Effect of all-trans retinoic acid on proliferation of human rhabdomyosarcoma and remission in an in vivo mouse xenograft model.

Abstract

9569 Background: Rhabdomyosarcoma (RMS) is the third most common soft tissue cancer in children. 30% of treated children will experience relapse, with poor outcome. New approaches are needed to improve cure rate and prevent relapse. Retinoic acid is a differentiation agent that is known to induce differentiation of normal myoblasts, among other cell types. When used in the setting of minimal residual disease, All-trans retinoic acid (ATRA) improves outcome of children with metastatic neuroblastoma, another childhood primitive tumor. Few in-vitro studies have been done to test the efficacy of retinoic acid in RMS. Methods: We used embryonal and alveolar rhabdomyosarcoma cell lines to evaluate the effect of ATRA on cultured RMS cells. We analyzed treated RMS cells (versus vehicle-treated controls) for effects on cell proliferation, apoptois, differentiation, and senescence. In addition, we used human RMS xenografts in immunosuppressed (NOG-SCID) mice, to evaluate the effect of ATRA therapy in-vivo. We treated mice carrying RMS xenografts with chemotherapy until tumors clinically resolved, then commenced “maintenance therapy” of presumed minimal residual disease with either ATRA or vehicle control for a period of four weeks. The time to tumor re-growth was subsequently monitored. Results: We found that ATRA had a significant effect on preventing RMS cell accumulation in culture. In addition to an inhibitory effect on cellular proliferation, we found that ATRA induced differentiation and formation of myotubes in embryonal, and to lesser extent alveolar, RMS cell lines. Using RMS cell lines as mouse xenografts, we found that using ATRA as maintenance therapy after remission induction by chemotherapy had a modest effect on delaying time to tumor relapse. Conclusions: Our results suggest that ATRA may be useful as maintenance therapy of minimal residual disease to prevent relapse of childhood rhabdomyosarcoma. Studies are underway to evaluate primary human RMS samples (biopsies) for expression of retinoic acid receptor elements, to identify the proportion of patients that may benefit from such therapy if incorporated into future clinical trials. No significant financial relationships to disclose.