Drug-target database lets researchers match old drugs to new uses

There are thousands of drugs that silence many thousands of cancer-causing genetic abnormalities. Some of these drugs are in use now, but many of these drugs are sitting on shelves or could be used beyond the disease for which they were originally approved. Repurposing these drugs depends on matching drugs to targets. A study recently published in the journal Bioinformatics describes a new database and pattern-matching algorithm that allows researchers to evaluate rational drugs and drug combinations, and also recommends a new drug combination to treat drug-resistant non-small cell lung cancer.

"Most cancers have more than one genetic alternation. And even genetically targeted drugs tend to affect more than only their stated target. And so the challenge is matching drugs with many effects to cancers with many causes in a way that best maps the drugs' effects onto the intended targets," says Aik Choon Tan, PhD, investigator at the University of Colorado Cancer Center and associate professor of Bioinformatics at the CU School of Medicine.

There are about 500 kinases in the human genome, each of which represents a potentially important target. Tan describes the database as a spreadsheet with 500 columns, each column representing a kinase. Heading each row is a drug and then in each column cell is that drug's activity against the kinase.

"Imagine you know a cancer is caused by five kinases acting in unison," Tan says. "Our approach would allow you to query the database for this pattern and discover the drug or combination of drugs that best match the genetic needs."

Because many of these drugs have already earned FDA approval for use in other diseases, the processes of repositioning these drugs for new diseases is much less involved and expensive than if drug developers had started fresh.

Tan and colleagues put the technique to use to recommend drugs that could turn off the kinases that non-small cell lung cancer uses to create resistance existing treatments. It's been an important question – many lung cancers depend on over-activation of the gene EGFR, but then when EGFR inhibitors like gefitinib or erlotinib are used, the cancers tend to activate other "kinases" that allow the cancer to by-pass around this dependence. Tan and colleagues asked what are these kinases that allow lung to evade gefitinib, and what other drug might turn them off.

The answer may be in the drug bosutinib, developed by Pfizer, which earned FDA approval in 2013 for the treatment of chronic myeloid leukemia. The drug out-competes the body's energy source, ATP, for space in kinases and so keeps them from being activated. And it turns out that bosutinib may inhibit the activity of exactly the that EGFR-dependent lung cancers need to mutate around the challenge of EGFR inhibitors.

In tests on EGFR-dependent cell lines, Tan and colleagues show that the drugs gefitinib and bosutinib "showed additive and synergistic effects."

In a mechanism that Tan hopes will become common, his group will now hand off this rational combination to other researchers at the CU Cancer Center and elsewhere who will move the drugs toward a human clinical trial.

More information: The K-Map database is online and free for use at tanlab.ucdenver.edu/kMap/

add to favorites email to friend print save as pdf

Related Stories

The right combination: Overcoming drug resistance in cancer

Jun 01, 2012

Overactive epidermal growth factor receptor (EGFR) signaling has been linked to the development of cancer. Several drug therapies have been developed to treat these EGFR-associated cancers; however, many patients have developed ...

Cancer stem cells linked to drug resistance

Apr 20, 2014

Most drugs used to treat lung, breast and pancreatic cancers also promote drug-resistance and ultimately spur tumor growth. Researchers at the University of California, San Diego School of Medicine have discovered ...

The current state of lung cancer treatment

Dec 11, 2012

A review in the December issue of the journal Archives of Pathology & Laboratory Medicine by Paul Bunn Jr, MD, University of Colorado Cancer Center investigator and past president of ASCO, IASLC and AACI describes the cu ...

Recommended for you

Experts want restrictions on testosterone drug use (Update)

4 hours ago

Federal health experts said Wednesday there is little evidence that testosterone-boosting drugs are effective for treating common signs of aging in men and that their use should be narrowed to exclude millions of Americans ...

Big cities take aim at prescription painkillers

Sep 16, 2014

Some of the nation's largest cities are ratcheting up their criticism of prescription painkillers, blaming the industry for a wave of addiction and overdoses that have ravaged their communities and busted local budgets.

World Health Organization policy improves use of medicines

Sep 16, 2014

In this issue of PLOS Medicine, Kathleen Holloway from WHO and David Henry (University of Toronto, Canada) evaluated data on reported adherence to WHO essential medicines practices and measures of quality use of medicines from 5 ...

User comments