Each year, more than 500,000 people are diagnosed with cancers of the head and neck. A recent study by researchers at Yale Cancer Center has identified a potential protocol that combines two targeted therapies to attack head and neck cancer. These cancers are known to be particularly difficult for patients, even those who are cured, as they can alter people’s appearances and their ability to eat and speak.
Cancer is generally the result of increased cell growth and proliferation, and one of the key proteins involved in that process is the Aurora kinase A (AURKA) protein. AURKA is responsible for regulating part of the cell cycle and interacting with p53-family proteins. Another important protein in a cell’s life cycle is the WEE1 protein. Both the AURKA and WEE1 proteins are involved in in these key cellular processes. During one phase of the cycle, the dividing cell creates “spindles” that help pull apart the two sets of DNA. AURKA is needed for the spindles to work properly, and WEE1 encourages the final separation of the cells.
Many cancer patients appear to show an increased level of the AURKA protein, but high AURKA levels may be associated with worse outcomes in patients with head and neck cancers. Researchers developed an ARUKA inhibitor called alisertib, but it was not effective on its own so researchers returned to the lab to look for other drugs to combine it with.
Research has shown that the WEE1 protein is able to boost the effects of cisplatin chemotherapy on head and neck tumors with p53 mutations and resulted in the creation of a WEE1 inhibitor called adavosertib. Researchers at Yale wondered if combining inhibitors for both the AURKA and WEE1 proteins could create a “synthetic lethal effect” against head and neck cancer.
Jong Woo Lee, PhD, the lead author of the paper, experimented with the combination of alisertib and adavosertib in human cells that had non-HPV-associated head and neck cancers and found that it killed more cells than either inhibitor on its own. Collaborators studied the effect further through in vivo models, in which tumors created from human cells were grafted into mouse models, and they found that the drug combination stopped tumor growth in these models.
Researchers are now designing an early clinical trial of the drug combination for patient testing. In a second trial, they plan to examine the effects of giving each drug alone, as well as in combination, to patients before surgery. The broad goal of the studies is to determine if combining AURKA and WEE1 inhibitors can act like a synthetic lethal therapy in other cancers that depend on AURKA and have p53 mutations.