Brain Disorders & Therapy

Targeting the microenvironment for therapy of primary and metastatic brain tumors

International Conference on Neuro Oncology and Rehabilitation

July 21-22, 2016 Brisbane, Australia

Sun Jin Kim

The University of Texas MD Anderson Cancer Center, USA

Posters & Accepted Abstracts: Brain Disord Ther

Abstract:

The 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 regress 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. Inhibition 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.

Biography :

Email: sunkim@mdanderson.org