OBP-301 significantly suppressed the growth of OST and SYO-1 tumors. Furthermore, fiber-modified OBP-405 showed antitumor effects on OBP-301-resistant OUMS-27 and NMFH-1 cells. A telomerase-specific oncolytic adenovirus is a promising antitumor reagent for the treatment of bone and soft tissue sarcomas.
Highlights
Bone and soft tissue sarcomas are annually diagnosed in 13,230 patients in the United States [1]
alternative lengthening of telomeres (ALT)-type sarcomas were sensitive to OBP-301 because of upregulation of human telomerase reverse transcriptase mRNA following virus infection
To rule out the possibility that cytopathic effect of OBP-301 is due to nonspecific toxicity based on the high uptake of virus particles into tumor cells, we examined the cytopathic activity of replication-deficient dl312 in U2OS and HOS cells. dl312 did not show any cytopathic effect in U2OS and HOS cells, even when these cells were infected with dl312 at high dose (50 and 100 multiplicity of infections (MOI); Supplementary Fig. S1)
Summary
Bone and soft tissue sarcomas are annually diagnosed in 13,230 patients in the United States [1]. They are the third most common cancer in children and account for 15.4% of all childhood malignancies. Bone and soft tissue sarcomas requires a multidisciplinary approach that involves orthopedic oncologists, musculoskeletal radiologists and pathologists, radiation oncologists, medical and pediatric oncologists, and microvascular surgeons [2, 3]. Despite major advances in the treatment of bone and soft tissue sarcomas, such as neoadjuvant and adjuvant multiagent chemotherapy and aggressive surgery, about one fourth of the patients show a poor response to conventional therapy, resulting in subsequent recurrence and leading to a poor prognosis [1]. The development of a novel therapeutic strategy is required to cure patients with bone and soft tissue sarcomas
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