Targeted Therapies Prove Effective Against Head and Neck Cancers

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.

Study Suggests New Standard for Kidney Cancer

Investigators at the Dana-Farber Cancer Institute recently completed a phase 3 clinical trial that could lead to changes in the standard treatment protocol for advanced kidney cancer. The trial tested a combination of the immunotherapy medication, avelumab, and axitinib, a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), against sunitinib, another VEGFR TKI, which is currently the standard treatment for advanced clear-cell renal carcinoma, the most common form of kidney cancer.

This trial was the first to combine avelumab with an agent that targets one of the receptors controlling angiogenesis. VEGFR inhibitors, like axitinib and sunitinib, are designed to block the blood supply to tumors, starving them of essential nutrients. Immunotherapy medications, like avelumab, block an immune checkpoint called PD-L1, and activate the body’s T-cells so they are more effective in fighting cancer cells.

The randomized study consisted of 886 patients with previously untreated, advanced renal cell carcinoma. Results of the study showed that patients receiving the combination of avelumab and axitinib had a higher response rate than those receiving sunitinib, causing greater tumor shrinkage. The results for patients whose cancer cells were positive for the PD-L1 checkpoint showed a median progression-free survival (PFS) of 13.8 months in the combination group compared to 7.2 months in the sunitinib group. The PFS for the overall population was the same for the combination group, and was 8.4 months in the sunitinib group. Tumor shrinkage was 55.2% in the combination group compared to 25.5% in the sunitinib group who were positive for PD-L1.  

While PFS improved with the drug combination, researchers plan to continue follow ups with patients to determine if the combination of medications extends the overall survival rate compared to the standard regimen. Senior author of the study, Toni Choueiri, MD, hopes the results will lead to an FDA approval for the combination in the near future and a shift in the standard of care for patients with this difficult-to-treat cancer.