Emerging Enzyme

July 26, 2017

Testing under way of small molecule that may block many disease pathways


Innovations in Pediatrics - Summer 2017

JOHN LETTERIO, MD

Division Chief, Pediatric Hematology & Oncology, UH Rainbow Babies & Children’s Hospital, Jane and Lee Seidman Chair in Pediatric Cancer Innovation; Professor of Pediatrics, Case Western Reserve University School of Medicine

Pediatric oncologist John Letterio, MD, has spent a career studying a variety of pathways important in cancer and immune cell biology. But when he and six members of his team left the National Institutes of Health for University Hospitals Rainbow Babies & Children’s Hospital 11 years ago, they embarked on a new line of inquiry. Their target? An enzyme called cyclin-dependent kinase 5 (cdk5).

“There was a huge amount of evidence that cdk5 played an important role in normal brain development and other processes in the nervous system, such as pain signaling,” says Dr. Letterio, Chief of Pediatric Hematology and Oncology and Director of the Angie Fowler Adolescent & Young Adult Cancer Institute at UH Rainbow. “But no one had described a role for this kinase outside of the brain and peripheral nerves. That was curious to us because it is expressed everywhere. We focused in two areas – how this kinase might regulate normal immune cell function and separately how it might be important in cancers that derive from the neural crest.”

Just over 10 years later, Dr. Letterio and his team have made significant progress on both scores. They’ve shown that cdk5 plays a critical role in the immune synapse, mediating interactions between antigen-presenting cells and lymphocytes.

“Rather surprisingly, cdk5 plays a very important role in regulating communication between various immune cells and we believe that it may be critical for forming immune memory,” he says. This, in turn, has opened the possibility of targeting this kinase in a variety of immune disorders where the function of T cells may be critical, such as multiple sclerosis (MS) and graft vs. host disease (GVHD), which is a complication that can follow bone marrow transplantation. In a paper recently published in the journal Blood, the team reported dramatically lower rates of GVHD among mice when the expression or activity cdk5 had been blocked.

“In preclinical models of MS, we’ve also shown that if we target cdk5 through genetic strategies, it’s protective against disease,” Dr. Letterio adds.

On the brain tumor front, Dr. Letterio partnered with Alex Huang, MD, Agne Petrosiute, MD, and Duncan Stearns, MD, colleagues from Angie’s Institute, to make important discoveries. Writing in the journal Science last summer, the team reported that cdk5 allows medulloblastoma to evade immune elimination – and that disrupting it genetically promotes anti-tumor immunity.

“When we disrupted the expression of this enzyme in medulloblastoma, the most common childhood brain tumor, it changed the way the tumor was recognized by the immune system,” he says. “It made the tumor more immunogenic – more readily recognized by the immune system. There may be a way for us to enhance the utility of immune-based therapies by targeting cdk5.”

To this end, Dr. Letterio and his team have designed the first small molecule that blocks specifically cdk5 but not other kinases within the cdk family. The unique structure impairs two domains required for the function of the enzyme, and represents and important innovation in the field.

“Cdk5 has been known as a target for diseases, but a major hurdle has been the inability to inhibit it specifically,” he says. “We are anxious to move this technology forward and show that it can be given to patients.”

Pharmacokinetic and pharmacodynamic testing of the molecule is currently under way, supported by funding from the Harrington Discovery Institute at University Hospitals.

“The Harrington Discovery Institute recognizes the potential value of this technology, and it is supporting our effort to move it through the next phase of its development,” Dr. Letterio says. “We know our molecule is absolutely specific – we’ve been able to test it against other members of the cdk family and we know it has no effect on those kinases. Our next step is to learn more about how it behaves once we administer it in preclinical models of human disease where we think cdk5 is a potential therapeutic target.”

Initially, the focus will be on preclinical models of neurodegenerative disease, T cell-mediated inflammatory disease and cancer.

”There is very good evidence that the accumulation of tau protein in the progression of Alzheimer’s disease is a consequence of hyperactivity of cdk5 in the brain,” Dr. Letterio says. “There’s a lot of interest in Cdk5 as a drug target for Alzheimer’s and other neurodegenerative disorders.”

However, Dr. Letterio and his team have learned to follow where the science leads them.

“With cdk5, the list of proteins that it modifies is so broad,” he says. “Every day there are new substrates that are being identified and whose function depends on this enzyme in one way or another. There are tremendous opportunities for human benefit if we can progress our technology toward clinical application. Inflammatory pain, for example, absolutely depends on cdk5. We are facing a major health care crisis as a consequence of addiction to opioids and other pain killers. If our molecule represents a strategy for non-opioid pain control, that could have tremendous value and significant potential for reducing pain and suffering.”

For more information on this research, email Peds.Innovations@UHhospitals.org.

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