Sunitinib in advanced alveolar soft part sarcoma: evidence of a direct antitumor effect.

Abstract

BACKGROUND:

The purpose of this study was to confirm sunitinib activity in alveolar soft part sarcoma (ASPS) and to report on new insights into the molecular bases thereof.

PATIENTS AND METHODS:

From July 2007, nine patients with progressive metastatic ASPS received sunitinib 37.5 mg/day, within a named use program. Cryopreserved material was available for five naive patients, among whom three received sunitinib. Immunofluorescence (IF)/confocal microscopy, biochemical, and molecular/cytogenetic analyses were carried out, complemented by antiproliferative and activation assays in a short-term culture derived from one case.

RESULTS:

All patients were eligible for response. Best RECIST response was partial response in five cases, stable disease in three, and progression in one. The median progression-free survival was 17 months. Positron emission tomography results were consistent. Two cases of interval progressions were recorded. Antiproliferative assays and biochemistry on short-term culture showed that sunitinib is able to markedly impair ASPS cells growth and switch-off PDGFRB. IF/confocal microscopy demonstrated coexpression and physical association between PDGFRB/vascular endothelial growth factor receptor 2 (VEGFR2) and RET/VEGFR2 in ASPS cells, which was validated by biochemistry. PDGFRB, RET, and MET ligand-dependent activation was confirmed.

CONCLUSIONS:

We confirm the clinical efficacy of sunitinib in ASPS, mediated by PDGFRB, VEGFR2, and RET, which are all expressed in tumor cells. A direct antitumor effect was shown in a short-term cell culture.

• Authors: S Stacchiotti, T Negri, N Zaffaroni, E Palassini, C Morosi, S Brich, E Conca, F Bozzi, G Cassinelli, A Gronchi, P G Casali, S Pilotti
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology (Ann Oncol) Vol. 22 Issue 7 Pg. 1682-1690 (Jul 2011) ISSN: 1569-8041 [Electronic] England
• PMID: 21242589 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Indoles
• Pyrroles
• Proto-Oncogene Proteins c-ret
• RET protein, human
• Receptor, Platelet-Derived Growth Factor beta
• Vascular Endothelial Growth Factor Receptor-2
• Sunitinib

Topics

• Adult
• Antineoplastic Agents (therapeutic use)
• Blotting, Western
• Cell Proliferation (drug effects)
• Female
• Flow Cytometry
• Fluorescent Antibody Technique
• Follow-Up Studies
• Humans
• Immunoenzyme Techniques
• Immunoprecipitation
• In Situ Hybridization, Fluorescence
• Indoles (therapeutic use)
• Male
• Middle Aged
• Proto-Oncogene Proteins c-ret (genetics, metabolism)
• Pyrroles (therapeutic use)
• Receptor, Platelet-Derived Growth Factor beta (antagonists & inhibitors, genetics, metabolism)
• Retrospective Studies
• Sarcoma, Alveolar Soft Part (drug therapy, genetics, metabolism)
• Sunitinib
• Survival Rate
• Treatment Outcome
• Vascular Endothelial Growth Factor Receptor-2 (antagonists & inhibitors, genetics, metabolism)
• Young Adult