Abstract B46: Targeting tumor-propagating cells in medulloblastoma through inhibition of G2/M cell cycle regulators

Abstract

Abstract Medulloblastoma is the most common malignant brain tumor in children. While the current treatment strategy of surgery plus radiation has a 60–80% cure rate, the survivors suffer severe side effects, including growth delays and cognitive deficits. Therefore, more effective, less toxic treatments are needed. One approach to achieving this is targeting the cells within a tumor that are capable of re-populating the tumor, known as tumor-propagating cells (TPCs). These cells are thought to be responsible for tumor resistance to conventional therapies. In the patched mutant mouse model of medulloblastoma, TPCs are marked by expression of the cell surface carbohydrate antigen CD15. Our previous studies have suggested that CD15+ cells display increased expression of genes associated with the G2/M phases of the cell cycle. Cell cycle analysis suggests that CD15+ cells move quickly through the G1 and S phases of the cell cycle, but accumulate in the G2/M phases. This accumulation in G2/M may represent a vulnerability of CD15+ TPCs, and inhibition of G2/M regulators, such as Aurora kinases, may represent one approach for targeting TPCs and overcoming therapeutic resistance. Treatment of tumor cells from patched mutant mice or human Hedgehog-associated medulloblastoma with Aurora kinase inhibitors in vitro leads to inhibition of proliferation, arrest in G2/M and apoptosis. Furthermore, in vivo treatment of tumor-bearing mice with Aurora kinase inhibitors significantly delays tumor progression and prolongs survival. Our findings suggest that targeting Aurora kinases in TPCs may represent a new approach for the treatment of human medulloblastoma.