Hits and misses in targeting pediatric cancers

Gastrointestinal stromal tumors (GISTs) are neoplasms of the interstitial cells of Cajal (ICCs), first described in the early 1980s 1. Gain-of-function mutations of c-KIT as a cause of these tumors were first postulated based on the converse: loss-of-function mutations caused depletion of ICCs in mouse models. The linkage between c-KIT mutation and GIST was definitively demonstrated subsequently in human tumors 2. About 85% of GISTs in adults have c-KIT mutations. A further 5–10% of adult GIST have gain-of-function mutations in platelet-derived-growth-factor (PDGF)-alpha 2. At around the same time these mutations were being described, imatinib, an inhibitor of several tyrosine kinases, including c-KIT and PDGF-alpha was being developed by a team at Novartis. Pre-clinical testing demonstrated the activity of imatinib against GIST cell lines and a primary GIST culture from a surgical resection specimen 3. GISTs are poorly responsive to cytotoxic chemotherapy. Prior to the development of tyrosine kinase inhibitors, only surgery was effective in their treatment. It was therefore reasonable to test the effectiveness of imatinib in patients with unresectable or metastatic GIST. The results of a randomized phase II study comparing two dose levels of imatinib showed good activity with little difference between the study arms, with median time to progression of 24 months, and median duration of survival of 57 months 4. Similar results were reported by the same group in a larger phase III study: median progression-free survival 18 months, median overall survival 55 months 5. The best results were in patients whose tumors harbored c-KIT exon 11 mutations (median survival 63 months), a finding confirmed by the same group in a correlative study of kinase genotype and clinical outcome 6. A small group of 13 patients had tumors which were histologically GISTs, but c-KIT-negative. While those patients responded to initial therapy with imatinib, they had significantly shorter overall survival than did patients whose tumors were c-KIT-positive (31 vs. 53 months, P = 0.02) 4. Patients whose tumors expressed wild-type c-KIT had an inferior outcome when compared with those whose tumors had an exon 11 c-KIT mutant protein 6. Pediatric patients have GISTs which express non-mutated (wild-type) c-KIT 7. The study by Janeway et al. reported in this issue includes a small series of pediatric patients and demonstrates that pediatric patients have short-lived responses to imatinib, and generally longer responses to the multi-targeted receptor tyrosine kinase inhibitor sunitinib 8. Adult GIST patients with wild-type c-KIT similarly have relatively favorable responses to sunitinib 9. The responses to imatinib reported in GIST are shorter lived than in chronic phase chronic myeloid leukemia (CML). Imatinib results in 97% complete hematologic response in patients with chronic phase CML and complete cytogenetic response in 82% (reviewed 10). Estimated 5-year progression free survival is 84%, estimated 5-year survival without progression to accelerated or blast phase is 93%, and 95% of patients survive 5 years, if deaths unrelated to CML are excluded 10. Life expectancy from the institution of therapy with imatinib in chronic phase CML patients has been estimated at 19 years 11. Similar results have been seen in children and youth, in whom CML seems to be biologically identical to that in adults 12. This is in contrast to the difference in molecular pathogenesis noted above for GIST. PDGF-alpha is expressed by many Ewing sarcoma cells, as is c-KIT. Imatinib demonstrated tumor kill in pre-clinical models of Ewing sarcoma 13, although questions were raised as to the mechanism of cytotoxicity. In CML cells, drug levels causing inhibition of the BCR/ABL oncogene were similar to those causing cell kill, whereas in Ewing, far higher levels were needed to kill cells than to inhibit c-KIT or PDGF-alpha, suggesting that their expression are not strictly linked to malignant cell survival 14. A Children's Oncology Group phase II study confirmed the absence of clinical activity of imatinib in patients with recurrent Ewing sarcoma 15. However, recent in vitro studies in Ewing cell lines have shown synergy of the combination of imatinib and an insulin-like growth factor I receptor inhibitor 16. We are beginning to understand the molecular basis of cancer, and beginning to unravel the similarities and differences in cancers of similar histology in adults, children, and youth. We are also beginning to target some of those cancers effectively based on understanding the underlying molecular biological mechanisms. The examples discussed show that there is much still to learn as we translate new findings in the laboratory into more effective therapies.

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