Oregon Health and Science University
Portland OR

Brian J. Druker, M.D.,
Howard Hughes Medical Institute
Oregon Health & Science University

T.J. Martell Foundation Funded Research at Oregon Health and Sciences University

We share the dream of the T J Martell Foundation to eradicate cancer and are grateful for their support in helping us to realize this goal. We recognize that accomplishment of this goal requires precise knowledge of the driving force behind the growth of cancer cells. Our work has focused on identifying the Achilles’ heels of cancer cells and developing treatments that target these abnormalities. This is exactly what we have accomplished with Gleevec. Gleevec targets the precise abnormality that drives the growth of white blood cells in patients with chronic myeloid leukemia (CML) and was FDA-approved for this disease just over 5 years ago. This well-tolerated, once a day pill has changed what was a routinely fatal disease into one with a five-year survival of 95%.

One of our current research programs is focused on optimizing treatment with Gleevec. In some patients with more advanced disease, we have seen relapses. Critical to our ability to circumvent relapses was gaining an understanding of why relapses occur. We have determined that in most patients whose disease recurs on therapy with Gleevec, the target of Gleevec mutates so that Gleevec can no longer inactivate it. With this knowledge, we identified a new class of drugs that could combat Gleevec resistance. Based on this knowledge, a new drug has completed clinical trials and was FDA-approved this year for patients with Gleevec resistance. Much like Gleevec, this pill is well-tolerated and highly effective. We are now determining how best to use this new medication, whether in combination with Gleevec or sequentially.

A second project we are working on aims to eradicate CML. Gleevec is a remarkable advance for patients with CML, but we currently view Gleevec as a life-long therapy. Specifically, Gleevec can control this disease extremely well, but we know that most patients have some remaining leukemia cells and if we stop treatment, these cells grow back. We are approaching this issue, which we term disease persistence, the same way we approached treating this disease with Gleevec and combating relapses during Gleevec therapy; that is, we are trying to determine what allows some leukemia cells to persist during Gleevec therapy and through this understanding, devising a way to eliminate these residual cells. This project requires us to develop new tools to purify leukemia cells from normal cells when the normal cells vastly outnumber the leukemia cells. Although technologically challenging, we view this as critical step in eradicating CML.

Lastly, we are exploring more rapid ways to identify the Achilles’ heels of other leukemias. We know that what drives the growth of CML is an enzyme that controls cell growth. This enzyme can either be on or off and is normally tightly regulated so that the right number of white blood cells is produced every day. When the enzyme is stuck on in CML, it produces large numbers of white blood cells. The enzyme that drives the growth of white blood cells in CML belongs to a family of enzymes that has 90 members and we have evidence that this family of enzymes is involved in driving the growth of other leukemias. We have developed techniques that allow us to sift through all 90 family members rapidly to determine whether targeting one of them would be an effective treatment for a specific patient’s leukemia. The long term goal of this project is to match the right patient with the right drug so that each patient has the most effective and least toxic treatment for their leukemia.

The support from the TJ Martell Foundation has again been critical to our progress in the past year and I look forward to another productive year.