Date Published: July 10, 2018
Publisher: Public Library of Science
Author(s): Onyinyechukwu Okolie, David M. Irvin, Juli R. Bago, Kevin Sheets, Andrew Satterlee, Abigail G. Carey-Ewend, Vivien Lettry, Raluca Dumitru, Scott Elton, Matthew G. Ewend, C. Ryan Miller, Shawn D. Hingtgen, Joseph Najbauer.
Cytotoxic neural stem cells (NSCs) have emerged as a promising treatment for Medulloblastoma (MB), the most common malignant primary pediatric brain tumor. The lack of accurate pre-clinical models incorporating surgical resection and tumor recurrence limits advancement in post-surgical MB treatments. Using cell lines from two of the 5 distinct MB molecular sub-groups, in this study, we developed an image-guided mouse model of MB surgical resection and investigate intra-cavity NSC therapy for post-operative MB.
Using D283 and Daoy human MB cells engineered to express multi-modality optical reporters, we created the first image-guided resection model of orthotopic MB. Brain-derived NSCs and novel induced NSCs (iNSCs) generated from pediatric skin were engineered to express the pro-drug/enzyme therapy thymidine kinase/ganciclovir, seeded into the post-operative cavity, and used to investigate intra-cavity therapy for post-surgical MB.
We found that surgery reduced MB volumes by 92%, and the rate of post-operative MB regrowth increased 3-fold compared to pre-resection growth. Real-time imaging showed NSCs rapidly homed to MB, migrating 1.6-fold faster and 2-fold farther in the presence of tumors, and co-localized with MB present in the contra-lateral hemisphere. Seeding of cytotoxic NSCs into the post-operative surgical cavity decreased MB volumes 15-fold and extended median survival 133%. As an initial step towards novel autologous therapy in human MB patients, we found skin-derived iNSCs homed to MB cells, while intra-cavity iNSC therapy suppressed post-surgical tumor growth and prolonged survival of MB-bearing mice by 123%.
We report a novel image-guided model of MB resection/recurrence and provide new evidence of cytotoxic NSCs/iNSCs delivered into the surgical cavity effectively target residual MB foci.
Medulloblastoma (MB) is the most common primary brain tumor in children [1, 2]. Molecular analysis has now shown that MB can be sub-divided into 5 molecular subtypes, with distinct transcriptional and epigenetic signatures. Standard MB treatment consists of maximal surgical resection followed by radiation and adjuvant multi-drug chemotherapy [3, 4]. This treatment yields a 5-year survival rate of 60–70% , but the nature of these treatments causes damage to the developing brain, and often leaves survivors suffering long-term neurological and developmental defects. In the set of children for which MB remains fatal, the highly aggressive nature of MB cells allows the cancer to evade surgical resection and escape chemo-radiation treatment [7, 8]. There is a significant need to develop new therapies to target the residual MB cells that remain after surgery, without the adverse effects on the non-diseased developing brain caused by current treatment strategies. Developing accurate pre-clinical models to test these therapies will be critical to ensure these new treatment strategies are efficacious in eventual patient testing.
Medulloblastoma (MB) is the most common childhood brain malignancy with a peak incidence at 7 years of age. Despite technological advances in the standard of care, nearly all patients who survive experience debilitating side-effects.[2, 3, 36] Thus, there remains an urgent need to minimize the life-changing side effects of treatment by providing alternative therapies. In this study, we developed a new MB resection and recurrence model to determine the impact of surgery on tumor recurrence and evaluate cytotoxic NSCs as a potential therapeutic approach. Using this model, we show that intracavity NSC therapy is effective against MB and may provide a method to control the post-operative disease in humans.