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May 15, 2013 (Vol. 33, No. 10)

Seasoned Drugs Offer Therapeutic Gold Mine

  • Understanding Mechanisms

    Indeed, not only are mechanisms important for drug repositioning, but we can also gain new insights into previously unknown mechanisms in the process. “In my opinion, mechanistic understanding is essential for the success of drug repositioning,” says Stephen Wong, Ph.D., chairman for department of systems medicine and bioengineering at the Methodist Hospital Research Institute, and director of the NCI Center for Modeling Cancer Development.

    Dr. Wong’s group uses an integrative approach that combines bioinformatics analysis, pathway reconstruction, high-throughput and high-content screening, and chemi-informatics methods to look at drug targets and pathways of the disease of interest. They follow this by validating the drugs in in vitro and preclinical experiments.

    “Many drug repositioning methods still follow a conventional hypothesis-driven approach, testing one drug or one target pathway at a time,” says Dr. Wong. “This does not take advantage of large amounts of data on many diseases and drugs available on the web and various public databases, nor the high-throughput biological automation capability today.”

    A characteristic of Dr. Wong’s research is his emphasis on mechanistic understanding, which he says is lacking in research that uses a more data-driven approach.

    “Many of those studies do not provide mechanism reasoning, nor uncover new potential targets not found in existing commercial or public databases,” he says. In contrast, his approach relies on a mechanistic interpretation, including molecular pathways or gene regulatory networks, as to a particular drug’s newfound effectiveness against a particular disease.

    “We developed a unique, network motif-based method to extend generic pathways in existing databases or literature into pathways of specific subtype of diseases of interest,” he says. “We also developed an integrative web-accessible database, DrugMap Central, to support efficient online querying and visualization of multidimensional drug information for repositioning studies, and identifying the application of known drugs and compounds to new indications or diseases.”

    Dr. Wong’s group recently worked with oncologists to reposition two drugs for new roles against cancer: sunitinib (previously used for imatinib-resistant GIST and renal cell carcinoma) for breast cancer brain metastasis, and chloroquine (previously used for malaria) for triple-negative brain metastases, now in Phase II trials.

  • Balancing Act

    Weighing the benefits of a drug against its undesirable side effects can make for an intricate balancing act, practiced daily by Mike Pollastri, Ph.D., associate professor in chemistry and chemical biology at Northeastern University. Dr. Pollastri’s group works on repositioning drugs for neglected tropical diseases such as sleeping sickness. They compare the parasite genome to the human genome, and look for targets and pathways that parasites and humans have in common.

    “Then we look for human drugs that target the closest homologous parasite molecules,” says Dr. Pollastri. “So if there’s a certain enzyme in a parasite, and we know that there is a drug that targets a homologous enzyme in humans, we would go after that one first.” Next they test those drugs against the parasites, and then use the drugs as a starting point for drug discovery.

    Dr. Pollastri calls it target class repurposing, in which a human drug that acts on a homologous parasitic target is used to begin developing an even more effective drug specifically against the parasite. They usually re-optimize the drug for enhanced functioning in the parasite, such as tweaking the dosage or solubility. “For sleeping sickness, often we have to re-engineer drugs so that they get into the brain,” says Dr. Pollastri. “We use the drugs themselves as a starting point, but we don’t repurpose the drugs themselves.”

    Recently they discovered that a drug made by Novartis, currently in clinical trials for cancer, is also extremely potent against sleeping sickness. Another repositioned drug, commonly used in Africa for sleeping sickness, was a failed cancer drug from the 1980s. Both cancer drugs target the same class of enzymes, decarboxylase inhibitors, that function both in mammalian cells and in parasites.

    One of the important optimizations they must wrestle with is the delicate balance between effectiveness, and the tolerance level for patient side effects. For example, PDE4 inhibitors kill parasites, but they also cause nausea and vomiting in humans, so this must be balanced with efficacy.

    “The biggest challenge is always going to be finding compounds that are effective against a parasitic infection and balancing that with the side-effect profile and the primary effect profile in humans,” says Dr. Pollastri. Another example is one of the main drugs used against sleeping sickness, melarsoprol. “Melarsoprol kills 5% of the patients,” he says. “It’s an arsenic compound. But the disease itself will certainly kill you if you’re not treated.”

    Regardless of the method, an important step of the repositioning process is validation. “We are particularly happy to enjoy the benefit of validation by collaboration,” says Dr. Persidis, referring to Biovista’s partnerships with both pharmaceutical companies and patient advocacy groups representing different diseases.

    “This exposure, together with our internal programs, is helping us stay at the forefront of repositioning research, both in terms of the COSS technology itself, and also in terms of advancing individual programs in our areas of interest,” he says. Indeed, Dr. Wong says that one thing above all else is key: “Validation, validation, and validation—or else all big data or systems biology approaches are academic exercises.”

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