A Blueprint toward Effective Treatments for Every Patient, Every Time

About 6,000 people in the United States are diagnosed with the blood cancer chronic myeloid leukemia (CML) each year. Before the current treatments were available, only about 50% of patients survived for five years after diagnosis. Now more than 90% make that mark. There’s a problem, though—20-30% of CML patients become resistant to one or more of the available treatments. Researchers from the Deininger/O’Hare Lab at Huntsman Cancer Institute (HCI) weren’t satisfied that any patients were left with no treatment options. They set out to challenge what’s possible for CML patients.

A chromosomal abnormality that produces an enzyme called BCR-ABL is the driving force in CML. Unlike normal white blood cells, CML cells produce and rely upon BCR-ABL for survival. The drugs currently available, called tyrosine kinase inhibitors (TKIs), target BCR-ABL. The disease is not cured, but the treatments let many patients get back to a normal life and a close-to-normal lifespan.

Most cases of CML resistance result from a single mutation in BCR-ABL, and drugs to control resistance to TKI treatment caused by various single mutations have already been discovered. But BCR-ABL mutants that contain two mutations in the same molecule, termed compound mutants, render some or all of the available TKIs ineffective.

The research team headed by Michael Deininger, MD, PhD, and Thomas O’Hare, PhD, co-senior authors of the study, focused on BCR-ABL compound mutants observed in patients and tested them against all approved TKIs, compiling data that can potentially help clinicians decide which drug will be most effective for each mutation combination. They found that none of the TKIs are effective for some compound mutations, underscoring the need to develop new treatments before this unmet clinical need expands.

The team performed gene sequencing on about 100 clinical samples. “This gave us a large body of data to shed light on the number of compound mutations and how they develop,” says Deininger, professor of internal medicine and an HCI investigator. “One key finding was that compound mutations containing an already known mutation called T315I tend to confer complete resistance to all available TKIs.”

John M. Goldman

In addition to Zabriskie, Deininger, and O’Hare, the study’s authors included 39 other researchers representing HCI, the University of Utah, and 22 other institutions worldwide. The Cancer Cell article was dedicated to the legacy of Professor John M. Goldman of Imperial College London, whose work and mentorship made a major mark on the field of CML. “His passing in December 2013 left a very big gap in the CML community,” says Deininger. (photo credit www.cibmtr.org)

“Fortunately, the problems we are studying affect a minority of CML patients, but still this leaves some patients with no good treatment option at all,” says O’Hare, associate professor in the Division of Hematology and Hematologic Malignancies. “Our goal is to have a TKI option for every patient.”

Working with HCI computational chemist Nadeem Vellore, PhD, the research team modeled at the molecular level why the drugs do not bind to certain BCR-ABL compound mutants. “This puts us in position to evaluate new drug candidates and work toward developing new treatments,” says O’Hare.

“Computational analysis was one of the most interesting parts of the study. It not only confirmed what we found but showed the reason behind it,” says Matthew Zabriskie, BS, co-lead author of the study. “We’ve established what the next level of TKI resistance is going to entail.”

According to O’Hare, it is only a matter of time until analogous compound mutations emerge in many other cancers, including non-small cell lung cancer (NSCLC) and acute myeloid leukemia (AML). In these diseases, scientists and clinicians are still learning how to control single mutation-based resistance. “Our findings in CML will provide a blueprint for contending with resistance in these highly aggressive diseases as well,” he says.

“Once you know exactly what’s wrong, you can use exactly the right tool to fix it. I guess this is what precision medicine is all about,” Deininger says.

This study was supported by the Leukemia & Lymphoma Society, the American Society of Hematology, Howard Hughes Medical Institute, Huntsman Cancer Foundation, and the National Institutes of Health/National Cancer Institute grants P30CA042014 and R01CA178397.