If cancer cells were a car, Dr. Eduardo Méndez of the Clinical Research Division at Fred Hutch has found a way to throw sand in the gears of certain head and neck cancers.
It’s a type of cancer for which patients struggle with quality of life, as the disfiguring tumors and current treatments for it can impinge on their ability to speak or eat. Less toxic, more targeted agents are needed, but to date, there is only one approved targeted agent and only about 10 percent of patients respond to this treatment.
With a new five-year, $2.2 million grant from the National Institutes of Health, Méndez and his team aim to develop the first targeted therapy that they hope will work for more patients with head and neck cancers.
Méndez studies the genomics of head and neck cancers, looking for vulnerabilities in the growth process of cancer cells. Even rapidly growing cancer cells need to stall their development at some points to make fixes, he said, and that’s where he’s looking for ways to stop cancer in its tracks.
“In a car race, you want to go fast but even so you have to strategize on when to stop to change tires or do other necessary maintenance,” Méndez explained.
Recent genomic studies have unveiled that loss of a gene called p53, a master regulator of cell growth, was the most frequently mutated gene in head and neck cancers and that this loss was associated with poor survival.
So far there’s no way therapeutically to restore p53, but Méndez and his team have discovered a promising alternative that could potentially benefit a large proportion of patients with head and neck cancers and possibly other tumors with this genetic defect.
With seed funding from the Fred Hutch/University of Washington Cancer Consortium and Seattle Translational Tumor Research, Méndez paired up with Dr. Christopher Kemp of the Fred Hutch Human Biology and Public Health Sciences divisions and co-founder of Cure First, a nonprofit research organization; and Dr. Carla Grandori, president and scientific director of Cure First, to look at potential vulnerabilities that p53-deficient tumors have developed.
“We reasoned that these tumors would depend on other partner genes that regulate cell division to repair DNA and maintain cell division,” Méndez said. “By targeting these partner genes, we figured that would render tumor cells incapable of repairing errors in their genetic code and cause uncoordinated cell division that would lead to cell death.”
Like if a car loses the main brake pedal, the parking brake could be used instead to slow it down and avoid a crash.
The Fred Hutch researchers did a series of experiments to see what other genes served as that second brake. It turned out to be a gene called WEE1, which acts as a backup checkpoint as cells divide. The gene pauses cell division to give cells a chance to repair any DNA mistakes. Without it, cells divide with damaged DNA and then they can’t survive.
After promising findings in preclinical models, Méndez opened a Phase 1 clinical trial using a drug that blocks WEE1. The results so far have been “astonishing” in the 11 patients treated, Méndez said.
What is more, they found that HPV-positive head and neck cancers were also sensitive to this treatment despite having a normal p53 protein. This is because the HPV proteins disable p53 to promote cancer growth. Thus, targeting WEE1 has the potential to treat not only p53 mutated tumors, but those in which p53 is inactivated by HPV.
“This couldn’t have been done without the support and collaborations available at the Hutch. It calls to the true spirit of ideas and doing things that individual labs cannot do on their own,” Méndez said.
This initial success through the seed funding provided the green light for him to apply for NIH funding.
With the new funding, Méndez has expanded his team to include experts in DNA replication stress, cell cycle and HPV: Dr. Bruce Clurman, Fred Hutch executive vice president and deputy director; Dr. Denise Galloway, associate director of the Human Biology Division at Fred Hutch; and Dr. Julia Sidorova of the University of Washington. The team will explore the mechanisms by which targeting WEE1 kills tumors with p53 deficiency and look for ways to improve treatments for more patients.
He will also look for other partner genes that work with WEE1.
“The hope is that targeting these partner genes in combination with WEE1 will lead to a more durable and effective response and lessen our reliance on toxic chemotherapy and radiation — the current standard of care for aggressive head and neck cancers.”
— Molly McElroy
Fred Hutch computational biologist Dr. Harlan Robins, co-founder of Adaptive Biotechnologies, has received a Pacific Northwest Entrepreneur of the Year Award in the life sciences/health care category. He shares the award with his brother Chad Robins, who is president and CEO of the company, a Hutch spinoff.
Adaptive Biotechnologies is a pioneer and leader in combining high-throughput sequencing and expert bioinformatics to profile T- and B-cell receptors in the adaptive immune system.
The Robins brothers received the honor June 9 at EY’s Entrepreneur of the Year Awards in Bellevue. The Pacific Northwest finals of the national business competition, to be held in November, recognized winners across seven categories. Finalists in the “enterprise technology” category also included another team of brothers: Rick and David Cantu of Redapt, a Redmond-based systems-integrator and cloud-services company.
— Kristen Woodward