September 12th, 2011
Posted by Shane Climie, Ph.D.
It’s increasingly clear to anyone who deals with human health – from the bench biologist to the clinical oncologist – that humans are a heterogeneous species. As a result, a drug that works well in one individual may not work at all in another. Thus, the field of targeted (or personalized) medicine came about so doctors could optimize patient care through the use of genetic and biomarker testing. Such tests help identify patients who are (or who are not) most likely to respond to a given therapy. The field is often promoted as a way to get the “right drug to the right patient at the right dose.”
Correct dosing is critical because about 25 percent of all outpatient prescription drugs in the U.S. are taken by patients with genetic variations (specifically, polymorphisms) that affect absorption, metabolism or excretion of those drugs. Again, at risk of stating the obvious, human beings are heterogeneous.
Today, genetic tests are widely used to identify so-called “fast” and “slow” metabolizers of specific drugs and to adjust the dosage according to how long the drug may persist in an individual’s body. Other tests are used to determine whether patients carry drug targets that are sensitive to drugs (like Herceptin), or whether they harbor mutations that will render drugs inactive, either through resistance (from conditions like HIV) or via the presence of alternate pathways that can circumvent—or short circuit—the effects of a drug.
These current tests can therefore reveal whether mutations have either a pharmacokinetic (i.e., drug metabolism) effect or a pharmacodynamic (i.e., drug target) effect. Genetic and biomarker tests are also proving to be important in the management of many diseases, particularly those for which there are multiple therapeutic options and in those cases where the underlying pathology is caused by one of several possible mutations or other risk factors (e.g., breast cancer and diabetes).
While the U.S. Food & Drug Administration website lists approximately 115 biomarker tests associated with just over 100 approved drugs, researchers are moving quickly to add additional tools to the personalized medicine toolbox. One exciting new advance is the use of induced pluripotent stems cells (iPSC) to test drug response directly in cells isolated from individual patients. The idea is that skin cells, or blood cells, can be isolated from individual patients and used to generate iPSC, which are then induced to differentiate into multiple cell types such as neurons, cardiomyocytes, and hepatocytes. Such cells harbor the genetic legacy of the patient from whom they were derived, and therefore a response (or non-response) of those cells to various drugs can be used to predict how a patient will respond.
The biotech firm, Cellular Dynamics International, which was co-founded by stem cell pioneer James Thomson, is now trying to undertake this approach. The firm is currently focused on the creation of iPSC-derived cardiomyocytes. However, it soon plans to add other cell types, including those from liver, brain and blood to the list.
So how “futuristic” is all of this? The good news is that many of the tools needed to realize the vision of personalized medicine are rapidly coming together. The combination of genomics, proteomics, stem cell biology, and other technologies are providing the information that is needed to drive the process. The challenge lies with the drugs themselves—the industry needs to apply the same tools more efficiently to guide the drug discovery process. Research, testing, approval, and application should work in tangent because the faster the next generation of drugs come into play and are FDA approved, the faster these new protocols of personalized medicine can be applied to save lives.
We also need to organize and apply the knowledge we’ve gained in genetic studies over the past ten years and apply this knowledge to evolving research. Effectively communicating the on-going research and applications of personalized medicine to the medical community will mean we’ll see designer drugs that are targeted to ever more specialized groups of patients. That day is on the near horizon, something that is of benefit to all of us, doctor and patient—the emergence of truly personalized medicine.
Are you involved in the discovery and/or development of companion diagnostics and/or drugs designed specifically for particular patient subsets? What do you see as the critical next steps to continue moving towards matching drugs with patients who will benefit most? Please share your thoughts with us here.