Validation of potential therapeutic targets in alveolar soft part

[D.ap]

Alexander J Lazar,1,2 Guy Lahat,2,3 Sarah E Myers,2,4 Kerrington D Smith,2,3 Changye Zou,2,3
Wei-Lien Wang,1 Dolores Lopez-Terrada5 & Dina Lev2,4
Departments of 1Pathology, 3Surgical Oncology, 4Cancer Biology and the 2Sarcoma Research Center, The University of
Texas M. D. Anderson Cancer Center, and 5Department of Pathology, Texas Children’s Hospital and Baylor College of
Medicine, Houston, TX, USA
Date of submission 22 June 2009
Accepted for publication 26 August 2009
Lazar A J, Lahat G, Myers S E, Smith K D, Zou C, Wang W-Lien, Lopez-Terrada D & Lev D
(2009) Histopathology 55, 750–755

Validation of potential therapeutic targets in alveolar soft part sarcoma: an
immunohistochemical study utilizing tissue microarray

Aims: The molecular signature of alveolar soft part
sarcoma (ASPS) is a specific der(17)t(X;17)(p11.2;q25)
translocation, resulting in a chimeric transcription
factor (ASPSCR1–TFE3). When this disease is no longer
amenable to surgical curative intervention, uniformly
efficacious therapies are lacking. The aim of this study
was to evaluate the expression of potential molecular
therapeutic targets in a cohort of ASPS tumour samples.
Methods and results: Immunohistochemical analysis for
hepatocyte growth factor, c-Met, phosphorylated
c-Met, phosphorylated AKT, phosphorylated MEK,
epidermal growth factor receptor (EGFR), vascular
endothelial growth factor (VEGF), p53 and vimentin
was performed on an ASPS tissue microarray, yielding
complete data from 26 tumours. Activation of c-Met
and its downstream effectors was noted, whereas only
limited EGFR expression was seen. VEGF was expressed
to varying degrees. Only one sample exhibited strong
nuclear p53 expression, while 10 expressed low levels.
Vimentin expression was negative in the vast majority
of samples (96%).
Conclusions: There is a crucial need for better anti-ASPS
therapies. Activated c-Met and the phosphorylation of
its downstream effectors validate an intact signalling
cascade probably induced by the ASPSCR1–TFE3
chimeric transcription factor. The angiogenic phenotype
of these tumours is supported by increased
angiogenic factor expression. Combination therapies
targeting both tumour cells and angiogenesis merit
further investigation.
Keywords: alveolar soft part sarcoma, angiogenesis, ASPSCR1-TFE3, c-Met, HGF, VEGF
Abbreviations: ASPS, alveolar soft part sarcoma; EGFR, epidermal growth factor receptor; HGF, hepatocyte growth
factor; TMA, tissue microarray; UTMDACC, University of Texas M. D. Anderson Cancer Center; VEGF, vascular






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