Prevailing importance of the hedgehog signaling pathway and the potential for treatment advancement in sarcoma.
The hedgehog signaling pathway is important in embryogenesis and post natal development. Constitutive activation of the pathway due to mutation of pathway components occurs in ~25% of medulloblastomas and also in basal cell carcinomas. In many other malignancies the therapeutic role for hedgehog inhibition though intriguing, based on preclinical data, is far from assured. Hedgehog inhibition is not an established part of the treatment paradigm of sarcoma but the scientific rationale for a possible benefit is compelling. In chondrosarcoma there is evidence of hedgehog pathway activation and an ontologic comparison between growth plate chondrocyte differentiation and different chondrosarcoma subtypes. Immunostaining epiphyseal growth plate for Indian hedgehog is particularly positive in the zone of pre-hypertrophic chondrocytes which correlates ontologically with conventional chondrosarcoma. In Ewing sarcoma/PNET tumors the Gli1 transcription factor is a direct target of the EWS-FLI1 oncoprotein present in 85% of cases. In many cases of rhabdomyosarcomas there is increased expression of Gli1 (Ragazzini et al., 2004). Additionally, a third of embryonal rhabdomyosarcomas have loss of Chr.9q22 that encompasses the patched locus (Bridge et al., 2000). The potential to treat osteosarcoma by inhibition of Gli2 and the role of the pathway in ovarian fibromas and other connective tissue tumors is also discussed (Nagao et al., 2011; Hirotsu et al., 2010). Emergence of acquired secondary resistance to targeted therapeutics is an important issue that is also relevant to hedgehog inhibition. In this context secondary resistance of medulloblastomas to treatment with a smoothened antagonist in two tumor mouse models is examined.
Sarcoma Service, Peter MacCallum Cancer Centre, 12 St. Andrew's Place, A'Beckitt Street, Melbourne, Victoria, Australia. fergalkelleher@hotmail.com
Fergal C
FC
Kelleher
Jason E
JE
Cain
Joan M
JM
Healy
D Neil
DN
Watkins
David M
DM
Thomas
D000813:Anilides / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis; D001478:Basal Cell Nevus Syndrome / Q000188:drug therapy; D002280:Basal Cell Carcinoma / Q000188:drug therapy; D002813:Chondrosarcoma / Q000188:drug therapy; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology; D008527:Medulloblastoma / Q000188:drug therapy; D059630:Mesenchymal Stem Cells / Q000473:pathology; D012516:Osteosarcoma / Q000188:drug therapy; D011725:Pyridines / Q000627:therapeutic use; D012509:Sarcoma / Q000188:drug therapy* / Q000209:etiology; D015398:Signal Transduction / Q000502:physiology*; D000075746:Zinc Finger Protein Gli2
D000813:Anilides; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; C538724:HhAntag691; D051741:Kruppel-Like Transcription Factors; D011725:Pyridines; D000075746:Zinc Finger Protein Gli2