Study finds potential to match tumors with known cancer drugs

February 05, 2013

ANN ARBOR, Mich. -- 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.
-end-
Additional authors: Vishal Kothari, Iris Wei, Sunita Shankar, Shanker Kalyana-Sundaram, Lidong Wang, Linda W. Ma, Pankaj Vats, Catherine S. Grasso, Dan R. Robinson, Yi-Mi Wu, Xuhong Cao, Diane M. Simeone, Arul M. Chinnaiyan, all from U-M

Funding: National Cancer Institute grants 5-R21-CA-155992-02, 2T32CA009672-21, R01CA131045-01, P50CA130810-1A; Department of Defense Era of Hope grant BC075023; Rich Rogel Fund for Pancreatic Cancer Research; Doris Duke Charitable Foundation; American Cancer Society; U-M's A. Alfred Taubman Research Institute; U-M GI SPORE

Disclosure: None

Reference: 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

Resources:
U-M Cancer AnswerLine, 800-865-1125
U-M Comprehensive Cancer Center, www.mcancer.org
Clinical trials at U-M, www.UMClinicalStudies.org/cancer

University of Michigan Health System

Related Breast Cancer Articles from Brightsurf:

Oncotarget: IGF2 expression in breast cancer tumors and in breast cancer cells
The Oncotarget authors propose that methylation of DVDMR represents a novel epigenetic biomarker that determines the levels of IGF2 protein expression in breast cancer.

Breast cancer: AI predicts which pre-malignant breast lesions will progress to advanced cancer
New research at Case Western Reserve University in Cleveland, Ohio, could help better determine which patients diagnosed with the pre-malignant breast cancer commonly as stage 0 are likely to progress to invasive breast cancer and therefore might benefit from additional therapy over and above surgery alone.

Partial breast irradiation effective treatment option for low-risk breast cancer
Partial breast irradiation produces similar long-term survival rates and risk for recurrence compared with whole breast irradiation for many women with low-risk, early stage breast cancer, according to new clinical data from a national clinical trial involving researchers from The Ohio State University Comprehensive Cancer Center - Arthur G.

Breast screening linked to 60 per cent lower risk of breast cancer death in first 10 years
Women who take part in breast screening have a significantly greater benefit from treatments than those who are not screened, according to a study of more than 50,000 women.

More clues revealed in link between normal breast changes and invasive breast cancer
A research team, led by investigators from Georgetown Lombardi Comprehensive Cancer Center, details how a natural and dramatic process -- changes in mammary glands to accommodate breastfeeding -- uses a molecular process believed to contribute to survival of pre-malignant breast cells.

Breast tissue tumor suppressor PTEN: A potential Achilles heel for breast cancer cells
A highly collaborative team of researchers at the Medical University of South Carolina and Ohio State University report in Nature Communications that they have identified a novel pathway for connective tissue PTEN in breast cancer cell response to radiotherapy.

Computers equal radiologists in assessing breast density and associated breast cancer risk
Automated breast-density evaluation was just as accurate in predicting women's risk of breast cancer, found and not found by mammography, as subjective evaluation done by radiologists, in a study led by researchers at UC San Francisco and Mayo Clinic.

Blood test can effectively rule out breast cancer, regardless of breast density
A new study published in PLOS ONE demonstrates that Videssa® Breast, a multi-protein biomarker blood test for breast cancer, is unaffected by breast density and can reliably rule out breast cancer in women with both dense and non-dense breast tissue.

Study shows influence of surgeons on likelihood of removal of healthy breast after breast cancer dia
Attending surgeons can have a strong influence on whether a patient undergoes contralateral prophylactic mastectomy after a diagnosis of breast cancer, according to a study published by JAMA Surgery.

Young breast cancer patients undergoing breast conserving surgery see improved prognosis
A new analysis indicates that breast cancer prognoses have improved over time in young women treated with breast conserving surgery.

Read More: Breast Cancer News and Breast Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.