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    Matching Tumors With The Optimal Cancer Drugs
    By News Staff | February 6th 2013 01:42 PM | 2 comments | Print | E-mail | Track Comments

    In a new paper,  researchers assess the complete landscape of a cancer's kinome expression and determine which kinases are acting up in a particular tumor.  Since the proteins are relatively easy to target with drugs and plenty of kinase inhibitors already exist, the work shows that those particular kinases can be targeted with drugs and can even lead to potentially combining multiple drugs to target multiple kinases. 

    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.


     "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. "A lot of samples showed one or two kinases that showed an outstandingly high 'outlier' expression."

    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, they write in 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.


     "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. "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."   

    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.


    Comments

    Gene sequencing for cancer, huh? That kind of sounds like the regenerative medicine Rongxiang Xu is doing over in China right now. Although I believe his is more based around the differentiation of pathways.

    Either way, amazing.

    gpawelski

    What of outlier analysis? What of those complicated diseases whose complexity and variability challenge even the best minds? How do they continue to bang the round peg of cancer therapy into the square hole of formulaic care? 

    In a conference sponsored by the Institute of Medicine, scientists representing both public and private institutions examined the obstacles that confront researchers in their efforts to develop effective combinations of targeted cancer agents. 

    In a periodical published by the American Society of Clinical Oncology (ASCO) in their September 1, 2011 issue of the ASCO Post, contributor Margo J. Fromer, who participated in the conference, wrote about it. 

    One of the participants, Jane Perlmutter, PhD, of the Gemini Group, pointed out that advances in genomics have provided sophisticated target therapies, but noted, “cellular pathways contain redundancies that can be activated in response to inhibition of one or another pathway, thus promoting emergence of resistant cells and clinical relapse.” 

    James Doroshow, MD, deputy director for clinical and translational research at the NCI, said, “the mechanism of actions for a growing number of targeted agents that are available for trials, are not completely understood.” 

    He went on to say that the “lack of the right assays or imaging tools means inability to assess the target effect of many agents.” He added that “we need to investigate the molecular effects . . . in surrogate tissues,” and concluded “this is a huge undertaking.” 

    Michael T. Barrett, PhD, of TGen, pointed out that “each patient’s cancer could require it’s own specific therapy.” This was followed by Kurt Bachman of GlaxoSmithKline, who opined, “the challenge is to identify the tumor types most likely to respond, to find biomarkers that predict response, and to define the relationship of the predictors to biology of the inhibitors.” 

    What they were describing was precisely the work that Laboratory Oncologists involved with phenotype analysis have been doing for the past two decades. One of those clinicians felt that there had been an epiphany. 

    The complexities and redundancies of human tumor biology had finally dawned on these investigators, who had previously clung unwaiveringly to their analyte-based molecular platforms. 

    The molecular biologists humbled by the manifest complexity of human tumor biology had finally recognized that they were outgunned and whole-cell experimental models had gained the hegemony they so rightly deserved.

    Genomics are far too limited in scope to encompass the vagaries and complexities of human cancer biology. The human genome project will give way to the human epigenome project which will give way to the human proteome and human kinome project. The next generation of tests will be biosystematic.