Glioblastoma multiforme (GBM) is the most malignant form of primary brain tumors, with a median survival time of approximately 14 months (1). Current treatments include surgery, radiation and chemotherapy. The chemotherapeutic agent used for GBM treatment is the DNA alkylating agent, temozolomide (TMZ). This drug is effective in combination with surgery and radiation or as a stand-alone chemotherapy (2). Unfortunately following treatment, tumors usually recur, and no longer respond to TMZ. Therapy options are then very limited. Therefore, the identification of a drug that is well-tolerated, cytotoxic for gliomas and able to cross the blood-brain-barrier would be extremely useful for the treatment of TMZ-resistant recurrent GBM.
Monoamine oxidase A (MAO A) is a mitochondrial-bound enzyme which catalyzes oxidative deamination of monoamine neurotransmitters such as serotonin, norepinephrine, dopamine and produces hydrogen peroxide (H2O2), a reactive oxygen species (ROS) which predisposes cancer cells to DNA damage, thereby promoting tumor initiation and progression. Previous studies in the inventors' lab showed that knock-down (KD) or pharmacological inhibition of MAO A in prostate cancer reduced or eliminated cancer progression (3). Clorgyline, a selective MAO A inhibitor (MAOI) which crosses the blood-brain-barrier (BBB), is used as an anti-depressant, and causes reduced prostate cancer growth in vivo. The clorgyline conjugate NMI significantly reduced tumor growth, and is selectively cytotoxic for cancer cells in vitro and in vivo, also crosses the BBB, and is visualized by near-infrared imaging useful for cancer diagnosis and monitoring cancer progression.
Increased MAO A expression has previously been reported in several cancers including prostate cancer and renal cell carcinoma (15, 16) and is down regulated in majority of human cancers, based on an ensemble of cancer GeneChip dataset (17). Previously, the inventors showed that elevated expressions of MAO A promoted prostate tumorigenesis, and induced epithelial-to-mesenchymal transition (EMT) in prostate cancer cells. Furthermore, inhibition of MAO A reduced the growth of LNCaP PCa cells in vitro and tumor xenograft in vivo (18, 3)
USPTO Backgrounds
USPTO Backgrounds