2002 CTOS Annual Meeting Oral Presentations — Medical Oncology

GLEEVEC THERAPY IN C-KIT NEGATIVE SOFT TISSUE SARCOMAS: A MOLECULAR RATIONALE
[Abstract ID: 57]

Category: Medical Oncology

Presentation: Oral

Authors: Dafydd Gareth Thomas¹, Thomas J. Giordano¹, Robert S. Benjamin², Dennis A. Priebat³, Brian L. Samuels⁴, Sarah S. Bacus⁵, Laurence H. Baker¹

Author Institutions: ¹University of Michigan Cancer Center, Michigan, United States; ²UT MD Anderson Cancer Center, Texas, United States; ³Washington Cancer Institute, Washington, D.C., United States; ⁴Lutheran General Cancer Care Center, Illinois, United States; ⁵Ventana Medical Systems Inc, Illinois, United States

Presenter: Dafydd Gareth Thomas
Thomasda@umich.edu

Correspondent: Dafydd Gareth Thomas
Thomasda@umich.edu
Ann Arbor Michigan United States 48109-0602
Ph: 734.763.2475
Fax: 734.647.1358

Objectives: Imatinib mesylate (Gleevec) therapy has revolutionized the treatment of c-KIT positive soft tissue sarcomas (STS) such as GIST. The North American branch of the Connective Tissue Oncology Society is currently conducting a phase II trial of Gleevec in patients with advanced non-GIST STSs. Recently, a patient with advanced Malignant Fibrous Histiocytoma (MFH) responded dramatically to Gleevec therapy. Immunohistochemical analysis of the resected tumor demonstrated the absence of c-KIT and the presence of PDGFR a and its ligand PDGF-A. The phosphorylated form of AKT was also present. PDGFR a and b are membrane bound receptor tyrosine kinases (RTK), which are thought to be alternate targets for the RTK inhibitor, Gleevec. The genomic sequence for these RTKs share extensive homology with both c-KIT and c-ABL, especially in the region coding for the ligand-binding domain. PDGFR a and b, c-KIT and c-ABL are all strongly inhibited by Gleevec. AKT is a cytoplasmic serine/threonine kinase, which is a common target for RTK phosphorylation. It is involved in the regulation of cell survival.

Methods: In order to further determine which patients would benefit from empirical Gleevec therapy, sections of a tissue microarray (TMA) with multiple cores from eight different STS subtypes (rhabdomyosarcoma (n=15), leiomyosarcoma (n=8), liposarcoma (n=10), angiosarcoma (n=8), MFH (n=16), GIST (n=5), synovial sarcoma (n=12), and fibrosarcoma (n=11)) were stained using routine immunohistochemical stains for PDGFR a and b, c-KIT and AKT. Sections were also stained with antibodies specific for the phosphorylated form of AKT.

Results: Analysis of the data indicates that although PDGFR a and b are ubiquitous in distribution amongst STS, c-KIT immunoreactivity was only observed in GISTs, synovial sarcomas and angiosarcomas. AKT immunoreactivity was observed in 68 of 85 STS (80%). The phosphorylated form of AKT was seen in 68%, ranging from 36% in fibrosarcomas to 87.5 % in MFH.

Conclusions: These results suggest that adjuvant therapy with Gleevec is may be useful in c-KIT negative STSs, where activated forms of AKT is present. The results also provide a molecular rationale for the dramatic response seen in the c-KIT negative MFH patient undergoing therapy with Gleevec.