With the start of a new year, I’d like to discuss the topic of precision medicine, which is reshaping traditional approaches to disease treatment and prevention and opening new possibilities for the treatment of NF. Precision medicine is also sometimes referred to as personalized or individualized medicine.  Many clinicians, however, prefer to use the term precision medicine because the terms personalized or individualized medicine imply that previous medical approaches have not been personalized. Medicine has always been personalized in treating people as individuals, but we now have powerful new approaches that vastly increase our ability to make a difference in a person’s health. 

Precision Medicine Tools

Precision medicine uses a variety of tools that help to identify the underlying mechanisms of disease and provide specific information about the most effective treatment. Traditional medical approaches develop strategies for a group or cohort of patients with a common clinical presentation, whereas precision medicine evaluates the impact of lifestyle, environment, and genetics on a person’s health. Precision medicine takes advantage of many advances in medical science, and especially of developments in imaging and in genomics. In the past, the diagnosis of tumors was based on inference from a clinical exam because imaging tools to detect a tumor were not available. Today, when clinical symptoms are present, advanced imaging such as CT or MRI can provide vivid and clear pictures of a tumor.

Genomics evaluates an individual’s genetic information through DNA sequencing of the genome. Genome sequencing can reveal the underlying causes of disease by identifying specific genetic alterations, or mutations. Understanding the genetic drivers of disease and tumors enables the development of more precisely targeted treatments that can minimize side effects and maximize benefits. For example, tumors are driven by an accumulation of genetic changes that drive the cancer cells to divide rapidly and spread throughout the body. Traditional cancer treatments, such as chemotherapy, kill all the rapidly dividing cells in the body, resulting in side effects such as nausea, vomiting, and hair loss.  Also, the tumors eventually develop resistance to treatment by acquiring further genetic mutations. Genomic medicine-based treatment approaches more precisely target the underlying mechanism driving the growth of a tumor. Because this targeted approach only affects the tumor cells and not healthy cells in the body, side effects should be minimized. The hope is to develop treatments that target multiple mechanisms simultaneously so that tumors are unable to develop resistance in response to treatment. 

An additional treatment challenge that can be addressed by precision medicine relates to individual patient responses to a particular medication. For a medication to be utilized effectively by the body, it must be absorbed, distributed, interact with its target, and then be metabolized and excreted. Each of these steps is controlled by an individual’s genetic make-up and can lead to a medicine not being metabolized quickly enough to achieve an optimal therapeutic effect, or accumulating so quickly as to cause side effects. Genomic medicine provides information that allows the choice and dosage of a medication to be customized to an individual’s genetic profile so that therapeutic benefits can be maximized and side effects minimized.

Precision Medicine in NF Treatment 

The discovery of the NF gene in 1990 revealed the underlying mechanism of NF that involves the activity of the Ras/MAPK cellular signaling pathway. This pathway, which is hyperactive in individuals with NF, helps to control cell growth and division. Precision medicine treatments have focused on blocking the activity of this pathway with inhibitors of the components of the pathway.  Using inhibitors to one of the components of the pathway called MEK, this approach has achieved success in shrinking plexiform neurofibromas. We are learning that the environment between tumor cells and surrounding cells is also important, and new drugs are in development to target this component of tumor growth. Advances in imaging have also enabled tumors to be detected earlier and targeted more effectively.

Another precision medicine-based approach is focused on restoring function to a mutated gene or gene product, or editing out the mutation entirely. An advantage of this approach to treatment of NF1 is that restoring function to the mutated gene might result in fewer side effects than drug treatments that block Ras signaling. Research on this approach is underway at UAB, though the challenges lie in targeting therapeutics to the right cells as well as precisely correcting the mutation or its effects on the protein.  We are hopeful that progress our scientists make in this area will eventually result in new treatments, that, together with other approaches such as the use of MEK inhibitors, will significantly improve quality of life for those who deal with NF.