Pharmacodynamic case study of sunitinib/SU11248 in a gastrointestinal stromal tumor patient: Evidence toward a mechanism of effect

9526 Background: Despite abundant pre-clinical data, the mechanisms of action in humans of multi-targeted small molecule tyrosine kinase inhibitors against sarcomas remain unclear. Herein, we sought evidence from pre- and post-treatment biospies to suggest whether the primary mechanism of action of sunitinib/SU11248 is anti-angiogenic or rather a direct anti-tumor cell effect. Methods: We report data regarding a 59 year old woman with imatinib-resistant GIST who demonstrated a marked tumor response to sunitinib treatment. Her gastric primary GIST tumor was previously resected, followed by recurrence one year later. A complete remission lasting 24 months was then attained on imatinib therapy. After progression of disease, sunitinib was started at 50 mg orally per day. A major clinico-radiographic response was seen after 12 months of therapy, followed by resection. To assess the pharmacodynamic effects of sunitinib, we undertook immunohistochemical analysis of formalin-fixed tissue sampled immediately prior to treatment and just after completing sunitinib, using anti-CD117, anti-CD34, or anti-CD31 antibodies, respectively. Results: We found a dramatic effect of sunitinib on the tumor parenchyma. Whereas the pretreatment biopsy revealed viable, mitotically active, CD117+ and CD34+ tumor cells, the post-treatment specimen was >90% sclerotic and necrotic. The CD31+ blood vessels appeared robust both pre- and post-treatment. Vessel counts did not differ significantly before and after treatment by CD31 staining (3.3±2.0 per field vs. 1.8±1.3, p= 0.09). Thus, the tumor cells were largely eliminated with sunitinib treatment, while blood vessels were still present after 12 months of therapy. Conclusions: This observation supports the assertion that the mechanism of sunitinib in GIST is predominantly cytotoxic against the tumor by directly targeting KIT and that an anti-angiogenic effect, either through the VEGF-R2 in endothelium or through the PDGF-R in pericytes, may be secondary. [Table: see text]