Genetic alteration in HNC may not be key to effective treatment

Although a large majority of head and neck cancers (HNC) have a deregulation of the PI3K/AKT/mTOR pathway, deregulation of this pathway does not necessarily signify that the tumor is dependent on it for survival and progression, according to a new study in Cancer Research (January 29, 2013).

Cancer, particularly HNC, is highly heterogeneous, with a large number of genetic alterations rendering it resistant to specific targeted treatments. Because cancer is linked to genetic abnormalities, genomic and proteomic biomarkers are currently being used to design targeted therapeutic intervention for various cancer indications.

Research has shown the PI3K/AKT/mTOR pathway is deregulated in a large majority of solid tumors, the researchers from India noted. Treatment with mTOR inhibitors results in robust activity in certain cancer cell lines, but they are not effective in all patients. Researchers are currently using biomarkers to try to stratify patients for response to mTOR inhibitors.

For the Cancer Research study, researchers from Mitra Biotech used a systems biology approach called the tumor explant model to distinguish driver mutations (those that are critical for a tumor's survival) from passenger mutations. This distinction is important for stratifying patients for current treatments and developing novel rational combinations of anticancer agents.

The researchers collected fresh tumor tissue from 22 patients with HNC and conducted ex-vivo explant experiments. They were able to identify responders to rapamycin, an mTOR inhibitor. However, a majority of the tumor samples did not have an antitumor effect after treatment with the mTOR inhibitor, possibly because rapamycin is known to activate the AKT pathway.

To combat the AKT pathway activation, the researchers treated the tumor samples with rapamycin in combination with an AKT inhibitor. Rapamycin-induced AKT activation was reversed, but a subset of patients still failed to respond.

Targeted phosphoproteomic characterization of tumors resistant to dual AKT/mTOR inhibitors showed that multiple pathways were supporting the tumors' proliferation and survival and likely responsible for treatment resistance. This approach of combining ex vivo functional analyses with molecular profiling could potentially be used to stratify patients for appropriate combination therapy, the researchers concluded.

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