Scientists identify key protein behind drug-resistant leukemia

Acute lymphoblastic leukemia, or ALL, is the most common form of childhood cancer. While most children treated for this disease survive, in a subgroup of patients the disease does not respond to treatment. Now a team of scientists led by researchers at Children's Hospital Los Angeles and the University of California San Francisco (UCSF) have identified the reason for this drug resistance: BCL6, a protein that leukemia cells use to stay alive in spite of chemotherapy. Targeting this protein provides a novel key mechanism to fighting drug-resistant leukemia.

"We believe this discovery is of immediate relevance to patient care," said Markus Müschen, MD, an investigator at The Saban Research Institute of Children's Hospital Los Angeles and lead author on the study.

In a significant breakthrough, investigators working at Children's Hospital Los Angeles and UCSF have been able to overcome resistance to targeted drug therapy, demonstrating complete eradication of the cancer in cell and animal studies. The study, published in the May 19 issue of Nature, shows that an investigational drug, RI-BPI, developed at the Weill Cornell College of Medicine, used in combination with the drug Gleevec, shut down stem cells that give rise to leukemic cancer cells. Gleevec is a targeted therapy effective against many different cancers including ALL, a cancer of white blood cells that affects older adults as well as young children. While Gleevec has greatly improved survival of leukemia patients, there continues to be a small subset of patients who do not respond to therapy and ultimately die from their disease.

"The desperate prognosis that exists for a subset of ALL patients may radically change given these results," said co-author Ari Melnick, MD, an associate professor of pharmacology at Weill Cornell Medical College, who initially developed RI-BPI. "I'm pleased to see that RI-BPI has such strong activity against leukemia. This opens up the possibility that the compound may have similar beneficial effects in other tumor types."

This new study demonstrates that BCL6 is active in ALL driven by the Philadelphia chromosome (Ph⁺ ALL), and that a combination of RI-BPI and Gleevec virtually "turns off" the cancer. As described in the journal Nature this week, Müschen and his colleagues showed that mice with drug-resistant leukemia can be cured of the disease when given conventional cancer drugs in combination with a compound that disables the BCL6 protein.

The BCL6 protein was already known to cancer researchers because it is active in other forms of cancer. Reasoning that blocking BCL6 would make leukemia cells more sensitive to chemotherapy, the scientists showed exactly that. Now Müschen is looking for ways to do the same thing with small molecules, which are generally easier to formulate into an oral drug and cheaper to mass-produce than biotech drugs like peptides. Last year, he was awarded a $3.6 million grant from the California Institute for Regenerative Medicine (CIRM) to develop such a molecule. Dr. Müschen is a Research Associate Professor of Pediatrics, Biochemistry and Molecular Biology at Children's Hospital Los Angeles and a professor of Laboratory Medicine at UCSF.

Source: Children's Hospital Los Angeles