Cutting off a cancer’s food supply
A drug developed at MD Anderson 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.”
Researchers at MD Anderson’s Institute for Applied Cancer Science (IACS) are hoping to put an end to that drought with a drug they developed to starve these malignant blood cells to death.
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.
“We’re hopeful we’ll soon see in patients the promising response to IACS-10759 that we observed in preclinical models,” says Giulio Draetta, M.D., Ph.D., head of Therapeutics Development and director of IACS.
While researchers have found AML to be vulnerable, they’ve also discovered that subgroups of tumors in lymphoma, glioblastoma, melanoma, colorectal and pancreatic cancers harbor this weakness.
Leukemia and Lymphoma Society funds innovative trial
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.
IACS aims to provide MD Anderson physicians and patients access to novel drugs tailored specifically to vulnerabilities found in tumors of unique groups of patients. These projects are based on findings coming from basic scientists at MD Anderson.
“The IACS model emphasizes the need for us to deeply understand the biological effects of drugs,” Draetta says. “We want to increase the precision with which we identify and develop new molecules, and to ask critical questions about the effects of any new drug within the most relevant contexts.”
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.
“We’re already working closely with several MD Anderson Cancer Moon Shots Program™ teams to develop IACS-10759 treatment for patients whose tumors rely on oxidative phosphorylation,” says IACS Executive Director Philip Jones, Ph.D.
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.
Marszalek and Di Francesco say the collaborative nature of MD Anderson clinicians is invaluable. They connected with Konopleva, whose knowledge of AML and preclinical models was vital to developing IACS-10759 and has enabled the development of clinical assays to study the biology of OXPHOS inhibition in the ongoing clinical trial.
Additionally, the institute has a pipeline of other experimental drugs working their way toward first-in-human use, with others expected to enter clinical trials in the next year.
“There’s no shortage of good ideas at a place like MD Anderson,” Jones says. “Identifying therapies that will be impactful for specific patient populations and moving those medicines into clinical trials at MD Anderson is our mission.”
A clinical trial takes on a deadly blood cancerwith an experimental drug
IACS-10759 was developed by the Institute for Applied Cancer Science, which wasestablished in 2011 to develop new treatment options for cancer patients.
IACS is aplatform of the Moon Shots Program™ — the ambitious effort launched in 2012 toreduce cancer deaths by more rapidly developing and implementing advances inprevention, early detection and treatment based on scientific discoveries.
The trial will enroll up to 48 patients with relapsed or resistant AML.
Primary goals: Determine the safety and tolerability of the drug, establish amaximum tolerated dose and a recommended dose for a Phase II trial.
Secondary goals: Learn more about the drug’s pharmacokinetics and earlyindications of clinical impact, including overall response rates, duration ofresponse, progression-free survival and overall survival.
The expansion phase allows for enrollment of 12 patients to receive therecommended Phase II dose.
Leukemia and Lymphoma Society funding also provides for analysis anddevelopment of biomarkers for the drug.
Acute myeloid leukemia occurs when the myeloid stem cells that usually become healthy versions of some types of white blood cells, platelets or red blood cells instead become immature versions of those cells.
The Leukemia and Lymphoma Society estimates there were 19,950 new cases of AML diagnosed in 2016, mostly in adults, and the disease caused some 10,430 deaths.