National Cancer Institute Award Funds Further Development of GAK, a Potential Target in DLBCL

Researchers at Sylvester Comprehensive Cancer Center, part of the University of Miami Miller School of Medicine, recently received a four-year $ 2.4 million award from the National Cancer Institute (NCI) to further explore their discovery of a new role for a protein called cyclin G associated kinase (GAK) in diffuse large B-cell lymphoma (DLBCL) – the most common form of blood cancer.[1]

In their earlier foundational work, the researchers found that 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.

Cyclin G-associated kinase (GAK) as a tumor-selective, readily druggable target whose inhibition killed DLBCL cell lines, while sparing normal, non-malignant blood cells. In ongoing studies, the researcher found that inhibition of GAK results in G2/M-phase cell cycle arrest. [1]

Based on these findings, the believe that GAK could provide a novel drug target for better treatments for DLBCL.

Further research
The research 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 of Medicine, will further explore this previously undiscovered aspect of cancer biology and investigate the possibility of treating DLBCL by targeting GAK.

The team’s grant proposal was ranked in the top 1% of all submissions nationwide.

“With the discovery of a brand-new role for the protein, the possibilities in front of the researchers are wide open,” 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,” he further noted.

Diffuse large B-cell lymphoma
“Diffuse large B-cell lymphoma or DLBCL makes up nearly a third of non-Hodgkin lymphoma (NHL) 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,” Schatz explained.

“Immunotherapies, including cellular therapy, can cure some patients with relapsed or refractory DLBCL, but many are left without other options to treat their disease,” he added.  As a result, there is a critical need to identify novel targeted therapies to improve outcomes. [1]

AI technologies
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 Ali and Vance Lemmon, Ph.D., professor of neurological surgery at the Miller School of Medicine.

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.

“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,” Schatz concluded.

Reference
[1] Lightfuss OB, Kumar P, Li L, Shastri T, Newsam AD, Manara P, Alaoui AY, Parets DEH, Younes PA, Chahar D, Arumov A, Coughlin CA, Williams IP, Fattakhov N, Martinez AB, Landgren O, Schurer SC, Lemmon V, Maura F, Bilbao D, Feng Y, Al-Ali H, Schatz JH. The cyclin-G associated kinase (GAK) is a novel mitotic kinase and therapeutic target in diffuse large B-cell lymphoma. bioRxiv [Preprint]. 2024 Oct 26:2024.10.21.619489. doi: 10.1101/2024.10.21.619489. PMID: 39484514; PMCID: PMC11526999.

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