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About SickKids

August 15, 2005

Researchers discover mechanism of tumour cell survival

Researchers at The Hospital for Sick Children (SickKids) have discovered a mechanism of tumour cell survival in a hypoxic environment, which may lead to new treatment options for patients with neuroblastoma. This research was reported in the August 15 edition of Cancer Research.

Tumour hypoxia is a lack of oxygen to the tumour. It contributes to drug resistance and angiogenesis (formation of new blood vessels) which ultimately lead to tumour aggressiveness and treatment failure. Drug resistance and angiogenesis are two important pillars of failure to treat neuroblastoma.

“We studied two signalling pathways in neuroblastoma, a childhood tumour originating from peripheral nervous system, and found that two proteins, MAPK (Mitogen Activated Protein Kinase) and HIF-1alpha (Hypoxia-Inducing Factor-1alpha), were linked to drug resistance and angiogenesis,” said Dr. Sylvain Baruchel, the study’s principal investigator, Staff Oncologist at SickKids, director of the New Agents and Innovative Therapies Program, a SickKids senior associate scientist in Cancer Research and an professor of paediatrics at The University of Toronto. “We found that both pathways are activated by an angiogenic growth factor called VEGF (Vascular Endothelial growth factor). During hypoxia, VEGF interacts with HIF and MAPK leading to drug resistance and angiogenesis.”

Baruchel and his team also showed that by targeting the VEGF pathway in vitro with antibodies against VEGF or a molecule such as ursolic acid, the hypoxia-mediated drug resistance could be reversed and angiogenesis could be modified in animal models. This work gives new insight into the hypoxia related tumour aggressiveness and treatment failure in neuroblastoma, and suggests that anti-VEGF drugs may be helpful in treating neuroblastoma patients.

“Our finding is the first step in the development of a new strategy to target tumour cells living under hypoxic condition,” says Dr. Bikul Das, lead author on the paper, a graduate student in the Institute of Medical Science at the University of Toronto. “We have already found that ursolic acid, a molecule found in Indian holy basil, can reverse hypoxia-mediated drug resistance and angiogenesis.”

The findings also suggest that anti-VEGF drugs may have potential to treat neuroblastoma patients.

“We are now investigating the hypoxia-related drug resistance in other childhood tumours such as rhabdomyosarcoma, osteosarcoma, medulloblastoma and Ewing’s sarcoma. More studies on neuroblastoma, are also planned, testing ursolic acid as a new drug against hypoxia-mediated drug resistance,” said Dr. Herman Yeger, the study’s co-principal study investigator, SickKids senior scientist in Cancer Research and an associate professor of Laboratory Medicine & Pathobiology at The University of Toronto.

This research was supported by the James Birrell Neuroblastoma Research Fund, B.R.A.I.N. Child, the Andrew Mizzoni Cancer Research Fund, the National Cancer Institute of Canada with funds from the Terry Fox Foundation, and SickKids Foundation.

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The Hospital for Sick Children