Crystal structure of human Wee1 kinase.
For about the last 40 years, the triad of surgery, chemotherapy, and radiation has been the standard of care for head and neck cancers. But the toll of chemotherapy and radiation can sometimes be as debilitating as the effects of the disease. This reality has led may researchers to seek alternative, more precise, therapies capable of selectively killing malignant cells while sparing healthy ones.
The laboratory run by Ahmed Diab, PhD, Assistant Professor of Otolaryngology – Head and Neck Surgery at the Perelman School of Medicine at the University of Pennsylvania, appears to be nearing such a discovery.
When Dr. Diab began his postdoctoral research in 2016 at the Fred Hutchinson Cancer Center in Seattle, researchers there were already three years into studying a potential new therapy for head and neck cancers that targeted the cell cycle enzyme WEE1 kinase.
WEE1 kinase is a checkpoint kinase that prevents cells from dividing when there’s evidence of damage to DNA – a critical function in light of all the possible threats the genome encounters on a daily basis, including alcohol and environmental pollutants, and mutations that occur naturally in our DNA.
“Cells need to fix that damage before they divide because if they incur too much damage, it can lead to cell death,” Dr. Diab says. “Our cells have mechanisms in place to monitor and help them deal with the damage, and one of them is created by this protein.”
A second checkpoint is created by a protein called p53, the loss of which is a theme in many cancers, according to Dr. Diab.
When this happens, cancer cells become entirely reliant on the WEE1 kinase checkpoint, now their only option for cell damage repair and survival.
The clinical trial led by the Fred Hutchinson Cancer Center studied the safety and efficacy of a WEE1 kinase inhibitor. The results, Dr. Diab says, “were very encouraging,” but they found that those who were positive for human papillomavirus (HPV), a sexually transmitted infection that 90 percent of sexually active men and 80 percent of sexually active women in the United States will contract in their lifetime, responded particularly well to the drug.
A tumor virologist, Dr. Diab’s research at the time focused on why that was. He knew that HPV makes a protein that directly disrupts p53 function. He would come to learn that HPV infection also rewires the cell cycle machinery in multiple ways that collectively increase their reliance upon the WEE1 kinase.
In that initial clinical trial, the researchers first treated participating patients with chemotherapy to induce DNA damage, essentially forcing the cancer cells to turn to the WEE1 kinase checkpoint. The team then administered Adavosertib (AZD1775), a potent selective small-molecule WEE1 kinase inhibitor developed by AstraZeneca.
The protocol safely activated apoptosis in the cancer cells, as the researchers hoped, but, the future of Adavosertib was dampened, Dr. Diab notes, when other studies, with different dosing and combination regimens, prompted concerns about the drug’s potential to be toxic for patients. As a result, AstraZeneca halted the clinical development of Adavosertib.
Many small pharmaceutical companies have since begun developing their own second-generation versions of the inhibitor, says Dr. Diab, who’s been using these drugs in his research at Penn.
“My lab now continues to investigate how inhibition of WEE1 kinase not only kills HPV-positive tumor cells but also signals to the larger tumor microenvironment to promote immune clearance of these tumors,” he says.
As part of a clinical department at Penn, Dr. Diab’s lab is working with head and neck surgeons to secure samples of patients’ tumors, which researchers are culturing, studying, and treating with the different second-generation inhibitors.
He describes the work as translational.
“It does happen that we go from the bedside to the bench and back to the bedside,” Dr. Diab says. “When we’re working at the bench, we have in mind, ‘How can we take this to the clinic?’ Aside from the pharmaceutical companies developing these drugs, we’re also working closely with our medical oncologists and surgeons here at the university to make sure that the science we are generating is relevant to the patients, that it’s actually helping them.”
The dynamic has also condensed a process that once unfolded over 15 years to just a couple of years, he adds.
For Dr. Diab, even glimpsing the hint of a light at the end of this particular tunnel is an achievement.
“Science itself is hard,” he says. “There’s a lot of disappointment. And there’s a lot of failure. Not every experiment you do works, not even every one in 10. So, what makes this exciting and fulfilling is the potential it carries: One day your work can help improve the lives of cancer patients and reduce their suffering. This hope is what keeps us moving forward.”