AE JD. Analyzed the data: RKK RAE CP JD. Contributed reagents/materials/analysis tools: RKK NvB RAE JD. Wrote the paper: RKK RAE JD. Despite CP-466722 CP466722 intensive treatment, approximately 30% of children with medulloblastoma die of their disease, whereas survivors often experience long term iatrogenic sequelae.New agents that are more effective and less toxic should be developed. As long as the molecular bases of tumorigenesis increase, new avenues for treating cancer are being explored. Because of the interplay between signaling pathways in tumor and tumor associated cells, the single targeted molecular agents are giving the way to agents able to concurrently inhibit multiple targets and biologic processes.
Aberrant signals through receptor tyrosine kinases, including those of the human epidermal receptor family, activate proliferation and prosurvival pathways that confer selective growth CAL-101 advantage to tumor cells. In addition, tumor cells require the formation of new vessels for nutrient and oxygen supplies. Numerous ligands are involved in Address all correspondence to: Tiziana Servidei, PhD, Department of PediatricOncology, Catholic University of Rome, Largo A. Gemelli, 8, 00168 Rome, Italy. E mail: [email protected] 1This work was supported by Fondazione per l,Oncologia Pediatrica and the Italian Association for the Fight against Neuroblastoma. The authors disclose any commercial affiliations or financial interests that may be considered conflicts of interest regarding this article. 2D.M. and T.S.
contributed equally in the experimental planning, data acquisition, and preparation of this article. Received 25 May 2010, Revised 25 May 2010, Accepted 14 June 2010 Copyright © 2010 Neoplasia Press, Inc. All rights reserved 1944 7124/10/$25.00 DOI 10.1593/tlo.10163 www.transonc.com Translational Oncology Volume 3 Number 5 October 2010 pp. 326 335 326 the coordinated processes that lead to angiogenesis, but vascular endothelial growth factor seems to play a pivotal role in controlling mitogenesis and survival of endothelial cells. VEGF binds to both VEGF receptor 1 and VEGFR2 on the surface of endothelial cells, VEGFR2 being, however, the main mediator of VEGF signaling. A functional link between HER family members and VEGF has been established.
Tumor cells can be stimulated by activation of HER1 to secrete VEGF, which, in turn, induces angiogenesis through paracrine mechanisms. HER2 has also been associated with increased angiogenic potential in experimental and clinical models. In breast cancer, HER2 signaling induced by ectopic overexpression of HER2 or ligand stimulation increases VEGF expression in vitro, and in biopsy specimens, HER2 expression positively correlates with VEGF. These data lend the experimental support for combined targeting of HER and VEGFR dependent pathways in clinical settings. One of the agents under development is AEE788, a member of the 7H pyrrolo class of pyrimidines, which inhibits tyrosine kinase activity of HER1/2 and VEGFR1/2 with similar affinity, thus potentially blocking both HER driven proliferation of tumor cells and vasculature neoformation mediated by VEGFRs. AEE788 has demonstrated antiproliferative activity against cell lines and xenografts from different tumors, such as carcinomas of lung, prostate, thyroid, and colon. Clinical trials