Development of targeted therapies for rhabdoid tumors based on the functions of INI1/hSNF5 tumor suppressor

Rhabdoid tumors (RTs) are rare, but highly aggressive and mostly incurable -pediatric malignancies (Strother 2005; Biegel 2006). RTs occur in children younger than 5 years of age and the peak incidence is between birth and 3 years of age (Biegel 2006). RTs were originally described in kidneys and termed Malignant Rhabdoid Tumors (MRT), and were subsequently found in the central nervous system (Atypical Teratoid and Rhabdoid Tumors, AT/RT), and soft tissues (extra-renal Rhabdoid Tumors) (Biegel 2006). Irrespective of their location, all RTs are characterized by the presence of sheets or nests of rhabdoid cells. Recent molecular genetic studies have established that RTs are distinguished from other tumors by the presence of recurrent biallelic deletions and/or mutations in the INI1/hSNF5 gene, located at chromosome 22q11.2, providing a definitive diagnostic criteria (Versteege et al. 1998; Biegel 1999; Biegel et al. 1999; Sevenet et al. 1999). Current therapeutic regimens for RT involve empirically selected combinations of chemotherapeutic agents that are highly toxic and rarely curative, as such, the survival rate for children with RTs remains poor (Packer et al. 2002; Reddy 2005; Strother 2005; Biegel 2006; Yamamoto et al. 2006). Thus, there is a dire need to develop novel therapeutic strategies for RTs, preferably based on the understanding of the molecular factors responsible for the genesis, growth, and survival of these tumors. In the following sections, we will describe features of RTs, current therapeutic practices, the molecular basis of rhabdoid tumorigenesis, and development of potential targeted therapies based on these understandings.