Rhabdomyosarcoma

Current challenges and their implications for developing therapies

Simone Hettmer, Zhizhong Li, Andrew N. Billin, Frederic G. Barr, D. Cornelison, Alan R. Ehrlich, Denis C. Guttridge, Andrea Hayes-Jordan, Lee J. Helman, Peter J. Houghton, Javed Khan, David M. Langenau, Corinne M. Linardic, Ranadip Pal, Terence A. Partridge, Grace K. Pavlath, Rossella Rota, Beat W. Schafer, Janet Shipley, Bruce Stillman & 3 others Leonard H. Wexler, Amy J. Wagers, Charles Keller

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Rhabdomyosarcoma (RMS) represents a rare, heterogeneous group of mesodermal malig- nancies with skeletal muscle differentiation. One major subgroup of RMS tumors (so-called “fusion-positive” tumors) carries exclusive chromosomal translocations that join the DNA- binding 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 spec- trum 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-neg- ative 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 indi- viduals with RMS, including all those diagnosed as adults, those diagnosed with fusion- positive 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 character- ization 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 microen- vironment, 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.

Original languageEnglish (US)
JournalCold Spring Harbor perspectives in medicine
Volume4
Issue number11
DOIs
StatePublished - 2014

Fingerprint

Rhabdomyosarcoma
Tumors
Fusion reactions
Neoplasms
Therapeutics
Industry
Genes
Tissue
Disease control
Genetic Translocation
Pediatrics
Tumor Microenvironment
Testing
Research
Sarcoma
Transcriptional Activation
Muscle
Skeletal Muscle
Chemical activation
DNA

ASJC Scopus subject areas

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Hettmer, S., Li, Z., Billin, A. N., Barr, F. G., Cornelison, D., Ehrlich, A. R., ... Keller, C. (2014). Rhabdomyosarcoma: Current challenges and their implications for developing therapies. Cold Spring Harbor perspectives in medicine, 4(11). https://doi.org/10.1101/cshperspect.a025650

Rhabdomyosarcoma : Current challenges and their implications for developing therapies. / Hettmer, Simone; Li, Zhizhong; Billin, Andrew N.; Barr, Frederic G.; Cornelison, D.; Ehrlich, Alan R.; Guttridge, Denis C.; Hayes-Jordan, Andrea; Helman, Lee J.; Houghton, Peter J.; Khan, Javed; Langenau, David M.; Linardic, Corinne M.; Pal, Ranadip; Partridge, Terence A.; Pavlath, Grace K.; Rota, Rossella; Schafer, Beat W.; Shipley, Janet; Stillman, Bruce; Wexler, Leonard H.; Wagers, Amy J.; Keller, Charles.

In: Cold Spring Harbor perspectives in medicine, Vol. 4, No. 11, 2014.

Research output: Contribution to journalArticle

Hettmer, S, Li, Z, Billin, AN, Barr, FG, Cornelison, D, Ehrlich, AR, Guttridge, DC, Hayes-Jordan, A, Helman, LJ, Houghton, PJ, Khan, J, Langenau, DM, Linardic, CM, Pal, R, Partridge, TA, Pavlath, GK, Rota, R, Schafer, BW, Shipley, J, Stillman, B, Wexler, LH, Wagers, AJ & Keller, C 2014, 'Rhabdomyosarcoma: Current challenges and their implications for developing therapies', Cold Spring Harbor perspectives in medicine, vol. 4, no. 11. https://doi.org/10.1101/cshperspect.a025650
Hettmer, Simone ; Li, Zhizhong ; Billin, Andrew N. ; Barr, Frederic G. ; Cornelison, D. ; Ehrlich, Alan R. ; Guttridge, Denis C. ; Hayes-Jordan, Andrea ; Helman, Lee J. ; Houghton, Peter J. ; Khan, Javed ; Langenau, David M. ; Linardic, Corinne M. ; Pal, Ranadip ; Partridge, Terence A. ; Pavlath, Grace K. ; Rota, Rossella ; Schafer, Beat W. ; Shipley, Janet ; Stillman, Bruce ; Wexler, Leonard H. ; Wagers, Amy J. ; Keller, Charles. / Rhabdomyosarcoma : Current challenges and their implications for developing therapies. In: Cold Spring Harbor perspectives in medicine. 2014 ; Vol. 4, No. 11.
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AU - Cornelison, D.

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AU - Guttridge, Denis C.

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