Inside Salk; Salk Insitute

Insider's View

William R. Brody

In his 2015 state of the union address, President Obama announced that he's launching the Precision Medicine Initiative—a bold new research effort to revolutionize how we improve health and treat disease.

Obama noted that most medical treatments have been designed for the average patient, a one-size-fits-all approach that can be very successful for some diseases but not for many others. "Precision medicine, on the other hand, is an innovative approach that takes into account individual differences in people's genes, environments and lifestyles," he said.

Precision medicine is particularly applicable to patients with cancer, and, in fact, has been applied for the past decade to thousands of patients with malignancies. Regardless of the cause, the accumulated effect of one or multiple genomic alterations is the proliferation of cancer cells that appear to have immortality and can migrate and divide rapidly.

Before precision medicine, drug therapy for cancerous tumors consisted of cytotoxic drugs, such as Cytoxan, Temodar and Matulan that non-specifically killed rapidly dividing cells. Because most cancers divide rapidly, they were highly susceptible to these agents, but so were other rapidly dividing cells such as those lining the intestine and bone marrow cells that produce blood cells—which resulted in serious side effects.

One form of blood cancer, chronic myelogenous leukemia (CML), was first recognized in 1845 and the first attempt at treatment using arsenic trioxide was reported in 1865, then 'rediscovered' in the 1930s. Little progress was made until 1960, when scientists Nowell and Hungerford discovered an altered chromosome, called the Philadelphia chromosome (Ph+), associated with certain forms of leukemia, especially CML.

In the late 1970s, Salk scientist Tony Hunter discovered an enzyme (protein) called tyrosine kinase that was associated with cancers in animals. Over the next several decades, Hunter and colleagues around the world discovered and described alterations in a family of over 500 protein kinases, about half of which have been implicated in various forms of cancer.

In 1973, scientist Janet Rowley reported that the Philadelphia chromosome resulted from segments of DNA on chromosome 9 that essentially traded places with segments on chromosome 22.

Over the next few years, the work of several researchers, including Salk Non-Resident Fellow David Baltimore, showed that the swapping of genes created a defective gene. The gene produced an altered tyrosine kinase that drove overproduction of defective white blood cells seen in CML. Shortly thereafter, scientists at Novartis and the Oregon Health and Science University developed a new drug called imatinib that inactivated the altered kinase enzyme. Many other scientists were involved in the chain of discoveries that lead to imatinib.

In CML patients who had the Philadelphia chromosome, imatinib was 97 percent successful in stopping the growth of the tumor. Results of this spectacular nature were previously unheard of in the annals of cancer medicine, and following FDA approval, Novartis marketed the drug under the name Gleevec. Many CML patients who started taking the drug in 2001 when the FDA approved it are still taking the drug and are healthy today.

Subsequent to the dramatic success of Gleevec, Novartis and other drug companies went on to develop drugs against many of the other altered forms of tyrosine kinases. Today, there are more than 100 drugs, either approved or in clinical trials, to target protein kinases, mostly for cancer therapy.

What we have learned is that the more detailed molecular knowledge we obtain from basic scientific studies about the nature of various forms of cancer the better we can evaluate a tumor's strengths and weaknesses. There are a myriad of changes that can occur following genetic alterations in cancer—these can affect enzymes, metabolic pathways (or networks of pathways) as well as regulatory genes, such as oncogenes or tumor suppressor genes. Analysis of these changes, called polyomics, creates a wealth of data that can inform the development of new therapies and the tailoring of treatment selections to an individual patient.

This, then, is the future potential of precision medicine: bringing together a wealth of information gained from basic scientific studies on cancer with polyomic analysis of an individual patient. There are many challenges to the widespread adoption of precision medicine for cancer, but in highly specialized cancer treatment centers—thanks to the foundational science of the past few decades—the future is already here.