Research Papers:
Alveolar rhabdomyosarcoma: morphoproteomics and personalized tumor graft testing further define the biology of PAX3FKHRFOXO1 subtype and provide targeted therapeutic options
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Robert E. Brown1, Jamie Buryanek1, Amanda M. Katz2, Keren Paz2, Johannes E. Wolff3
1Department of Pathology & Laboratory Medicine, UT Health, McGovern Medical School, Houston, TX 77025, USA
2Scientific Operations, Champions Oncology, Baltimore, MD 21205, USA
3Present address: Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA
Correspondence to:
Robert E. Brown, email: [email protected]
Keywords: alveolar rhabdomyosarcoma, PAX3-FKHR subtype, morphoproteomics, xenograft testing, targeted therapy
Received: April 08, 2016 Accepted: June 03, 2016 Published: June 15, 2016
ABSTRACT
Alveolar rhabdomyosarcoma (ARMS) represents a block in differentiation of malignant myoblasts. Genomic events implicated in the pathogenesis of ARMS involve PAX3-FKHR (FOXO1) or PAX7-FKHR (FOXO1) translocation with corresponding fusion transcripts and fusion proteins. Commonalities in ARMS include uncontrollable proliferation and failure to differentiate. The genomic-molecular correlates contributing to the etiopathogenesis of ARMS incorporate PAX3-FKHR (FOXO1) fusion protein stimulation of the IGF-1R, c-Met and GSK3-β pathways. With sequential morphoproteomic profiling on such a case in conjunction with personalized tumor graft testing, we provide an expanded definition of the biology of PAX3-FKHR (FOXO1) ARMS that integrates genomics, proteomics and pharmacogenomics. Moreover, therapies that target the genomic and molecular biology and lead to tumoral regression and/or tumoral growth inhibition in a xenograft model of ARMS are identified.
Significance: This case study could serve as a model for clinical trials using relatively low toxicity agents in both initial and maintenance therapies to induce remission and reduce the risk of recurrent disease in PAX3-FKHR (FOXO1) subtype of ARMS.