Glioblastoma

Glioblastoma (GBM) is an incurable brain cancer. A major reason for the dismal prognosis is the existence of brain tumor-initiating cells (BTICs), which are self-renewing chemo- and radio-resistant cancer stem cells that lead to tumor recurrence and progression despite treatment. We discovered that the immune defense cells of the CNS, microglia, and their circulating counterparts, monocytes (which become macrophages in tissues), are highly effective at reducing BTIC growth in culture but that this competency is lost in monocytes, macrophages and microglia (collectively referred to as myeloid cells) from GBM patients. My research project screened a library of 1,040 medications and discovered a compound that promotes myeloid cells activity to reduce BTIC growth in culture: niacin (vitamin B3).  In mice with intracranial syngeneic or patient-derived BTICs, niacin elevates myeloid cells in brain tumor, reduces tumor volume on MRI and histology, and significantly prolongs survival of tumor-bearing mice. My current research work attempts to investigate the mechanisms and determinants of niacin in suppressing BTIC growth and test the overarching hypothesis that the compromised myeloid cells in patients with GBM can be reinvigorated by niacin to control the tumorigenecity of BTICs. I seek to mobilize the normally protective immunity to improve the prognosis of GBM.  To translate the laboratory data to the clinic, a multi-disciplinary proposal that spans the laboratory to a Phase 1/2 clinical trial has been proposed.

Researcher: Susobhan Sarkar

Glioblastoma (GBM) is a devastating brain tumor that has been difficult to treat and continues to be resistant to the current treatments directed at it.  An important and novel approach would thus be to rejuvenate the compromised immune cells such as T cells to contain GBM cells.  Checkpoint inhibitors that target the PD-1 and PD-L1 lock-and-key interaction reverse T cell exhaustion and reanimate anti-cancer T cells, thus enabling the patient’s immune system to curb tumor growth. However, PD-1 checkpoint blockade therapy in GBMs is still under debate, and clinical trials with anti-PD1 antibodies have not been successful in GBMs. Part of the reason for this limited success may be because of relatively low T cell infiltration within the GBM microenvironment. More importantly, the blood-brain barrier (BBB) is a significant impediment to the penetration of antibodies into the CNS. My project aims to overcome these obstacles in GBM patients and identify novel approaches for new immunotherapies that can abrogate PD-1 functions within the tumor microenvironment and ameliorate brain tumors. 

Researcher: Reza Mirzaei