An MD Anderson drug developed to starve cancer is tested on an aggressive leukemia
For decades, combination chemotherapy has been the main treatment for patients with acute myeloid leukemia (AML) – an aggressive cancer of the blood and bone marrow.
“About 40 percent of younger patients survive long term, and for those over 65, survival drops to 10 percent,” says Marina Konopleva, M.D., Ph.D., professor of Leukemia. “There’s been no drug approved for the last 40 years for AML, and outcomes haven’t significantly improved with targeted therapies.”
The initial Phase I clinical trial of the drug known as IACS-10759 opened for patients in October, a milestone for IACS, which acts as a biotech company embedded in a cancer center. The institute connects MD Anderson faculty with drug discovery and development expertise.
Konopleva and Naval Daver, M.D., assistant professor of Leukemia, lead the AML trial, which is funded by a $3.5 million investment from the Leukemia and Lymphoma Society under its Therapy Acceleration Program, part of an intensive campaign the society launched against AML in late 2016.
Putting cancer on a lethal diet
Based on an approach discovered by the institute, IACS-10759 is designed to target a metabolic vulnerability of AML cells.
Most cells rely on two metabolic processes to survive. Cellular organelles called mitochondria use oxygen to convert energy stored in sugars, fatty acids and proteins into energy through a process called oxidative phosphorylation (OXPHOS). Cells also convert glucose to energy in the absence of oxygen through a less efficient process called glycolysis. IACS-10759 inhibits OXPHOS, thus one of two arms of metabolism that provide energy and building blocks to cancer cells.
Konopleva says her team’s research has shown that AML cells are highly dependent on these mitochondria-driven processes.
“OXPHOS is how they survive, but no one has had a clinically viable inhibitor,” she says.
Enter IACS, where scientists, applying their drug development expertise and capacity for rapidly testing and understanding the mechanism of possible drugs in preclinical models, developed IACS-10759.
“Normal cells can get around OXPHOS inhibition by turning up glycolysis, but we’ve identified some cancers like AML that can’t do that enough to survive,” says Joseph Marszalek, Ph.D., head of Translational Biology for the Center for Co-Clinical Trials.
Create, test, refine, test again
It’s taken a team of more than 25 people to successfully bring IACS-10759 into clinical trials. Emilia Di Francesco, Ph.D., associate director of Medicinal Chemistry at IACS, leads a group that crafts small-molecule drugs to efficiently hit targets in cancer cells while avoiding off-target effects.
Marszalek’s group puts those drugs to the test in cell lines and mouse models. What they discover about the drug’s efficacy and side effects is fed back to Di Francesco’s group, which fine-tunes the drug.
This intensive, reiterative process allowed them to analyze a series of molecules over 18 months before zeroing in on IACS-10759 for development.
“We needed to refine the drug for the clinic and build in all the properties to make it more effective in patients,” Di Francesco says.
Joseph Marszalek, Ph.D., head of Translational Biology for the Center for Co-Clinical Trials, and Emilia Di Francesco, Ph.D., associate director of Medicinal Chemistry at the Institute for Applied Cancer Science. photo by Wyatt McSpadden