Screening for genes that head and neck squamous cell carcinomas (HNSCC) need to survive, researchers have identified a potential new drug for the disease that will enter clinical trials later this year.
Eduardo MÃ©ndez, M.D., of the head and neck surgery department at the University of Washington Medical Center and the Fred Hutchinson Cancer Research Center, in Seattle and colleagues specifically used HNSCC cells derived from primary and metastatic tumors that harbor mutations in p53, a difficult to target tumor suppressor gene that is present in as many as 50% of HNSCC.
“Such mutations are common in head and neck cancers but render the cancer much harder to treat,” said MÃ©ndez in a statement. “Patients with these mutations tend to fare even worse than those without the genetic defect.”
The researchers used a so-called "functional genomics" approach to identify possible new targets to treat HNSCC. The team screened for kinase genes that when turned off, curb the ability of tumor cells, but not normal cells, to grow. The screen resulted in 38 drug candidates for these p53-mutated tumors.
The results showed that these tumor cells are sensitive to inhibition of the cell cycle, SFK, PI3 kinase, and FAK pathways. One of the top kinase candidates was WEE1, a G2–M cell cycle regulatory kinase. WEE1 regulates the entry of cells into mitosis. When WEE1 was inhibited with the investigational cancer drug AZD-1775 (AstraZeneca, previously MK-1775), survival of both cell lines derived from metastatic and primary tumors was significantly compromised.
In a xenograft mouse model of p53-mutated HNSCC, mice treated with the combination of AZD-1775 and the chemotherapy cisplatin had greater tumor regression compared to those mice treated with each therapy alone.
Head and neck cancer can start from cells in the larynx, throat, nose, or mouth, and is the sixth most common cancer worldwide. Both tobacco use and human papillomavirus (HPV) infection are associated with risk of the cancer. The only targeted therapies being tested for HNSCC are epidermal growth factor receptor (EGFR) inhibitors). HNSCC patients typically undergo surgery followed by radiation--sometimes combined with platinum-based chemotherapy. But this treatment course often leads to tumor recurrence at which point patients have few options other than palliative care.
Cisplain is often too toxic for patients, but according to the authors, the new drug combination may allow for a lower dose of cisplatin that would still be effective while lessening the normal side effects of the chemotherapy. “The degree by which MK-1775 enhances response to cisplatin would not only increase the effectiveness of existing therapy, but would open the possibility of reducing cisplatin dosing to minimize side-effects and broaden patient candidacy to these regimens,” stated the authors in their discussion.
Based on these results, the Seattle Cancer Care Alliance will begin an early-stage clinical trial of AZD-1775 for head and neck cancer patients. The study plans to enroll 20 patients with locally advanced head and neck cancers--both whose tumors are p53 mutated and wild-type p53. The trial will investigate whether AZD-1775 plus cisplatin can shrink tumors and improve the outcomes of subsequent surgery.
AZD-1775 is currently being tested in two phase 2 lung cancer trials. According to an accompanying press release, this new head and neck cancer trial will be the first to test AZD-1775 prior to surgery.