Research: Unraveling the mysteries of cancer and neurodegeneration

Picture of Drs. Kun Ping Lu and Xiao Zhen Zhou
Scientists Drs. Kun Ping Lu and Xiao Zhen Zhou are navigating a delicate balancing act.

They are studying a stress response enzyme involved in a puzzling inverse relationship between cancer and Alzheimer’s disease: People at risk for one disease are less likely to get the other.

Lu and Zhou believe this enzyme, called Pin1, plays a role in both diseases – its overexpression is linked to cancer, while its absence is associated with Alzheimer’s.

“It’s like studying two sides of the same coin,” said Zhou. “It’s a big challenge.”

The accomplished duo has brought their research program to Schulich Medicine & Dentistry, making the move from Harvard University to join the Departments of Biochemistry and Pathology and Laboratory Medicine.

“Our biggest goal is to translate our discoveries into clinical practice,” said Lu. “The School is championing this development from basic science to the clinic, so we feel it’s a perfect match.”

Keeping the balance

The Pin1 enzyme plays an important role in protein management, helping a particular set of proteins maintain their correct shape and function.

Included in this group is the tau protein, a vital player in brain health. When dysregulated, tau can deform into a highly toxic neuroprotein known as cis tau, an early disease driver leading to the formation of the neurofibrillary tangles observed in Alzheimer’s.

When Pin1 levels are too low, the tau protein deforms. But when levels are too high, Pin1 also participates in several cancer-associated signaling pathways that promote the onset and growth of cancer cells.

This enzyme is a master regulator of aging, and its dysregulation can have a huge impact. 

Lu and Zhou are looking at ways to manipulate Pin1, developing novel therapeutics to target the enzyme and its substrates, and improve treatment for both cancer and Alzheimer’s patients.

In their early studies, the pair made the unexpected discovery that Pin1 is the major cellular target for approved leukemia drugs to cure over 90 per cent of acute promyelocytic leukemia (APL). In one ground-breaking study, they further investigated whether targeting Pin1 using these approved drugs can make tumors responsive to an immunotherapy in animal models of pancreatic cancer, finding the approach to be 90 per cent effective. The first in the world to demonstrate this, the research is now informing new clinical trials to be started in the US and UK.

But despite the promising result, the challenge remains that by inhibiting Pin1 to treat cancer, the risk for Alzheimer’s may eventually increase.

“We will need to find a balance,” said Lu. “Fortunately, mice lacking Pin1 are normal for over half of their lifespan before developing Alzheimer’s disease, suggesting that Pin1 inhibitors might be safe for an extended period of time for treating aggressive cancer.” 

Tackling concussion

As part of her early work on Alzheimer’s, Zhou developed an antibody to target the misshapen cis tau protein. The researchers have shown that this same antibody can reverse concussion-related brain damage as well as stroke-related brain damage in mice.

Cis tau can be detected in the blood within eight to 24 hours after a traumatic brain injury, and higher levels are linked to increased severity and worse outcomes, including increased risk for chronic traumatic encephalopathy and Alzheimer’ disease. Moreover, in Alzheimer’s disease patients, cis tau can also be detected in the blood before any clinical symptoms appear.

The antibody interrupts the effects of this toxic protein, blocking the spread of cis tau in the brain and preserving cognitive function. The researchers co-founded start-up company Pinteon Therapeutics in 2014 to commercialize the antibody, which is now undergoing the first of two clinical trials.

“Our work shows the direct causal relationship between traumatic brain injury and neurodegeneration,” said Zhou.

Since the longer-term effects of neurodegeneration associated with brain injury don’t appear until many years or decades later, the antibody could prove to be a game-changing preventative treatment.

“Neurodegeneration is a slow process,” explained Zhou. “This toxic protein appears early after brain injury or stroke, and in Alzheimer’s disease, so if we can detect it early and stop it, we may also be able to stop neurodegeneration and memory loss.”

Collaborating together

As life and lab partners, Lu and Zhou have forged a unique and successful collaboration.

“There are challenges, but we have found balance,” said Lu. “We each take care of different aspects of the research. Xiao knows the technology and she tells me if my ideas are practical or unrealistic, and then translates them.”

“We complement one another,” added Zhou.

Lu completed a medical degree at Fujian Medical University and pursued a master’s program at Suzhou Medical College, which sparked an interest in cell-growth regulation. He was recruited to join the doctoral program at Baylor College of Medicine in Houston, later transferring to Duke University. He then completed a postdoctoral fellowship at the Salk Institute for Biological Studies, where he discovered Pin1.

Zhou completed her medical degree at Suzhou Medical College and accepted research positions at the University of Texas and Duke University before completing her postdoctoral training at the Scripps Research Institute.

Their research interests converged as faculty members at Harvard, where they worked together for 25 years.

New adventures

Arriving at Schulich Medicine & Dentistry earlier this year, the husband-and-wife team are looking forward to engaging with Western’s research community.

“There are other scientists at the University studying Pin1, so it is a great fit for us,” said Lu. “The Canadian research environment is very collaborative.”

Lu and Zhou are also invested in training and mentorship. “We cannot do this work without trainees, they are a very important part of our lab and help us succeed as principal investigators,” said Lu. “We need to pass knowledge on to the next generation, so they can lead into the future."