Resistance to anti-angiogenic therapy in pediatric solid tumors.
Institution:Feinstein Institute for Medical Research - North Shore
Researcher(s):Samuel Soffer, MD
Grant Type:Young Investigator Grants
Type of Childhood Cancer:Wilms Tumor
Anti-angiogenic therapies are a novel treatment modality for many adult and pediatric cancers and use of anti-angiogenic agents in the adult clinical world has already begun. In prior work done at Columbia University, Dr Soffer and his colleagues have shown that antibody to Vascular Endothelial Growth Factor (VEGF), the most important of a large cadre of angiogenic factors, blocks tumor growth in both Wilms tumor and neuroblastoma. This anti-VEGF agent, Bevacizumab, is in current clinical use in the treatment of metastatic colon cancer. However, we have also shown in the lab that prolonged treatments with anti-VEGF strategies leads to aberrant blood vessel formation and tumor recurrence. The PIK/Akt signaling pathway functions downstream of VEGF to promote endothelial cell survival. Akt1 expression is required for the pathologic angiogenesis seen in animal models and is directly phosphorylated by the mammalian target of rapamycin (mTOR), which also regulates VEGF-induced tumor angiogenesis. The mTOR pathway was defined and can be effectively blocked by the immunosuppressant rapamycin, which may have intrinsic anti-angiogenic properties as well. The ability to block endothelial mTOR with rapamycin may provide an attractive herapeutic option, since it may circumvent the need to block multiple individual proangiogenic factors which each activate PI3K/Akt/mTOR in endothelium. Thus, we hypothesize that Akt and mTOR play critical roles in tumor angiogenesis in human Wilms tumor and in particular resistance to prolonged anti-VEGF treatment. Furthermore, blockade of these molecules using rapamycin in addition to VEGF blockade, will yield a more durable tumor suppression.