92IN - Treating sarcoma (including GIST) subtypes based on molecular characteristics

Date 29 September 2012
Event ESMO Congress 2012
Session Subtyping soft tissue sarcomas for treatment approaches
Topics Anticancer Agents
Pathology/Molecular Biology
Basic Scientific Principles
Biological Therapy
Presenter Jean-Yves Blay
Authors J. Blay
  • University Claude Bernard Lyon I, Centre Léon Bérard, 69008 - Lyon CEDEX/FR


Recent progress in the understanding of the biology of soft tissue sarcomas and locally aggressive connective tissue tumors have enabled the identification of distinct molecular and pathological entities: six molecular subgroups of connective tissue tumors may be distinguished: 1) sarcoma with specific translocations generating fusion gene whose protein products modulate transcription or may act as growth factors (e.g. EWS/Fli1 in Ewing sarcomas, PDGF-col1a1 in DFSP); 2) sarcomas with mutated activated kinases (KIT in GIST); 3) sarcomas with deletion of tumor suppressor genes such as NF1 sarcomas, or rhabdoid tumors (INI1); 4) Sarcomas with simple genetic alterations (mdm2/cdk4 amplification in WD/DD liposarcomas; 5) Sarcomas with gross genetic alterations (e.g. leiomyosarcomas); 6) Tumors with alterations of the intercellular adhesion pathways (aggressive fibromatosis with APC deletion or b catenin mutations). These classifications are rapidly evolving. The identification of the “driver” mutation in some of these diseases paved the way for the selection of efficient targeted therapies in sarcomas and locally aggressive connective tissue tumors such as GIST, DFSP, PEComas, PVNS … Even though the driving molecular event is not known, giant cell tumors of the bone fit in this category. Interestingly, with the refinement of molecular typing, even rare nosological entities evolve towards further fragmentation: the identification of KIT and PDGFRA mutations, then Raf, NF1, SDH mitated in GIST led to a rapid development of imatinib, sunitinib, and regorafenib, but with the more recent characterization of Raf, NF1, SDH gene muations, it is now recognized that GIST gathers probably 10 different molecular entities with different therapeutic rules and prognosis in localized and advanced phase. Recently, it was shown that targeting MdM2/p53 interaction in sarcomas with MDM2 amplification can lead to an efficient reactivation of p53 and biological response in tumor cell. Targeting CDK4 may also be worth exploring in similar context. Targeting a pathway downstream of the driver mutation can however be more challenging: in Ewing sarcoma, whose fusion gene product regulates IGFBP3, anti–IGF1R Ab yielded responses in now several phase I and II trials but only in a small proportion of patents for reasons yet unknown. In addition to these examples, more empiric approaches have been successfully developed, with anti-angiogenics (pazopanib) and mTOR inhibitors (ridaforolimus) showing efficacy in phase III trials, in a broader group of sarcoma subtypes. Treating sarcoma subtypes according to their molecular characteristics is critical for the development of new treatments, and will also be essential to understand the biological mechanisms of response and resistance.


J. Blay: Suppoted by grants from Novartis, GSK, Roche, Pharmamar