%0 Journal Article
%T Activating Death Receptor DR5 as a Therapeutic Strategy for Rhabdomyosarcoma
%A Zhigang Kang
%A Shi-Yong Sun
%A Liang Cao
%J ISRN Oncology
%D 2012
%R 10.5402/2012/395952
%X Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. It is believed to arise from skeletal muscle progenitors, preserving the expression of genes critical for embryonic myogenic development such as MYOD1 and myogenin. RMS is classified as embryonal, which is more common in younger children, or alveolar, which is more prevalent in elder children and adults. Despite aggressive management including surgery, radiation, and chemotherapy, the outcome for children with metastatic RMS is dismal, and the prognosis has remained unchanged for decades. Apoptosis is a highly regulated process critical for embryonic development and tissue and organ homeostasis. Like other types of cancers, RMS develops by evading intrinsic apoptosis via mutations in the p53 tumor suppressor gene. However, the ability to induce apoptosis via the death receptor-dependent extrinsic pathway remains largely intact in tumors with p53 mutations. This paper focuses on activating extrinsic apoptosis as a therapeutic strategy for RMS by targeting the death receptor DR5 with a recombinant TRAIL ligand or agonistic antibodies directed against DR5. 1. Introduction Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue tumor. Despite extensive research and aggressive clinical management, the overall outcome for children with metastatic disease is dismal with a prognosis largely unchanged in decades [1, 2]. RMS tumors are histologically classified into two major subtypes, embryonic (ERMS) and alveolar (ARMS), which are associated with unique genetic changes. The majority of ARMSs are characterized by the presence of PAX3/7:FOXO1 translocation [3, 4]. ERMSs, on the other hand, are more frequently associated with activated RAS signaling via mutations in RAS genes or deletions in NF1, a tumor suppressor that encodes an RAS inhibitor [5¨C7]. The two subtypes of RMS also have distinct prognoses. ERMSs are often found in younger patients who generally do better, whereas ARMSs are more frequently diagnosed in adolescents and young adults who have a worse prognosis with a five-year survival rate of less than 50% [8¨C11]. Additional mutations in tumor suppressors are important for the development of RMS. In particular, RMS is the most common pediatric cancer in families with Li-Fraumeni syndrome [12]. Mutations in p53 are important for pathogenesis and commonly found in RMS [13, 14]. Despite advances in radiation and chemotherapy, there has been little change in the 5-year survival rate for pediatric RMS [10]. The cure rate for advanced RMS is not expected to improve
%U http://www.hindawi.com/journals/isrn.oncology/2012/395952/