Rhabdomyosarcoma: Current Challenges and Their Implications for Developing Therapies

Abstract

Rhabdomyosarcoma (RMS) represents a rare, heterogeneous group of mesodermal malignancies with skeletal muscle differentiation. One major subgroup of RMS tumors (so-called "fusion-positive" tumors) carries exclusive chromosomal translocations that join the DNAbinding domain of the PAX3 or PAX7 gene to the transactivation domain of the FOXO1 ( previously known as FKHR) gene. Fusion-negative RMS represents a heterogeneous spectrum of tumors with frequent RAS pathway activation. Overtly metastatic disease at diagnosis is more frequently found in individuals with fusion-positive than in those with fusion-negative tumors. RMS is the most common pediatric soft-tissue sarcoma, and approximately 60% of all children and adolescents diagnosed with RMS are cured by currently available multimodal therapies. However, a curative outcome is achieved in ,30% of high-risk individuals with RMS, including all those diagnosed as adults, those diagnosed with fusionpositive tumors during childhood (including metastatic and nonmetastatic tumors), and those diagnosed with metastatic disease during childhood (including fusion-positive and fusion-negative tumors). This white paper outlines current challenges in RMS research and their implications for developing more effective therapies. Urgent clinical problems include local control, systemic disease, need for improved risk stratification, and characterization of differences in disease course in children and adults. Biological challenges include definition of the cellular functions of PAX-FOXO1 fusion proteins, clarification of disease heterogeneity, elucidation of the cellular origins of RMS, delineation of the tumor microenvironment, and identification of means for rational selection and testing of new combination therapies. To streamline future therapeutic developments, it will be critical to improve access to fresh tumor tissue for research purposes, consider alternative trial designs to optimize early clinical testing of candidate drugs, coalesce advocacy efforts to garner public and industry support, and facilitate collaborative efforts between academia and industry.

Uncovering metabolism in rhabdomyosarcoma

“…21,22 Patients who have localized RMS have a 5-year survival greater than 70% following a multimodal approach that includes chemotherapy, radiation therapy, and surgery; yet, overall survival of patients with metastasis remains poor. 23,24 Cells mainly deriving from myogenic lineages have been shown to contribute to RMS development in mouse [25][26][27][28] and zebrafish models, 29 yet even nonmyogenic lineages could participate in the formation of RMS. 30 As a result, these tumors can arise in or near to skeletal muscle districts as well as in sites that lack skeletal muscle, such as the biliary and genitourinary tract.…”

Probing for a deeper understanding of rhabdomyosarcoma: insights from complementary model systems

“…Despite these advances, therapies targeting molecular RMS oncogenic drivers are lacking. (For excellent reviews in these areas, we refer readers to Sokolowski et al 20 , Hettmer et al 21 ; and Keller and Guttridge 22 .) Consequently, investigators have made substantial efforts over the past decade to generate new genetic tools with which to dissect RMS (fig.…”

Matrine inhibits cell proliferation and induces apoptosis of human rhabdomyosarcoma cells via downregulation of the extracellular signal-regulated kinase pathway

“…It originates from immature striated muscles and is mainly found in the head, neck, extremities and genitourinary system (3). Two major types of RMS exist: Embryonal RMS (ERMS) and alveolar RMS (ARMS).…”