A new research has revealed how resistance to targeted drug therapy emerges in colorectal cancers. The study also discusses about a multidrug approach that could be helpful in managing the many cancers, if the said form of cancer is not curable.
A Harvard researcher who is working on the evolution of drug resistance in cancer says that in coming decades many, many forms of cancers could be manageable.
"Many people are dying needlessly of cancer, and this research may offer a new strategy in that battle," Martin Nowak, a professor of mathematics and of biology and director of the Program for Evolutionary Dynamics has been quoted as saying.
"One hundred years ago, many people died of bacterial infections. Now, we have treatment for such infections - those people don't have to die. I believe we are approaching a similar point with cancer," he added.
The key, Nowak's research suggests, is to change the way clinicians battle the disease.
Of late Physicians and researchers have increasingly turned to "targeted therapies" - drugs that combat cancer by interrupting its ability to grow and spread - instead of traditional chemotherapy, but such treatment is far from perfect. A majority of targeted therapies are effective for only a few months and soon cancer becomes resistant to the drugs.
The main reason behind the colon cancer treatment as per the new study is the KRAS gene that produces a protein to regulate cell division. In active condition KRAS gene helps cancer cells develop resistance to targeted-therapy drugs that makes treatment useless.
To comprehend the role of KRAS gene in drug resistance, a team of researchers led by Bert Vogelstein, the Clayton Professor of Oncology and Pathology at the Johns Hopkins Kimmel Cancer Center, launched a study which started by testing patients to determine if the KRAS gene was in active state in their tumours.
Patients in which an activated KRAS gene underwent a normal round of targeted therapy treatment and the initial results - as expected - were found successful. Tests performed after the treatment broke down, however, showed a different result as the KRAS gene had been activated.
During their research, Vogelstein's team analyzed a handful of mutations that can lead to the activation of the KRAS gene. In order to interpret those results, they sought help of Nowak's team, including mathematicians Benjamin Allen, a postdoctoral fellow in mathematical biology, and Ivana Bozic, a postdoctoral fellow in mathematics.
Analyzing the clinical results, Allen and Bozic were able to mathematically explained the exponential growth of the cancer and determine whether the mutation that led to drug resistance was pre-existing, or whether it occurred after beginning of cancer.
Their model was able to predict, with surprising accuracy, the window of time from when the drug is first administered to when resistance arises and the drug begins to fail.
"By looking at their results mathematically, we were able to determine conclusively that the resistance was already there, so the therapy was doomed from the start," Allen has been quoted as saying.
"That had been an unresolved question before this study. Clinicians were finding that these kinds of therapies typically don't work for longer than six months, and our finding provides an explanation for why that failure occurs," he said.
Put simply, Nowak said, the findings suggest that, of the billions of cancer cells that exist in a patient, only a tiny percentage - about one in a million - are resistant to drugs used in targeted therapy. When treatment starts, the nonresistant cells are wiped out. The few resistant cells, however, quickly repopulate the cancer, causing the treatment to fail.
"Whether you have resistance prior to the start of treatment was one of the large, outstanding questions associated with this type of treatment. Our study offers a quantitative understanding of how resistance evolves, and shows that, because resistance is there at the start, the single-drug therapy won't work," Bozic said.
The answer, Nowak said, is simple: Rather than the one drug used in targeted therapy, treatments must involve at least two drugs.
The treatment should be according to the needs of the the patient, and patient's genetic makeup should be taken into consideration. Nowak said that importantly the two drugs used simultaneously must not overlap. If a single mutation enables the cancer to become resistant to both drugs, the treatment will fail just as the single-drug therapy does.
According to Nowak estimates hundreds of drugs might be needed to address all the possible treatment variations. But developing these drugs is very challenging.
The findings of the study have been published in the 28th June issue of the nature.
--with inputs from ANI
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