Common genetic alteration found in head and neck cancers may not be key to effective treatment

January 29, 2013

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 rendering it resistant to specific targeted treatments. Because cancer is linked to , genomic and proteomic biomarkers are currently being used to design targeted therapeutic intervention for a variety of cancer indications.

Research has shown the /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 at Mitra Biotech, Bangalore, India.

Majumder and colleagues used a 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 .

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."

Explore further: Patients with aberrations in two genes respond better to drugs blocking a well-known cancer pathway

Related Stories

Patients with aberrations in two genes respond better to drugs blocking a well-known cancer pathway

November 7, 2012
Cancer patients with mutations or variations in two genes -– PIK3CA and PTEN -– who have failed to respond to several, standard treatments, respond significantly better to anti-cancer drugs that inhibit these genes' pathways ...

Scientists link two cancer-promoting pathways in esophageal cancer

March 19, 2012
Identification of a non-traditional pathway for spiriting a cancer-promoting protein into the cell nucleus points to a possible combination therapy for esophageal cancer and indicates a mechanism of resistance for new drugs ...

Hedgehog pathway key in tamoxifen-resistant breast CA

November 6, 2012
(HealthDay)—Noncanonical Hedgehog (Hh) signaling is activated in tamoxifen-resistant tumors, and the phosphoinositide 3-kinase inhibitor/protein kinase B (PI3K/AKT) pathway plays a key role protecting Hh signaling molecules, ...

Possible therapy for tamoxifen resistant breast cancer identified

August 30, 2012
(Medical Xpress)—A study by researchers at the Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) has discovered how tamoxifen-resistant ...

Recommended for you

Scientists develop novel 'dot' system to improve cancer detection

August 24, 2017
Researchers at Sanford Burnham Prebys Medical Discovery Institute (SBP) have developed a proof-of-concept nanosystem that dramatically improves the visualization of tumors. Published today in Nature Communications, the platform ...

Study provides insight into link between two rare tumor syndromes

August 22, 2017
UCLA researchers have discovered that timing is everything when it comes to preventing a specific gene mutation in mice from developing rare and fast-growing cancerous tumors, which also affects young children. This mutation ...

Retaining one normal BRCA gene in breast, ovarian cancers influences patient survival

August 22, 2017
Determining which cancer patients are likely to be resistant to initial treatment is a major research effort of oncologists and laboratory scientists. Now, ascertaining who might fall into that category may become a little ...

Study identifies miR122 target sites in liver cancer and links a gene to patient survival

August 22, 2017
A new study of a molecule that regulates liver-cell metabolism and suppresses liver-cancer development shows that the molecule interacts with thousands of genes in liver cells, and that when levels of the molecule go down, ...

Zebrafish larvae could be used as 'avatars' to optimize personalized treatment of cancer

August 21, 2017
Portuguese scientists have for the first time shown that the larvae of a tiny fish could one day become the preferred model for predicting, in advance, the response of human malignant tumors to the various therapeutic drugs ...

Scientists discover vitamin C regulates stem cell function, curbs leukemia development

August 21, 2017
Not much is known about stem cell metabolism, but a new study from the Children's Medical Center Research Institute at UT Southwestern (CRI) has found that stem cells take up unusually high levels of vitamin C, which then ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.