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Oncogene identified as viable drug target

21-Jan-2005

The identification of an oncogene, which is associated with cancers such as leukaemia, could lead to the development of targeted molecular therapeutics, controlling cancer development through regulation of the errant gene.

Oncogenes are genes that, when mutated or dysfunctional, lead normal cells to become cancerous. The investigators have named the gene POKEMON (for POK Erythroid Myeloid Ontogenic factor).

The discovery could also open the door to screening processes that can identify patients for treatment strategies as well as becoming a useful diagnostic marker as well as make it an attractive target for therapeutic intervention.

"There are a number of genes that can cause cancer, the so-called oncogenes, but Pokemon is unique in that it is needed for other oncogenes to cause cancer." said cancer geneticist Pier Paolo Pandolfi, senior author of the study, which took place at the Memorial Sloan-Kettering Cancer Centre (MSKCC).

"More important, because the Pokemon protein plays such a crucial role in the formation of cancer, it could prove to be an effective target for new drug therapies," he added.

Pokemon works by controlling the pathways required to transform normal cells to cancerous ones. The researchers found when they "knocked out" the Pokemon gene in mice, that transformation was blocked and cells do not become cancerous.

A drug that could block the protein's function in the same way could be a powerful anticancer agent.

"Pokemon is a main switch in the molecular network that leads toward cancer," Dr. Pandolfi added. "If we could turn Pokemon off, it may block this oncogenic circuitry and stall the malignant process."

Pokemon does its damage by repressing the function of other proteins, including a tumour suppressor called ARF. The mice developed aggressive, fatal forms of lymphoma.

In further work, using a technique called tissue micro arrays to study tumour samples from people with many types of cancer, they confirmed that Pokemon is present in very high levels in certain types of B-cell and T-cell lymphomas. They also found that tumours with high levels of Pokemon protein were much more likely to be aggressive.

"Pokemon is a member of a family of proteins that are known to be transcription factors and are mutated in human cancer," said Takahiro Maeda, a postdoctoral research fellow in Dr. Pandolfi's laboratory who was the paper's first author.

"It is likely that the protein plays a role in solid tumours as well, and we now have means to specifically interfere with the activity of these transcription factors," he added.

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