Axitinib has a previously unrecognized action as a potent inhibitor of the dominant mutation that confers drug resistance to all well-tolerated treatments in patients with certain types of leukemia. These findings were published in Nature (2015; doi:10.1038/nature14119).

The international research team included researchers at the Institute for Molecular Medicine Finland FIMM and Faculty of Medicine, University of Helsinki and the Helsinki University Central Hospital Comprehensive Cancer Center, in close collaboration with researchers at Pfizer, the manufacturer of axitinib.

They studied cancer cells from patients with chronic myelogenous leukemia (CML) and acute lymphoblastic leukemia (ALL) that had developed resistance to currently available treatments. These cancers are driven by the BCR-ABL1 fusion protein and resistance to treatment developed due to a new genetic mutation in that fusion gene in the cancer cells.

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Two critical factors were integral to the outcome of this study. First, the Drug Sensitivity and Resistance Testing (DSRT) method developed at FIMM made it possible to study the response of these cancer patients’ leukemia cells to a large panel of drugs simultaneously, thus identifying axitinib as a promising drug candidate. Using this approach, the researchers found that axitinib, a tyrosine kinase inhibitor currently approved to treat advanced renal cell carcinoma in certain patients, effectively eliminated these patient-derived drug-resistant leukemia cells.

“This screening method is a key component of FIMM’s Individualized Systems Medicine strategy. The drug panel covers all approved and many emerging cancer therapeutics, and thus enables an individualized selection of potentially effective therapies for leukemia patients,” explained Krister Wennerberg, PhD, FIMM-EMBL Group Leader and a corresponding study author.

Second, by coupling this screening method with Pfizer’s deep oncology and structure-based drug discovery expertise, the researchers were also able to define the mechanism by which axitinib binds to the drug-resistant version of the BCR-ABL1 protein, providing fundamental new molecular insights into how cancer-causing kinases can be blocked.

“If you think of the targeted protein as a lock into which the cancer drug fits in as a key, the resistant protein changes in such a way that we need a different key. In the case of axitinib, it acts as two distinct keys, one for renal cell carcinoma and one for leukemia” said Brion Murray, PhD, Pfizer Research Fellow and one of the lead authors of the study.

“Since axitinib is already used to treat cancer, its safety is known and a formal exploration of its clinical utility in drug-resistant leukemia can now be done in a fast-track mode. Thus, the normally very long path from lab bench to bedside is now significantly shortened,” said Kimmo Porkka, MD, PhD, Head of Hematology at Helsinki University Central Hospital Comprehensive Cancer Center and one of the lead authors.

“Our findings highlight the power of drug repositioning, in other words, searching for novel uses for existing, emerging, and abandoned drugs. This study shows what can be achieved when academic institutions and pharmaceutical companies team up to study effects of drugs using cells directly obtained from patients,” said Olli Kallioniemi, MD, PhD, the Director of FIMM.