Specific Targets in Sarcoma (review article - includes ASPS)

[Fictional]

Brock and I do Medscape for our CME and this article (attached) came up for a review of specific targets in Sarcoma.

I'll attach the 2 paragraphs that include specific mention of ASPS. It's the VEGF inhibitors and Met again. It was surprising to me to see mention of Sutent's efficacy independent of VEGF2. Maybe that's why XL880 didn't work for some ASPS patients. The mTORs also theoretically looked good on paper, but they look fairly disappointing according to the review. It might be that the newer agents (e.g. TORC 1 + TORC 2 inhibition) may be more effective - but the rebound effects like other antiangiogenesis agents - needs to be watched.
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In a series of 4 evaluable patients with advanced alveolar soft part sarcoma (ASPS), treatment with sunitinib resulted in radiographic responses in 2 patients and stable disease in 1.[40] A biochemical analysis of frozen samples from these patients showed activation of VGFR2 in only 1 tumor, whereas other kinases sensitive to sunitinib were active, suggesting that the VEGFR pathway may not be a therapeutic target in this disease. However, early clinical studies of the more-selective VEGFR inhibitor cediranib have shown this agent to have significant activity against ASPS.[41] Of 7 patients treated in 2 studies, 4 experienced partial responses, 2 experienced minor responses, and 1 had stable disease. These observations suggest that further study of the role of VEFGR inhibition in ASPS is warranted.

MET expression and activation has been shown in several sarcoma subtypes, including clear cell sarcoma (CCS), ASPS, alveolar rhabdomyosarcoma (aRMS), and osteosarcoma.[43–54] With CCS and ASPS, MET expression seems to be driven at least partly by the activity of the MITF or TFE3 transcription factor oncogenes. In CCS, MITF is overexpressed as a direct transcriptional target of the pathognomonic EWRS1–ATF1 fusion gene product, which binds and activates the MITF promoter. MITF then induces expression of various genes, including MET. CCS cell lines and tumors also express high levels of HGF, and inhibition of HGF/MET binding or of MET activity itself significantly impairs CCS proliferation in vitro and in vivo. Similarly, TFE3, the product of the gene characteristically translocated in ASPS, has been shown to transcriptionally up-regulate MET expression. These findings have provided the rationale for a phase II multi-institutional study of the investigational MET inhibitor ARQ197 in patients with advanced CCS and ASPS. With accrual ongoing, a partial response was reported in 1 patient with advanced CCS, and prolonged disease stability noted in several patients with ASPS, although this may be difficult to distinguish from the natural history of this often indolent disease.