Mesothelioma Researchers Encouraged to Look for the “Magic Shotgun”
The problem with treating mesothelioma and other cancers is that, for many, the treatment brings on side effects that impact the patients’ quality of life leaving them seemingly sicker than they were prior to the diagnosis. Researchers continually look for treatments with low toxicity levels that target a specific biomarker to limit side effects and to improve the effectiveness of the treatment. However, a new report shows that researchers may need to expand the focus of their drug from one target, or gene, to a set of targets.
Mesothelioma is a unique and rare form of cancer, typically affecting the lining of the lungs, caused by exposure to asbestos fibers. Personalized care targeted to a patient’s unique mesothelioma characteristics, such as a specific genetic trait, optimizes the potential for success of the treatment and offers treatment options that may not otherwise have been considered. But developing medicines that look at just one gene, may not offer the most optimal treatments.
According to researchers at the University of California, San Francisco (UCSF) and Mt. Sinai, New York, when looking for a treatment or cure for a disease, taking the “shotgun approach” is favorable over the “magic bullet.” They explain that this “new approach looks to find “magic shotguns” by sifting through the known universe of chemicals to find the few special molecules that broadly disrupt the whole diseases process.”
The article published earlier this month in Nature explains that drugs are designed to disrupt the disease process by interfering with the proteins and genes that cause the disease. The larger the disruption the drug causes, the more effective it is. But, the same drug’s toxicity level will also disrupt healthy systems leading to side effects.
According to the article, the therapeutic index (the ratio of effective dose to toxic dose) is used to identify how toxic a drug may be. For comparison, a “safe” drug may have a therapeutic index of 20, whereas many cancer drugs have a therapeutic index of 1. The index indicates how many times more of the prescribed dose a patient would have to take to suffer severe side effects.
The current chemotherapy standard of care for the treatment of pleural mesothelioma is a combination therapy utilizing pemetrexed and cisplatin. Vomiting, fatigue and nausea are common side effects from the chemotherapy treatments, and with such a low therapeutic index, the side effects are inevitable.
Using fruit flies, the authors found a way to “screen compounds to find the few that best disrupt an entire network of interacting genes and proteins.” As opposed to determining the effectiveness of a drug according to how well it inhibits a specific target, the researchers assessed efficacy of the compounds by its ability to inhibit the specific target as well as its ability to disrupt other parts of the network “while not interacting with other genes and proteins that would cause toxic side effects.”
“This is a magic shotgun — it doesn’t inhibit one target but a set of targets — and that gives us a much, much better ability to stop the cancer without causing as many side effects,” said Kevan Shokat, PhD, a Howard Hughes Medical Institute Investigator and chair of the Department of Cellular and Molecular Pharmacology at UCSF.
Nearly 3,000 Americans are diagnosed with mesothelioma each year, and many of these die within a year of diagnosis. There is no cure for the cancer and finding a treatment that can extend the lives of patients has remained elusive for researchers. Hopefully, researchers that follow the approach of finding the “magic shotgun” will make progress in finding a new, safer mesothelioma treatment.