|開催日時：||2017年11月2日 １３：００ ～ １４：００|
|所属：||Laboratory of Genetics, Salk Institute for Biological Studies Staff Researcher|
|演題：||Targeting Tumor-derived Endothelial Cells and Hyper-invasiveness to Overcome Anti-VEGF Therapy Resistance in Glioblastoma Multiforme|
Glioblastoma multiforme (GBM) is one of the most vascularized tumors, and anti-angiogenic therapies have been widely used for GBM patients. Most patients, however, become resistant to anti-VEGF therapy after an initial response. Previously, we found that tumor-derived endothelial cells (TDECs), which are differentiated from tumor cells, form functional blood vessels and cause anti-VEGF therapy resistance. To overcome this resistance, we targeted TDECs as well as regular endothelial cells using brivanib, a dual inhibitor of VEGFR2 and FGFRs. As expected, brivanib successfully decreased the tumor size as well as the number of blood vessels including TDECs-forming vessels in GBM mouse models; however unexpectedly, it did not improve survival due to significant enhancement of tumor invasion. In the hyper-invasive tumor cells, focal adhesion kinase (FAK), which regulates integrin signaling, was activated. It was suggested that the interaction between integrin 1 and syndecans through overexpression of Chi3L1, which binds to syndecans, was involved in this process. Chi3L1 and integrin b1 expression was upregulated in hypoxic condition where we could see hyper-invasive tumor cells. Using hypoxia-inducible factor 1a (HIF-1a) conditional knock out mouse model, we found that a HIF-1-independent mechanism was responsible for the upregulation. To determine the effect of integrin signaling inhibition on angiogenesis and hyper-invasiveness in tumor development, we employed a FAK inhibitor TAE226 in combination with brivanib for GBM mouse treatment. As a result, this combination decreased the number of blood vessels and tumor size accompanied with significant extension of survival. These results suggested potential benefit of triple targeting of regular and TDEC angiogenesis and hyper-invasiveness in GBM therapy. We will also discuss new strategies for cancer treatment using 5-aminolevulinic acid.
|世話人：||〇東條 有伸 （分子療法分野）
谷 憲三朗 （ALA先端医療学）