Methylthioadenosine Phosphorylase and Activated Insulin-Like Growth Factor 1-Receptor: Potential Therapeutic Targets in Chordoma
JB Sommer, DM Itani, KC Homlar, SJ Olson, GE Holt, HS Schwartz, CM Coffin, MJ Kelley, JM Cates. Duke University Medical Center, Durham, NC; Vanderbilt University Medical Center, Nashville, TN; Vanderbilt Orthopaedic Institute, Nashville, TN
Background: Chemotherapeutic protocols are largely ineffective against chordoma. Advances in targeted molecular therapy, coupled with increased understanding of the molecular pathogenesis of chordoma, may be applicable in the systemic treatment of this aggressive disease. Recent studies have reported co-expression of the insulin-like growth factor-1 receptor (IGF1R) and its ligand in chordoma, but it is unknown whether this receptor tyrosine kinase is activated. Genetic studies have confirmed deletions of chromosome 9p in a subset of chordomas. One of the genes in this region, methylthioadenosine phosphorylase (MTAP) is an essential enzyme in the purine salvage pathway, and is of potential therapeutic relevance because MTAP-deficient cells are sensitive to inhibitors of de novo purine synthesis, such as pemetrexed.
Design: Archived chordoma samples (23 conventional chordomas, 5 chondroid chordomas, and 1 dedifferentiated chordoma), 2 benign notochordal cell tumors (BNCT), and 3 samples of human notochord (17 to 28 weeks gestational age) were stained for the activated isoform of IGF1R (phosphorylated at Y1161) and MTAP by immunohistochemistry (IHC). Cytoplasmic MTAP staining was scored as either negative (MTAP-deficient) or positive. Phospho-IGF1R was scored as positive if there was any specific membranous staining of tumor cells. Overall and disease-free Kaplan-Meier survival curves were compared using the log-rank test.
Results: Phospho-IGF1R was detected in 48% of conventional chordomas. Activated IGF1R was not observed in chondroid chordoma, BNCT, or fetal notochord. Overall, 38% of chordomas were deficient for MTAP by IHC analysis. Patients with phospho-IGF1R-positive tumors had decreased median disease-free survival (15.2 months vs. 48.1 months for negative tumors, p=0.029). MTAP status did not predict overall or disease-free survival.
Conclusions: A significant subset of chordomas demonstrates activation of IGF1R or loss of a key enzyme in the purine salvage pathway. A tendency toward shorter disease-free interval was noted for chordomas with activated IGF1R. Aberrant signaling cascades and disrupted metabolic pathways in chordoma may represent targets for molecular pharmacotherapy in selected susceptible patient populations.
Category: Bone & Soft Tissue
Tuesday, March 10, 2009 9:30 AM
Poster Session III # 13, Tuesday Morning