Targeting sonic hedgehog-associated medulloblastoma through inhibition of Aurora and Polo-like kinases.
Medulloblastoma is the most common malignant brain tumor in children. Although aggressive surgery, radiation, and chemotherapy have improved outcomes, survivors suffer severe long-term side effects, and many patients still succumb to their disease. For patients whose tumors are driven by mutations in the sonic hedgehog (SHH) pathway, SHH antagonists offer some hope. However, many SHH-associated medulloblastomas do not respond to these drugs, and those that do may develop resistance. Therefore, more effective treatment strategies are needed for both SHH and non-SHH-associated medulloblastoma. One such strategy involves targeting the cells that are critical for maintaining tumor growth, known as tumor-propagating cells (TPC). We previously identified a population of TPCs in tumors from patched mutant mice, a model for SHH-dependent medulloblastoma. These cells express the surface antigen CD15/SSEA-1 and have elevated levels of genes associated with the G2-M phases of the cell cycle. Here, we show that CD15(+) cells progress more rapidly through the cell cycle than CD15(-) cells and contain an increased proportion of cells in G2-M, suggesting that they might be vulnerable to inhibitors of this phase. Indeed, exposure of tumor cells to inhibitors of Aurora kinase (Aurk) and Polo-like kinases (Plk), key regulators of G2-M, induces cell-cycle arrest, apoptosis, and enhanced sensitivity to conventional chemotherapy. Moreover, treatment of tumor-bearing mice with these agents significantly inhibits tumor progression. Importantly, cells from human patient-derived medulloblastoma xenografts are also sensitive to Aurk and Plk inhibitors. Our findings suggest that targeting G2-M regulators may represent a novel approach for treatment of human medulloblastoma.
Authors' Affiliations: Tumor Initiation and Maintenance Program, National Cancer Institute (NCI)-Designated Cancer Center, Sanford-Burnham Medical Research Institute; Sanford Consortium for Regenerative Medicine; Departments of Pediatrics, Neurosciences, and Neurosurgery, University of California San Diego, La Jolla; Rady Children's Hospital, San Diego, California; Departments of Pharmacology and Cancer Biology, Medicine, Division of Pulmonary, Allergy, and Critical Care, Pediatrics, Division of Pediatric Hematology/Oncology, and Surgery, Duke University Medical Center, Durham, North Carolina; German Cancer Research Center (DKFZ), Heidelberg, Germany; and Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Shirley L
SL
Markant
Lourdes Adriana
LA
Esparza
Jesse
J
Sun
Kelly L
KL
Barton
Lisa M
LM
McCoig
Gerald A
GA
Grant
John R
JR
Crawford
Michael L
ML
Levy
Paul A
PA
Northcott
David
D
Shih
Marc
M
Remke
Michael D
MD
Taylor
Robert J
RJ
Wechsler-Reya
D000818:Animals; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000097869:Polo-Like Kinase 1
D064096:Aurora Kinase A; D018797:Cell Cycle Proteins; D053823:Hedgehog Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D000097869:Polo-Like Kinase 1