Common genetic alteration found in head and neck cancers may not be key to effective treatment
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."
Journal reference: Cancer Research
Provided by American Association for Cancer Research
- Patients with aberrations in two genes respond better to drugs blocking a well-known cancer pathway Nov 07, 2012 | not rated yet | 0
- Cancer therapy: A role for MAPK inhibitors combined with mTORC1 inhibitors Aug 22, 2008 | not rated yet | 0
- Scientists link two cancer-promoting pathways in esophageal cancer Mar 19, 2012 | not rated yet | 0
- Hedgehog pathway key in tamoxifen-resistant breast CA Nov 06, 2012 | not rated yet | 0
- Possible therapy for tamoxifen resistant breast cancer identified Aug 30, 2012 | not rated yet | 0
- Motion perception revisited: High Phi effect challenges established motion perception assumptions Apr 23, 2013 | 3 / 5 (2) | 2
- Anything you can do I can do better: Neuromolecular foundations of the superiority illusion (Update) Apr 02, 2013 | 4.5 / 5 (11) | 5
- The visual system as economist: Neural resource allocation in visual adaptation Mar 30, 2013 | 5 / 5 (2) | 9
- Separate lives: Neuronal and organismal lifespans decoupled Mar 27, 2013 | 4.9 / 5 (8) | 0
- Sizing things up: The evolutionary neurobiology of scale invariance Feb 28, 2013 | 4.8 / 5 (10) | 14
Why is zone 1 in liver more prone to ischemic injury?
May 23, 2013 Hi, Is it because around central vein, there is only deoxygenated blood from the vein where as in the periphery there is hepatic artery. Also why...
How can there be villous adenoma in colon, if there are no villi there
May 22, 2013 As title suggest. Thanks :smile:
How can there be a term called "intestinal metaplasia" of stomach
May 21, 2013 Hello everyone, Ok Stomach's normal epithelium is simple columnar, now in intestinal type of adenocarcinoma of stomach it undergoes "intestinal...
Pressure-volume curve: Elastic Recoil Pressure don't make sense
May 18, 2013 From pressure-volume curve of the lung and chest wall (attached photo), I don't understand why would the elastic recoil pressure of the lung is...
If you became brain-dead, would you want them to pull the plug?
May 17, 2013 I'd want the rest of me to stay alive. Sure it's a lousy way to live but it beats being all-the-way dead. Maybe if I make it 20 years they'll...
MRI bill question
May 15, 2013 Dear PFers, The hospital gave us a $12k bill for one MRI (head with contrast). The people I talked to at the hospital tell me that they do not...
- More from Physics Forums - Medical Sciences
More news stories
In recent years, microRNAs (miRNAs) and other non-coding RNAs are small molecules that help control the expression of specific proteins. In recent years they have emerged as disease biomarkers. miRNA profiles have been used ...
Cancer 13 hours ago | not rated yet | 0
Cancer cells spread and grow by avoiding detection and destruction by the immune system. Stimulation of the immune system can help to eliminate cancer cells; however, there are many factors that cause the immune system to ...
Cancer 13 hours ago | 5 / 5 (1) | 0
Researchers from London's Kingston University have begun a two-year study which could help prolong the lives of people with colorectal tumours.
Cancer 17 hours ago | 5 / 5 (1) | 0
Transformative research from Western University has identified new hormones in the body which may suppress breast cancer and stimulate the regression of breast tumors.
Cancer 17 hours ago | 5 / 5 (1) | 0
(Medical Xpress)—Curtin University researchers have found evidence that targeting specific cells in the body can reverse the effects of cancer on the immune system.
Cancer 18 hours ago | 5 / 5 (4) | 0
(Medical Xpress)—A new study by researchers in the US has shown that an ancient virus can be modified to help in the fight against the simian immunodeficiency virus SIV, which is the equivalent in monkeys ...
17 hours ago | 5 / 5 (3) | 0 |
Two mutations central to the development of infantile myofibromatosis (IM)—a disorder characterized by multiple tumors involving the skin, bone, and soft tissue—may provide new therapeutic targets, according to researchers ...
11 hours ago | 3 / 5 (2) | 0 |
Women at a particular stage in their monthly menstrual cycle may be more vulnerable to some of the psychological side-effects associated with stressful experiences, according to a study from UCL.
14 hours ago | 3.7 / 5 (3) | 0 |
Biological processes are generally based on events at the molecular and cellular level. To understand what happens in the course of infections, diseases or normal bodily functions, scientists would need to ...
14 hours ago | 5 / 5 (4) | 0 |
How can healthy people who hear voices help schizophrenics? Finding the answer for this is at the centre of research conducted at the University of Bergen.
17 hours ago | 4 / 5 (2) | 2
(Medical Xpress)—The way Alzheimer's disease is portrayed by advocacy groups and the media is having undue influence on the euthanasia debate, according to a Deakin University nursing ethics professor.
18 hours ago | not rated yet | 2