Stem cells make potential drug side effects personal
In a promising development that strengthens the case for personalized cancer care, scientists in Singapore have demonstrated the possibility of predicting the potential for an individual to have adverse side effects to different drugs by first testing them on stem cells made from the patient's own blood.
For doctors, prescribing cancer drugs is often a hit-or-miss affair. Even though a therapy has been approved by a regulatory body, there's still a chance someone could have a bad reaction and develop severe side effects, such as liver failure. Such cases are termed idiosyncratic, as opposed to intrinsic, which can be predicted and therefore avoided. As the name suggests, with idiosyncratic drug-induced liver injury (DILI) it is difficult to predict a drug's side effects on an individual patient in advance, which could lead to hospitalization and even death.
Pazopanib is a drug commonly prescribed for advanced kidney cancer. However, like many cancer therapies, it doesn't work for everyone and has been known to cause liver damage in patients who react badly to it. In the study, researchers at the Institute of Bioengineering and Nanotechnology (IBN) and the National Cancer Centre Singapore (NCCS) used induced pluripotent stem cells (iPSCs) – adult cells that have been genetically reprogrammed into an embryonic cell-like state – to create liver cells from the blood of five kidney cancer patients, three of whom were known to have adverse reactions to the cancer drug. The goal was to find out if they could reproduce adverse reactions to pazopanib in these cells.
When these newly created liver cells were exposed to the drug, the researchers found that not only were the results similar to post-treatment data derived from liver biopsies, they were also able to gain a better understanding of how the drug caused liver damage, which was previously unknown to doctors. This is the first time that a study has demonstrated the ability of genetically matched iPSCs to model drug-induced idiosyncratic side effects, which may result from predisposing genetic factors that an individual patient might have. What the results make clear is that idiosyncratic DILI has multiple causative factors and cannot be attributed to a single risk factor.
"Our hypothesis was that liver cells made from the individual's blood might show similar sensitivity or resistance to pazopanib," says study author Min-Han Tan, a medical oncologist. "This study is the first proof-of-concept that our approach can predict drug-induced liver damage for an individual. Importantly, we were able to figure out how the drug works from the way they react to the liver cells, which was unknown to doctors, even after many years of using this drug."
Among the findings was the identification of the role altered iron metabolism could play in pazopanib-induced liver injury. NCCS consultant Ravindran Kanesvaran believes understanding the mechanism of this particular side effect of the drug could lead to ways to overcome it.
While the study's small sample size might bring with it statistical limitations, the researchers, who are currently planning formal clinical trials, believe these findings could provide impetus for using patient-specific stem cells to screen for idiosyncratic drug reactions, especially since there is currently no suitable test for these cases.
Further studies on drugs that affect other organs are in the pipeline, and the researchers say in the future it might be possible to predict a patient's reaction to a drug by screening personalized stem cells comprising a range of liver, lung, kidney and heart cells.
Apart from benefitting patients, such a procedure could also help keep promising therapies on the market. Presently, phase III clinical trials (i.e. the stage that assesses the effectiveness of a new therapy) involve patient groups comprising between 300 and 3,000 people. And because they are so rare, it is easy for cases of idioscyncratic DILI to slip under the radar during these trials. As the study's authors note, this results in "considerable morbidity, mortality, treatment dose attenuation and interruption," which often leads to drugs being pulled off the market, depriving patients who do not have such reactions of what could be a promising treatment for them.
"Currently, new drugs are tested for toxicity using generic liver cells, which cannot model patient-specific reaction," says team leader and principal research scientist Hanry Yu. "By personalizing liver cells from the blood of individual patients, we can help doctors to prescribe safer and more effective therapies."
The paper was published in Scientific Reports.