Infectivity enhanced, hTERT promoter-based conditionally replicative adenoviruses are useful for SCLC treatment

Abstract

Treatment of advanced small-cell lung cancer (SCLC) remains one of the major challenges in current medicine because of the high morbidity and mortality of the disease. Advanced stage lung cancer is refractory to conventional therapies and it also has an extremely poor prognosis. As a result, new therapeutic approaches are needed. Telomere maintenance to the regulation of replicative lifespan strongly implies that alterations in telomere biology play an important role during malignant transformation. Cancers that exhibit high levels of telomerase activity, such as all of the SCLC, were examined in a previous study. In this study, we turned the expression of human telomerase reverse transcriptase (hTERT) by tumors to a therapeutic advantage using a conditionally replication-competent adenovirus (CRAd) in which the expression of E1 (early region 1) is controlled by the hTERT promoter. This virus achieved good levels of viral replication in SCLC cells and induced a substantial anticancer effect in vitro and in vivo. As a further enhancement, the cancer cell killing effect was improved with a tropism modification of the virus to express the knob domain of Ad3 (serotype 3 adenovirus), and this improved infectivity for cancer cells. Conversely, the hTERT promoter has low activity in normal tissues, and the CRAd caused no damage to normal lung fibroblast cells. Since the telomerase activity is common in many types of cancers, these CRAds may be applicable to a wide range of tumors. We concluded that the use of hTERT promoterbased CRAds may be a potentially effective strategy for cancer treatment.

Evolving gene therapy approaches for osteosarcoma using viral vectors: Review

“…The first CRAd developed via this approach was CN706 (CV706) that specifically replicates in prostate-specific antigen (PSA) expressing cells (125). Based on the same principle, CRAds with the viral essential genes under the COX-2 promoter, the human tyrosine promoter, the midkine promoter and the hTERT promoter demonstrated efficacy in respectively pancreas cancer and gastric cancer (110,160), metastatic melanoma (106) pediatric solid tumors (2) and small cell lung cancer (144). The hTERT promoter-driven CRAd is a possible candidate for OS as telomerase expression is frequently observed in OS and correlates with a poor prognosis (129).…”

Gene therapy for malignant mesothelioma: beyond the infant years

“…In particular, expression of transgenes under the control of tumor-specific promoters is promising, as shown for the human telomerase promoter. 101 Since mesothelin is highly upregulated in mesothelioma, 94,102 use of the mesothelin promoter 103 to drive adenovirus-based transgene expression could show potential. Beyond adenovirus vectors, it is notable that the potential of vaccinia virus recombinants as (immuno-) gene therapy vectors has remained relatively underdeveloped.…”

A chimeric fusion of the hASH1 and EZH2 promoters mediates high and specific reporter and suicide gene expression and cytotoxicity in small cell lung cancer cells

“…A number of promoters (including regions of the neuron-specific enolase and human telomerase catalytic subunit promoters) have been suggested as regulatory candidates for SCLC gene therapy, [5][6][7][8] but demonstrate incomplete SCLC specificity and/or insufficient activity.…”