Alveolar soft part sarcomas: molecular pathogenesis and implications for novel targeted therapies

Abstract

Alveolar soft part sarcoma (ASPS) is a very rare soft tissue sarcoma which arises primarily in children and young adults. Despite its unique histology and well-characterized genetic translocation, many questions remain regarding the pathogenesis and treatment of this tumor type. Though collective clinical experience with this tumor type spans more than 60 years, there has been little progress made in treating this uncommon but frequently fatal disease. This paper focuses on the available data regarding its molecular pathogenesis and insights into targeted therapeutics as well as the results of clinical trials performed to date to hopefully improve the outcome of patients with this rare malignancy.

Figure 1

The t(X;17)(p11;25) translocation. (a) The ASPSCR-1 gene is located at chromosome 17q25 and the TFE3 gene at Xp11. The breakpoint found in the ASPSCR-1 gene is marked at “1”, and the two defined breakpoints in the TFE3 gene are marked “2” and “3”. (b) Following translocation, two variants of the ASPSCR-1-TFE3 fusion gene can be created. The Type 1 translocation retains the N-terminal activation domain of the TFE3 gene.

Figure 2

Signaling schematic for ASPS tumors and novel therapeutic targets. (a) Overexpression of the MET tyrosine receptor kinase is induced by the ASPSCR1-TFE3 fusion protein. This leads to intracellular activation of the promitotic growth kinases Akt and MEK1/2; these in turn lead to unchecked cellular proliferation. (b) Targets for novel therapeutics include the VEGF tyrosine kinase receptor and its ligand (Recentin and Avastin, resp.), as well as tumor cell receptor tyrosine kinases (Sutent, Nexavar, and ARQ 197). Perifosine is a unique inhibitor of the Akt kinase.