A novel conditionally replicative oncolytic adenovirus under the control of the SALL4 promoter inhibits the growth of rhabdoid tumors

Abstract Rhabdoid tumors (RTs) are highly aggressive pediatric malignancies with limited treatment options. SALL4, a gene essential for embryonic stem cell pluripotency and self-renewal, is frequently overexpressed in RTs. To exploit this, we developed a conditionally replicating oncolytic adenovirus (pSALL4-OAd) by placing the E1 region under the control of the SALL4 promoter, restricting viral replication to SALL4-positive cells. SALL4 protein expression was analyzed in 10 clinical RT specimens via immunohistochemistry, while SALL4 mRNA levels and promoter activity were assessed in eight RT cell lines using quantitative PCR and dual-luciferase assays. The replication selectivity and cytopathic effects of pSALL4-OAd were tested in vitro at doses of 0–1000 viral particles (vp)/cell. In vivo, 1.0 × 10^7 G401 cells were implanted subcutaneously into immunodeficient mice, followed by intratumoral administration of pSALL4-OAd (3 × 10^10 vp) or phosphate-buffered saline. Tumor growth was monitored over the treatment period. SALL4 protein was detected in 40% of clinical RT specimens, and RT cell lines exhibited 4- to 400-fold higher SALL4 mRNA levels compared with normal tissues. Elevated SALL4 promoter activity was confirmed in three of five RT cell lines. pSALL4-OAd selectively replicated in SALL4-positive cells and induced significant cytopathic effects proportional to promoter activity in vitro. In vivo, pSALL4-OAd administration caused tumor necrosis, reduced SALL4-positive cells, and suppressed tumor proliferation. These results demonstrate the potential of pSALL4-OAd as a targeted and effective therapeutic strategy for SALL4-expressing RTs.