Grant: Travel Awards - Institute Community Support

Rhabdomyosarcoma (RMS) is the most common soft tissue cancer in children. When treated aggressively, RMS patients have a high long-term survival rate; however, chemotherapeutic resistance remains a problem due to acquired defects in cell death (apoptosis) pathways. Smac mimetic compounds (SMCs) are a novel class of inhibitor of apoptosis (IAP) antagonists that are currently under clinical development as cancer therapeutics. We previously reported that cIAP1 levels are elevated in human primary RMS tumors and in patient-derived RMS cell lines where it drives resistance to apoptosis. Reducing levels of cIAP1 with SMCs sensitizes RMS cells to tumor necrosis factor alpha-mediated apoptosis and inhibits the growth of xenograft tumors in mice. Recent reports suggest that inflammatory cytokine production triggered by activators of the innate immune system synergize with SMCs to increase cancer cell death in mouse carcinoma models. Indeed, we show that innate immune stimuli (oncolytic virus, interferon gamma, and tumor necrosis factor-like weak inducer of apoptosis (TWEAK)) combine with SMCs to induce cell death in Kym-1 RMS cancer cells. In contrast, SMC-resistant RMS cell lines have reduced expression of FN14, the receptor for TWEAK, which may result in impaired NF-kappa B signalling and defects in the apoptotic program. Further studies will establish the mechanism of apoptotic resistance in human and mouse RMS cells and will determine whether specific targeting of IAPs provides a therapeutic benefit to patients with RMS.