Study finds potential to match tumors with known cancer drugs
When it comes to gene sequencing and personalized medicine for cancer, spotting an aberrant kinase is a home run. The proteins are relatively easy to target with drugs and plenty of kinase inhibitors already exist.
Now in a new study, University of Michigan Comprehensive Cancer Center researchers assess the complete landscape of a cancer's "kinome" expression and determine which kinases are acting up in a particular tumor. They go on to show that those particular kinases can be targeted with drugs – potentially combining multiple drugs to target multiple kinases.
"We have a small but effective inventory of 'druggable' mutations that we know play a role in cancer. As we are doing more sequencing, we're coming to realize just how small that inventory is. On the one hand, it's a limitation. On the other hand, there are numerous oncogenic kinases, and there are a lot of kinase inhibitors. Our goal is to determine how to match more of these therapies with the right patients," says senior study author Chandan Kumar-Sinha, Ph.D., research assistant professor at the Michigan Center for Translational Pathology.
The researchers looked at RNA sequencing data from 482 samples of both cancerous and non-cancerous tissue and identified the most highly expressed kinases in individual breast cancer and pancreatic cancer samples. They found certain common themes.
"A lot of samples showed one or two kinases that showed an outstandingly high 'outlier' expression," says Kumar-Sinha. It wasn't that the researchers always found a mutation – just that one or more kinases were expressed at a far higher level than all other kinases.
"We don't always know what's causing it to be overexpressed. But since it's there, we know that somehow the high expression of oncogenic kinases is advantageous to the cancer, and so we can therapeutically exploit that dependency," Kumar-Sinha says.
Results of the study appear online in the journal Cancer Discovery.
In breast cancer, the researchers spotted outlier expression of ERBB2 kinase in HER2-positive tumors, which would be expected. HER2-positive tumors can be treated with Herceptin. But they also found another kinase, called FGFR4 – and they found that adding a drug that blocks FGFR4, in combination with Herceptin, improved the anti-cancer effect. This was done only in cells in the laboratory, but the FGFR4-inhibitor continued to be effective in cells even after they became resistant to Herceptin.
In the pancreatic cancer samples, the researchers found several different kinases that have drugs that work against them, including MET, AKT and PLK. Pancreatic cancer is one of the most deadly types of cancer, often diagnosed in its late stages when treatments are not very effective. The main driver of pancreatic cancer, a mutation in a gene called KRAS, has proven difficult to target with treatments.
In the lab, researchers blocked the outlier kinases and found it had an effect against the cancer cells. They then blocked KRAS – something that can be done in the lab but has not been achieved in patients with pancreatic cancer – and found an even larger effect.
"If in the future we could target KRAS in patients and also hit the outlier kinases, it could have a huge impact on treatment of pancreatic cancer," Kumar-Sinha says.
These findings must still be tested in patients, but researchers are hopeful that targeting specific kinases expressed in an individual patient's tumor could make a difference.
The U-M Comprehensive Cancer Center is currently using gene sequencing techniques to help match advanced cancer patients with potential clinical trial opportunities based on the make-up of their tumor.
"We hope kinases will represent another available avenue with whole genome sequencing. If we can identify rational multiple targets for treatment, it's more effective. This gets us one of those targets," Kumar-Sinha says.
More information: Cancer Discovery, "Outlier Kinase Expression by RNA Sequencing as Targets for Precision Therapy," published online Feb. 5, 2013, doi:10.1158/2159-8290.CD-12-0336
Journal reference: Cancer Discovery
Provided by University of Michigan Health System
- Combination therapies for drug-resistant cancers Oct 10, 2011 | not rated yet | 0
- Kinase test may yield big gains for drug-resistant cancers Apr 12, 2012 | not rated yet | 0
- First-of-its-kind study creates new tool for targeted cancer drug development Oct 30, 2011 | not rated yet | 0
- Map of substrate-kinase interactions may lead to more effective cancer drugs Mar 27, 2012 | not rated yet | 0
- Herceptin targets breast cancer stem cells Jul 09, 2008 | 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 May 24, 2013 | 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 May 24, 2013 | 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 May 24, 2013 | 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 May 24, 2013 | 5 / 5 (2) | 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 May 24, 2013 | 5 / 5 (4) | 0
Coenzyme Q10 decreases all cause mortality by half, according to the results of a multicentre randomised double blind trial presented today at Heart Failure 2013 congress. It is the first drug to improve heart failure mortality ...
17 hours ago | 5 / 5 (5) | 5
(HealthDay)—Animals make great companions for senior citizens, but elderly people who always drive with a pet in the car are far more likely to crash than those who never drive with a pet, researchers have ...
9 hours ago | not rated yet | 1
Heart failure accelerates the aging process and brings on early andropausal syndrome (AS), according to research presented today at the Heart Failure Congress 2013. AS, also referred to as male 'menopause', was four times ...
17 hours ago | 5 / 5 (1) | 1
Mortality and length of stay are highest in heart failure patients admitted in January, on Friday, and overnight, according to research presented today at the Heart Failure Congress 2013. The analysis of nearly 1 million ...
17 hours ago | not rated yet | 0
(AP)—Department of Justice lawyers have again asked a federal appeals court in New York to delay lifting age restrictions and prescription requirements on an emergency contraceptive popularly known as the morning-after ...
17 hours ago | not rated yet | 0