Exploring the Biology of Lymphoma to Identify New Drug Targets
Summary
- Sylvester researchers discovered a new role for a protein, GAK, in diffuse large B-cell lymphoma, the most common form of lymphoma.
- Due to GAK’s role in helping cells divide, the scientists believe it could be a powerful drug target to combat this cancer.
- They recently received a $2.4M award from the National Cancer Institute to further uncover GAK’s biology and explore its potential as a therapeutic target.
Researchers at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, have uncovered a new aspect of cancer biology that could lead to improved treatments for diffuse large B-cell lymphoma (DLBCL), the most common form of blood cancer.
Through an innovative platform they designed, the researchers found that the protein cyclin-G associated kinase, or GAK, is essential for DLBCL cells to survive. The protein appears to play a key role in how these lymphoma cells divide. It could provide a novel drug target for better treatments for DLBCL.
The team, led by Jonathan Schatz, M.D., professor of medicine in the Division of Hematology at Sylvester, and Hassan Al Ali, Ph.D., associate professor of neurological surgery and medicine at the Miller School, recently received a four-year, $2.4 million award from the National Cancer Institute to support further exploration of this previously undiscovered aspect of cancer biology and to investigate the possibility of treating DLBCL by targeting GAK. The team’s grant proposal was ranked in the top 1% of all submissions nationwide, a rare achievement.
With the discovery of a brand-new role for the protein, the possibilities in front of the researchers are wide open, Dr. Schatz said.
“That’s a really exciting aspect of this project,” he said. “It’s completely undefined how this protein works. There’s a lot to discover, and our starting point is a blank slate.”
Unmet Need for Lymphoma Treatments
DLBCL makes up nearly one-third of non-Hodgkin lymphoma cases, with more than 30,000 new diagnoses every year in the U.S. Front-line therapies for the disease can be very effective, but leave around one-third of patients uncured, Dr. Schatz said. Immunotherapies, including cellular therapy, can cure some patients with relapsed or refractory DLBCL, but many are left without other options to treat their disease.
“It is still the case that the majority of people with relapsed or refractory DLBCL unfortunately will pass away from complications of their disease,” Dr. Schatz said. “That represents thousands of patients per year in the U.S. and tens of thousands around the world with unmet clinical needs.”
A New Platform for Drug Discovery
The team’s finding that GAK may play an important role in lymphoma came from a new technique that combines screening and AI technologies devised by Dr. Ali and Vance Lemmon, Ph.D., professor of neurological surgery and the Walter G. Ross Distinguished Chair in Developmental Neuroscience at the Miller School. The scientists aimed to improve the discovery of new drug targets, thereby streamlining the drug discovery process and reducing costs and time before new treatments make it to patients. Their platform is aimed at identifying cellular enzymes known as kinases that play many important roles in our cells.
Although Dr. Ali and his colleagues originally used the platform to identify potential targets for treatment of neurological diseases, he realized that it could be useful for finding undiscovered targets for cancer therapeutics as well. He teamed up with Dr. Schatz to find possible new drug targets for DLBCL and their studies uncovered GAK. In their initial experiments, blocking GAK’s kinase activity in the cell appears to kill DLBCL but not healthy cells, implying that treatments targeting GAK could be specific for the cancer and potentially spare patients from toxic side effects.
“Most chemotherapies are problematic due to broad toxicity,” Dr. Ali said. “The twist here is that we wanted to identify a drug target that will selectively kill the cancer cells and spare the normal cells.”
A New Role in the Cell
Before the Sylvester team’s work, GAK was known to act at the surface of cells, mediating transport of molecules into the cell. But the Sylvester researchers discovered that GAK’s activity is also essential in cell division, or mitosis. During the cell cycle as one cell splits into two, GAK helps dividing cells pull duplicated chromosomes apart, correctly partitioning them so each daughter cell receives the same number. This role for the protein had been suggested by some previous work, but the Sylvester researchers showed for the first time these activities are critically dependent on GAK’s enzymatic kinase function, the very thing that drugs are able to inhibit.
The majority of people with relapsed or refractory DLBCL unfortunately will pass away from complications of their disease. That represents thousands of patients per year in the U.S. and tens of thousands around the world with unmet clinical needs.
Dr. Jonathan Schatz
Cancer grows and divides rapidly, so it makes sense that a protein involved in cell division is important for cancer growth. It’s not yet clear why blocking GAK’s activity kills DLBLC cells but not healthy cells. That’s one of the mysteries the scientists are hoping to solve through the new project.
Drug Discovery and Repurposing
In a previous projects supported by a Small Business Technology Transfer grant from the National Center for Translational Science and the state of Florida’s William G. “Bill” Bankhead, Jr. and David Coley Cancer Research Program, the team also worked to identify new compounds that block GAK’s activity. That work now continues in parallel with the biological studies in the new project. But they also found that some existing drugs, including some that have been approved by the Food and Drug Administration for other cancers, also inhibit GAK.
In their new project, the researchers plan to test those compounds against DLBCL in preclinical studies with lymphoma, including some with patient-derived lymphomas. If any of these drugs show promise in the studies, they could be good candidates to test in clinical trials.
“We think GAK presents a very promising opportunity to define some new biology of mitosis, develop new understanding of cell cycle deregulation in lymphoma, and open up a new target for exploitation for drugs in lymphoma,” said Dr. Schatz.
Other researchers involved in the GAK project include Olivia Farag, Indigo Williams, Paola Manara, Ph.D., Preet Kumar, Lingxiao Li, Ph.D., and Santiago Vilar, Ph.D.
Tags: cancer research, diffuse large B cell lymphoma, Dr. Hassan Ali, Dr. Jonathan Schatz, drug discovery, immunotherapy, lymphoma, Sylvester Comprehensive Cancer Center