Just how 'dirty' should a cancer drug be? While it's not a question cancer patients typically ponder, the answer could profoundly affect their treatment. Dirty drugs - those that simultaneously inhibit more than one of a tumor's driving forces - are one of the hottest topics in cancer drug development and the subject of an editorial in the Oct. 13 issue of Nature.
"One of the greatest tensions in the cancer research field today is how clean or dirty cancer drugs should be," said Michael Heinrich, M.D., an Oregon Health & Science University Cancer Institute researcher whose work was featured in the piece.
The editorial, written by Simon Frantz, chronicles a transformation in thinking among medical researchers about molecularly targeted therapies. With a greater understanding of cancer biology in hand, the trend of the last two decades has been toward the development of clean drugs with a single tumor-stopping target - in the case of cancer, the molecular action that turns on the cancer switch.
However, more recently, research and drug development have shown that drugs with multiple targets - dirty drugs - may be better options for complex diseases like cancer, according to the editorial by Frantz, news editor for Nature Reviews Drug Discovery.
There is no disagreement that both clean and dirty drugs present considerable improvements over conventional chemotherapy, a broad brushstroke approach to eradicating cancer cells that sacrifices healthy cells in the process. Conventional chemotherapy does not directly attack the molecular causes of cancer, but largely targets rapidly dividing cells. However, normal bone marrow and gastrointestinal tract lining cells also contain rapidly dividing cells that are killed by chemotherapy. Because of this effect on normal cells, the side effects of chemotherapy can be serious or even life threatening.
"The dirtiest of molecularly targeted therapies are a vast improvement over conventional chemotherapy," Heinrich said.
Both dirty and clean drugs are molecularly targeted therapies, so they don't harm healthy cells and have fewer side affects. Clean drugs have just one target, so they are better understood by scientists. This simplicity and deeper understanding make it possible to identify more precisely patients and diseases that would benefit most from therapy.
"The trick is that most cancers have more than one target. They might have five or six targets and you have to knock out three to stop the cancer," Heinrich said. "This is where dirty drugs come into play. You might be able to develop one dirty drug with three targets instead of three clean drugs with one target each."
Gleevec for the treatment of the blood cancer chronic myeloid leukemia (CML) was thought to be the exemplary clean drug. A revolutionary cancer treatment, most CML patients show a remarkable response to the drug and experience few side effects. Gleevec was developed by Brian Druker, M.D., the JELD-WEN chair of leukemia research at the OHSU Cancer Institute and a Howard Hughes Medical Institute investigator, and Novartis scientists.
"CML has just one target. At first, Gleevec seemed to be a very specific drug that affected the single mechanism of action behind CML," Heinrich said. "We thought Gleevec was a clean drug, but it turned out to be dirty."
Further research demonstrated that Gleevec was useful against a number of other targets including the one that shuts down CML. Heinrich, who knew the biology behind complex family of gut cancers now known gastrointestinal stromal tumors (GISTs), made the connection between these new targets and GISTs.
"Gleevec for CML was not an accident. Druker understood both the drug and the target. And because we knew how Gleevec worked, we made the step to GIST," Heinrich said. "In the case of GIST, we are using a side effect of Gleevec to treat cancer."
Heinrich says that the transfer of knowledge works both ways from drug to disease and back again. "If we understand how a dirty drug works, we can use that knowledge to better understand the disease it is effective in treating."
He cautions against taking dirty drugs too far, however. "More and more targets may mean more toxicity and more side affects, exactly what were trying to avoid with chemotherapy," Heinrich said.
Heinrich describes the tension between clean and dirty drugs as a balancing act in which cancer biology, effectiveness, side effects, cost and convenience should all be weighed. "Patients may be willing to accept a few minor side effects in return for taking three pills a day instead of eight," Heinrich said.
About the OHSU Cancer Institute
The OHSU Cancer Institute is the only National Cancer Institute-designated cancer center between Sacramento and Seattle. It comprises some 120 clinical researchers and basic scientists who work together to translate scientific understanding into longer and better lives for people living with cancer. In the lab, basic scientists examine cancer to uncover molecular abnormalities that cause disease. This basic science is empowered by more than 200 open clinical trials that test in patients what's been proved in the laboratory. Visit ohsucancer.com for more information about the OHSU Cancer Institute.
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