PHILADELPHIA — Although a large majority of head and neck cancers have a deregulation of the PI3K/AKT/mTOR pathway, data recently published in Cancer Research, a journal of the American Association for Cancer Research, indicated that deregulation of this pathway does not necessarily signify that the tumor is dependent on it for survival and progression.
Cancer, particularly of the head and neck, 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 a variety of cancer indications.
Research has shown the PI3K/AKT/mTOR pathway is deregulated in a large majority of solid tumors. 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.
"However, these technologies have limited success due to their inherent limitations in lack of clarity in distinguishing driver mutations in pathways from those of passengers," said Pradip K. Majumder, Ph.D., of the division of cancer biology at Mitra Biotech, Bangalore, India.
Majumder and colleagues used a systems biology approach called tumor explant model to distinguish driver mutations, or those that are critical for a tumor's survival, from passenger mutations. This distinction is important for stratifying patients for current treatments and for developing novel rational combinations of anticancer agents.
The researchers collected fresh tumor tissue from 22 patients with head and neck cancers 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, Majumder and colleagues 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.
"While few tumors are dependent on only mTOR, others are dependent on both mTOR and AKT," Majumder said. "However, a majority of the mTOR pathway-activated tumors seemed to not be dependent on this axis for survival or maintenance."
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, according to Majumder.
"A majority of anticancer drugs fail in the phase II efficacy stage of clinical development due to a lack of technologies to identify and appropriately stratify patients according to their tumor pathway dependence," Majumder said. "Using this approach, researchers may be able to develop a translational tool for further clinical development of novel anticancer drugs."
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About the American Association for Cancer Research
Founded in 1907, the American Association for Cancer Research (AACR) is the world's first and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 17,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer.
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