Therapeutic targeting of subdural medulloblastomas using human neural stem cells expressing carboxylesterase

Abstract

The prognosis of medulloblastoma has improved significantly because of advances in multi-modal treatments; however, metastasis remains one of the prognostic factors for a poor outcome and is usually associated with tumor recurrence. We evaluated the migratory potential and therapeutic efficacy of genetically engineered human neural stem cells (NSCs) that encode a prodrug enzyme in the subdural medulloblastoma model. We genetically modified HB1.F3 (F3) immortalized human NSCs to express rabbit carboxylesterase (rCE) enzyme, which efficiently converts the prodrug CPT-11 (Irinotecan) into an active anti-cancer agent (SN-38). To simulate clinical metastatic medulloblastomas, we implanted human medulloblastoma cells into the subdural spaces of nude mice. rCE expressing NSCs (F3.rCE) were labeled with fluorescence magnetic nanoparticle for in vivo imaging. The therapeutic potential of F3.rCE was confirmed using a mouse subdural medulloblastoma model. The majority of intravenously (i.v.) injected, F3.rCE cells migrated to the subdural medulloblastoma site and a small number of F3.rCE cells were found in the lungs, pancreas, kidney and liver. Animals that received F3.rCE cells in combination with prodrug CPT-11 survived significantly longer (median survival: 142 days) than control mice that received F3.rCE cells only (median survival: 80 days, Po0.001) or CPT-11 only (median survival: 118 days, Po0.001). In conclusion, i.v. injected F3.rCE NSCs were able to target subdural medulloblastomas and demonstrate therapeutic efficacy. Our study provides data that supports further investigation of stem-cell-based gene therapy against metastatic medulloblastomas.

Human Neural Stem Cells Overexpressing a Carboxylesterase Inhibit Bladder Tumor Growth

“…F3.CE cells were used to treat various cancer cell types (subdural medulloblastomas, breast cancer, and lung cancer). These previous studies also reported the tropism of stem cells to cancer cells (16)(17)(18).…”

In vivo bioluminescence imaging for leptomeningeal dissemination of medulloblastoma in mouse models

“…Therefore, the establishment of an effective MB seeding model and the evaluation of the extent of tumor spread in live conditions are essential for studies on innovative therapeutics. For MB xenograft mouse models, four different injection routes have been introduced: intracerebral, subdural, intracerebellar, and intracisternal [4, 7, 9, 10]. Intracerebral and subdural (into the supratentorial subdural space) injections of MB cells have inherent limitations to identify MB characteristics in vivo because MB develops in or around the cerebellum and spreads via subarachnoid spaces.…”

“…Several methods have been described to establish the MB seeding model and involve transplanting human MB cells into the mouse cerebrum [7], cerebellum [8], subdural space [9], or cisterna magna [4, 10, 11]. However, each method possesses some limitations, such as the risks of surgical techniques, complexity of quantitative analysis in live animals, and difficulties of precisely simulating MB characteristics.…”

Tumor-specific gene therapy for pancreatic cancer using human neural stem cells encoding carboxylesterase

“…In turn, SN-38 preferentially kills dividing cancer cells specifically at the tumor sites [30]. We have previously reported that F3.CE cells migrate selectively to tumor sites and they have a therapeutic effect on disseminated neuroblastoma [26, 30], melanoma [28], ovarian cancer [19], breast cancer brain metastasis [17] and medulloblastoma [29] upon administration of prodrug CPT-11. Recently we also have reported that the NSCs expressing the cytosine deaminase (CD).…”