Unravelling the mysteries of cancer and neurodegeneration
Drs. Kun Ping Lu and Xiao Zhen Zhou are studying a stress-response enzyme involved in a puzzling inverse relationship between cancer and Alzheimer’s disease
By Emily Leighton, MA’13
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.
“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.
The 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 more than 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 tumours responsive to 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.
“We will need to find a balance. 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.”
— Dr. Kun Ping Lu
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 more than 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’s 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.”
