Eradicating malignant brain tumors with “armed” Neural Stem Cells
TUGBA BAGCI ÖNDER, Ph.D.
Koç University School of Medicine
In addition to their applications in regenerative medicine, neural stem cells (NSCs) have recently been recognized as efficient delivery vehicles in a number of malignancies including brain tumors. Several studies have shown that engrafted NSCs have migratory abilities and are inherently tumor-tropic. Therefore, engineering NSCs to express tumor-specific cytotoxic reagents offers great potential in the treatment of the most malignant brain tumor type: glioblastoma multiforme (GBM). To this end, we have genetically engineered NSCs to express a secreted form of tumor necrosis factor related apoptosis-inducing ligand (S-TRAIL). Using live cell microscopy of NSC-GBM cell co-cultures, we have shown that NSCs expressing S-TRAIL induce caspase-mediated apoptosis in GBM cells. In addition, engraftment of therapeutic NSCs in the vicinity of tumors has led to efficient tumor eradication in solid and invasive mouse models of GBM, without affecting the normal brain. The anti-tumor potency of S-TRAIL is greatly dependent on the tumor specific expression levels of death receptors, DR4 and DR5. Therefore, identifying additional molecules that can modulate DR4/5 expression might sensitize TRAIL-resistant tumor populations to TRAIL and broaden the therapeutic utility of NSC-delivered S-TRAIL. To this end, we have identified several compounds, such as a PI3 Kinase inhibitor and a Histone Deacetylase inhibitor that can act in concert with NSC-delivered TRAIL. Our current research is directed towards identifying novel molecular players of TRAIL response as well as additional TRAIL-sensitizing compounds that can augment the efficacy of NSC-delivered TRAIL in GBMs. Together, combining engineered NSCs and small molecule inhibitors might serve as a novel therapeutic approach against these devastating cancers.