Research Interest

Molecular basis of sarcomas in relation to therapy

Sarcomas are rare cancers comprising >50 individual tumour types that together amount to ≤ 1% of human cancers. They affect all age groups, being disproportionately represented in children and young adults, and can occur at any site in the body. Broadly speaking sarcomas can be divided into those driven by a specific molecular event, possibly a mutation, more commonly a chromosomal translocation, in which case the tumours appear relatively bland and monomorphic, and those with a chaotic karyotype, associated with pleomorphic histology. The precise basis for the genetic instability in these latter tumours is currently not known, although DNA repair defects have been described. 

GIST became the paradigm for the molecularly targeted therapy of solid tumours, owing to the success of imatinib in this disease via inhibition of KIT or PDGFRA, activated by mutation. Secondary mutations are the commonest cause of acquired resistance and a number of agents with differing susceptibility to these are in development, including agents which are active against the T670I gatekeeper mutation and others which bind to the active conformation of KIT or PDGFRA, unlike imatinib and sunitinib. Mutant KIT is also a client for HSP90 and there is major interest in testing HSP90 inhibitors in this disease. The first such attempt, using an analogue of 17AAG, IPI504, failed owing to toxicity, but novel synthetic inhibitors are being developed which do not have the same pharmaceutical, metabolic and toxicity limitations. 

It is a major frustration that in spite of the fact that the first translocation-related sarcoma was characterised at RMH / ICR more than 20 years ago (the t(X;18) translocation in synovial sarcoma^[1]) until very recently a knowledge of these fundamental molecular abnormalities has not resulted in the identification of suitable targets for therapy. 

One of the hypotheses proposed to explain the importance of the insulin-like growth factor signalling pathway in Ewing sarcoma is that the EWS-FLI1 fusion protein, produced by the t(11;22) translocation, acting as an oncogenic transcription factor, binds to the IGF binding protein 3 (IGFBP3) promoter, blocking production of IGFBP3 and hence upregulating IGF1^[2]. Inhibition of the receptor with monoclonal antibodies or small molecules blocks the action of IGF1. Activity against Ewing sarcoma was first reported in a phase I trial of R1507 ^[3] and subsequently in an expanded phase I cohort with figitumumab^[4]. The activity was ultimately disappointing but work is ongoing to try and understand how resistance develops and how this might be overcome. 

Recently we have seen a growing list of genetically defined sarcomas for which a specific therapy can at least be proposed, including mTOR inhibitors for PEComa, associated with loss of function of the tumour suppressor genes TSC1 or TSC2; MET inhibitors in clear cell sarcoma, where the translocation, t(12;22)(q13;q12) gives rise to a EWSR1/ATF1 gene fusion resulting in upregulation of MET^[5]; imatinib as an inhibitor of PDGFR-B for DFSP, driven by t(17;22)(q22;q13) and the resulting COL1A1/PDGFB fusion gene; imatinib as an inhibitor of M-CSF-R in pigmented villonodular synovitis, driven by t(1;2) and a COL6A3/CSF1 fusion gene^[6]. De-differentiated liposarcoma is characterised by a chromosomal amplification resulting in overexpression of MDM2 (HDM2) and CDK4. CDK inhibitors have yet to find a role, but there will be interest in testing newly developed HDM2 inhibitors currently in the pipeline in this disease. 

More generic treatments have also shown promise, including angiogenesis inhibitors, sometimes with quite startlingly good results in rare diseases, such as alveolar soft part sarcoma, another translocation driven disease^[7]. 

References

1. Reeves BR, Smith S, Fisher C, Warren W, Knight J, Martin C, Chan AM, Gusterson BA, Westbury G, Cooper CS: Characterization of the translocation between chromosomes X and 18 in human synovial sarcomas. Oncogene 1989;4:373-378.
2. Prieur A, Tirode F, Cohen P, Delattre O: EWS/FLI-1 silencing and gene profiling of Ewing cells reveal downstream oncogenic pathways and a crucial role for repression of insulin-like growth factor binding protein 3. Mol Cell Biol 2004;24:7275-7283.
3. Leong S. GL, Benjamin R., Warren T.L., Eckhardt S.G., Camidge D.R., Dias C., Greig G., Frankel S.R., Kurzrock R.: A phase I study of R1507, a human monoclonal antibody Igf-1R (insulin-like growth factor receptor) antagonist given weekly in patients with advanced solid tumors. Proceedings AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics 2007;October 22-26, 2007:90 abstract A78.
4. Olmos D, Postel-Vinay S, Molife LR, Okuno SH, Schuetze SM, Paccagnella ML, Batzel GN, Yin D, Pritchard-Jones K, Judson I, Worden FP, Gualberto A, Scurr M, de Bono JS, Haluska P: Safety, pharmacokinetics, and preliminary activity of the anti-Igf-1R antibody figitumumab (cp-751,871) in patients with sarcoma and Ewing's sarcoma: A phase 1 expansion cohort study. Lancet Oncol;11:129-135.
5. Davis IJ, McFadden AW, Zhang Y, Coxon A, Burgess TL, Wagner AJ, Fisher DE: Identification of the receptor tyrosine kinase c-met and its ligand, hepatocyte growth factor, as therapeutic targets in clear cell sarcoma. Cancer Res;70:639-645.
6. Blay JY, El Sayadi H, Thiesse P, Garret J, Ray-Coquard I: Complete response to imatinib in relapsing pigmented villonodular synovitis/tenosynovial giant cell tumor (PVNS/TGCT). Ann Oncol 2008;19:821-822.
7. Stacchiotti S, Tamborini E, Marrari A, Brich S, Rota SA, Orsenigo M, Crippa F, Morosi C, Gronchi A, Pierotti MA, Casali PG, Pilotti S: Response to sunitinib malate in advanced alveolar soft part sarcoma. Clin Cancer Res 2009;15:1096-1104.