Sun Jin kim
University of Texas,USA
Dr. Sun Jin Kim received MD in 1986 and PhD in 1993 from the College of Medicine and the Graduate School of Seoul National University. He completed the residency in the Seoul National University Hospital and postdoctoral fellowship in the University of Texas MD Anderson Cancer Center. He was an invited scientist in the National Cancer Center Research Institute, Tokyo, Japan. He is a professor in the Department of Cancer Biology, UTMDACC and has published more than 80 papers in peer-reviewed journals. He has been involved in clinical translational research programs developing the clinical trials of novel molecules and protocols.
rnThe median survival of patients with the primary or metastatic brain tumor is limited due to resistance to all standard therapies. The mechanism of pan-resistance against the systemic therapy has been attributed to the blood-brain-barrier and/or p-glycoprotein, which prevent the drugs from reaching the brain lesions. We have recently reported that activated astrocytes and endothelial cells establish gap-junction communication channel with the tumor cells and protect tumor cells from chemotherapeutic agents by a mechanism involving the phosphorylation of endothelin receptors on tumor cells leading to up-regulation of multiple genes, among which are survival or anti-apoptotic genes. We translated in vitro observation into the preclinical in vivo models that nude mice bearing orthotopic human glioblastoma or metastatic human breast or lung cancers in brain were treated by the blockade of the endothelin axis, using the dual antagonist, macitentan, combined with taxol or temozolomide. The combination therapy significantly regressed the established primary or metastatic brain tumors and prolonged the disease free survival of mice for months after mice in other treatment groups died. Immunohistochemical analysis demonstrated that treatment with macitentan inhibited phosphorylation of the endothelin receptors A and B on tumor cells and tumor-associated endothelial cells. The addition of chemotherapeutic agents produced massive apoptosis in both tumor cells and dividing tumor-associated endothelial cells.rnInhibition of endothelin receptor phosphorylation on both tumor cells and tumor-associated endothelial cells inhibits survival pathways in these cells, which enhances their sensitivity to chemotherapy. Macitentan plus chemotherapy is well tolerated, produces durable responses, and clinical evaluation is ongoing.rn