How science is using the genetics of disease to make drugs better

Treated as an individual. Whatmatdoes

Personalised medicine is the ability to tailor therapy to an individual patient so that, as it’s often put, the right treatment is given to the right patient at the right time. But just how personal is it?

While the phrase might conjure up images of each patient getting their own individual therapeutic cocktail – this isn’t actually the case. Designing an individually tailored package would be too labour intensive and (at least currently) too expensive. Instead, the answer lies in understanding the genetics of patients and disease.

Diseases are not (genetically) equal

Up until the end of the 1990s (and in some diseases much more recently), we tended to employ a one-size-fits-all approach to the treatment of human disease. The traditional dogma has been as follows: a patient has a particular disease, say bowel cancer; we develop a drug or therapy that appears to be effective against it, and all patients with bowel cancer are given this drug or therapy. While some patients respond positively to the treatment and may even be cured, others show no response and derive no benefit from the treatment (perhaps even some side-effects). The drug continues to be prescribed.

This raises an issue: if all bowel cancer patients have the same disease, surely the treatment should work the same? Not true. How we respond to drugs and treatment can depend on our genetic makeup, or more precisely with this example, in the genetic make-up of the bowel cancer cells.

Recent technological developments have essentially allowed us to take a molecular snap-shot of bowel cancer cells (or any other disease cell type we wish to study) and these have revealed that not all bowel cancers are the same. The precise annotation of the genetic/molecular changes or mutations in bowel cancer cells varies.

What’s more, mutations or molecular changes in one or many genes in different individuals can govern whether patients with the “same” disease will respond in a similar fashion to the same treatment. Understanding this “genetic context” allows us to rethink how we approach therapy; if we know about the molecular change in a patient, we can design a specific drug that “targets” it. So although all patients may have different genetics (making an individual therapy for each patient unrealistic), subgroups of patients can share common mutations/changes which allows medicines to be designed for patient subgroups.

Testing it out on leukaemia

One of the first diseases where this approach was successfully used was in Chronic Myeloid Leukaemia (CML). A one-size-fits-all approach to chemotherapy wasn’t working and were potentially toxic. Bone marrow transplants, though effective, were limited to those patients who had a donor.

CML patients have a genetic change in their bone marrow cells that leads to the production of a leukemia-specific protein (called BCR-ABL) that is hyperactive in CML cells. CML was a perfect candidate for developing a personalised medicine because a single genetic change in the disease cell characterises an entire condition. Because of this, researchers – from both the academic and pharmaceutical sectors – were able to develop Imatinib Mesylate, a drug that simply inhibited the activity of BCR-ABL. The drug has been so successful that it has replaced both chemotherapy and bone marrow transplantation as the treatment for CML.

Stratifying disease

While Imatinib Mesylate has become the poster child for personalised medicine, most conditions aren’t characterised by a single genetic change in a disease cell. There may be five or even ten molecular sub-types of bowel cancer, for example, each defined by particular genetic/molecular changes called predictive biomarkers, that can also be thought of as “signatures”.

Knowing these biomarkers can help us to tell us who will and won’t respond to certain drugs and treatments and doctors can use this information to separate or “stratify” patients. This is particularly beneficial for cancer chemotherapy – if we know that the genetic make-up of a patient’s cancer cells won’t respond to the treatment, alternative treatment can be considered and they can be spared the potential toxic side effects chemotherapy can bring.

This method (sometimes called the stratified medicine approach) is a key component of personalised medicine and is increasingly being used in modern cancer therapy and work that is being done to find an even more precise definition of the genetic architecture of cancer cells is also identifying new targets for therapy , so there is still more scope for how far we can go in personalising medicine.

Although many of the early successes of personalised medicine have been in cancer, there is now evidence that this approach can be applied in other diseases such as cystic fibrosis (with significant success using a drug called ivacaftor which targets a particular mutation in the disease), cardiovascular disease and diabetes. And progress is also being made in the field of autoimmune and infectious disease.

The era of personalised medicine has well and truly arrived.