Therapeutic Efficacy of NM404 Analogs against Glioblastoma Cancer Stem Cells

Glioblastomas (GBM) are the most common and deadly primary tumors of the central nervous system, with median survival only 14 months after diagnosis. Even with surgical removal and radio- and chemo-therapy, GBMs inevitably recur due to therapeutically resistant cancer cells.  Cancer stem cells (CSC) are a small sub-population of GBM cells hypothesized to be responsible for tumor growth, therapeutic resistance, and recurrence. Cancer stem cell targeted therapies could eliminate cancer by killing the cells driving tumor growth and recurrence. NM404 is a novel phospholipid ether analog being tested as a diagnostic and therapeutic agent in multiple cancers. NM404 may exert therapeutic benefit through inhibition of AKT, which is an oncogene implicated in GBM initiation and propagation. Therefore, we evaluated NM404 therapeutic efficacy toward CSCs. We tested various concentrations of NM404 on cancer stem cells and normal neural stem cells. A dose response curve was calculated to identify any effects of NM404 on the viability and proliferation of the cells. We examined NM404-mediated AKT signaling modulation using immunoblotting. After 24 hour administration followed by removal of NM404, GSCs and neural stem cells as well was collected up to 2 weeks. NM404 decreased GBM CSC proliferation and survival, with minimal lethality to normal stem and neural cells. NM404 inhibits activation of AKT, a key protein involved in GBM CSC self-renewal, proliferation, and survival. Results suggest that NM404 is efficacious in therapeutically targeting CSCs that drive tumor growth and recurrence, and could be a novel therapy in improving survival of patients with GBM.