Differentiation Therapy for Rhabdoid Tumors
Malignant rhabdoid tumors are uncommon but extremely aggressive childhood sarcomas for which there is no adequate therapy. Since rhabdoid tumors are characterized by defects in mesenchymal progenitor cell differentiation, therapies that target and correct these defects and induce terminal differentiation are an attractive alternative to the cytotoxic therapies currently used to treat these tumors. However, little is known about the molecular changes that occur in rhabdoid tumors, which limits the development of targeted therapies. We observed frequent expression of the HOXB13 gene in rhabdoid tumors. HOXB13 is known to play an important role in cell determination during embryogenesis but its potential role in sarcomagenesis has not been studied. Our data show that the silencing of HOXB13 in a rhabdoid tumor cell line facilitates differentiation of tumors into bone. Conversely, expression of HOXB13 in mesenchymal progenitor cell lines inhibits differentiation and promotes retention of stem cell characteristics. Additionally, we show that HOXB13 is involved in the epigenetic regulation of a chromatin state and the repression of osteogenic genes. These data indicate that HOXB13 may be responsible for the maintenance of an undifferentiated state in rhabdoid tumors. We propose that targeting HOXB13 or downstream effectors that are required for its function may induce a differentiation program in rhabdoid tumors with consequential loss of the malignant phenotype. Aim 1 is to identify transcriptional effectors of HOXB13 as possible therapeutic targets for rhabdoid tumors. Transcription profiling of tumors in which differentiation is induced by HOXB13 knockdown will be used to define the molecular mechanisms by which HOXB13 inhibition leads to tumor differentiation. Gain-of-function and loss-of-function approaches will then be used to validate the roles of the candidate genes in differentiation. Computational approaches will be used to identify compounds that target the differentiation pathways that are altered by HOXB13. The efficacy of these compounds will be tested in mouse xenograft models. Aim 2 is to test the efficacy of epigenetic reprogramming as differentiation therapy for rhabdoid tumors. Inhibitors of enzymes that induce chromatin modifications will be tested, as monotherapy or in combination with other differentiating agents, for their efficacy in inducing differentiation in rhabdoid tumors.