Alveolar rhabdomyosarcoma: morphoproteomics and personalized tumor graft testing further define the biology of PAX3-FKHR(FOXO1) subtype and provide targeted therapeutic options.
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.


CONCLUSIONS
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.
Department of Pathology & Laboratory Medicine, UT Health, McGovern Medical School, Houston, TX 77025, USA.
Robert E
RE
Brown
Department of Pathology & Laboratory Medicine, UT Health, McGovern Medical School, Houston, TX 77025, USA.
Jamie
J
Buryanek
Scientific Operations, Champions Oncology, Baltimore, MD 21205, USA.
Amanda M
AM
Katz
Scientific Operations, Champions Oncology, Baltimore, MD 21205, USA.
Keren
K
Paz
Present address: Novartis Pharmaceuticals Corporation, East Hanover, NJ 07936, USA.
Johannes E
JE
Wolff
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002648:Child; D006225:Hand / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D057285:Precision Medicine / Q000379:methods*; D040901:Proteomics; D018232:Rhabdomyosarcoma, Alveolar / Q000235:genetics* / Q000473:pathology*; D012983:Soft Tissue Neoplasms / Q000235:genetics* / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
D015514:Oncogene Proteins, Fusion; C523321:PAX3-FKHR fusion protein, human
PAX3-FKHR subtype; alveolar rhabdomyosarcoma; morphoproteomics; targeted therapy; xenograft testing