Novel Therapeutic Targets Pave the Way for Improved Treatment of Head and Neck Cancer

Eduardo Méndez, MD, MS, FACS

The protein kinase,Wee1, has been identified as a novel therapeutic target for p53-mutant head and neck squamous cell carcinoma (HNSCC). An early-phase clinical trial focusing on Wee1 inhibition will begin later this year.

In a functional kinomics approach, researchers have identified this and other kinases required for survival of cancer-specific cells, where kinase inhibition may slow the growth of HNSCC tumors.

Together with colleagues, Russell Moser, PhD, and Chang Xu, PhD, from Fred Hutchinson Cancer Research Center in Seattle, Washington, reported their findings in the August 15, 2014 issue ofClinical Cancer Research.¹

Head and neck squamous cell carcinoma is the sixth leading cancer worldwide, driven by tobacco and alcohol consumption as well as infection with human papillomavirus. Only 40% to 50% of HNSCC patients survive more than 5 years.

The disease affects the mucosal linings of the upper aerodigestive tract, including the pharynx, larynx, trachea, paranasal sinuses, and the nasal and oral cavities. Patients often suffer from disfiguring tumors greatly affecting their quality of life.

“Patients have to wear their disease for the public to see, or perceive, or hear, so there is a sense of urgency and a sense of need, not just to eradicate the disease, but to do so in a way that the patient can thrive and be functional,” said senior author, Eduardo Méndez, MD.²

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Current treatment involves surgery followed by radiation, which is often combined with cisplatin chemotherapy. Unfortunately, the disease often presents with distant metastases, and rates of recurrence are high. Standard treatment is often disfiguring, associated with high-grade toxicities, and subject to cisplatin- or radiation-resistance, leaving nonresponders limited to palliative care.

Over 50% of HNSCC cases are associated with mutations in the tumor-suppressor gene,p53, which increases the risk of metastasis, therapy resistance, and poor clinical outcome. “Patients with these mutations tend to fare even worse than those without the genetic defect,” said Méndez.²

As the activity of this transcription factor is regulated by phosphorylation, the protein kinases catalyzing these modifications are becoming common therapeutic targets.

In this study, the authors performed large-scale screens to identify kinases important for HNSCC cell survival. They then determined whether or not inhibition of these targets might provide therapeutic benefit by slowing tumor growth and inducing cell death.

With a cross-species comparison of human and mouse kinome-wide screens, they identified 38 candidates required for the survival of HNSCC cells. Knockdown of these kinases via RNA interference had a negative effect on both human and mouse cancer cell viability.

Due to the high degree of heterogeneity in human cancer cells, the authors selected for kinases that were conserved between species. “We reasoned that these evolutionarily conserved kinases might represent more robust therapeutic targets,” they wrote.¹

Candidates underwent additional validation to remove those that caused excess toxicity, and select for those influencing cancer cell viability in both primary and recurrent HNSCC tumors, as well as those with mutations inp53.

Knockdown of the kinasesWee1,Nek4, andAURKA, for instance, reduced cell viability and increased apoptosis in over 75% of HNSCC cell lines tested, without affecting wild-type cells.

Commercial, small-molecule inhibitors were already available for several of the selected kinases. The Wee1 kinase inhibitor, AZD-1775 (formerly MK-1775, AstraZeneca), demonstrated the most robust effect on HNSCC cell survival and was selected for preclinical validation.

In a mouse xenograft model, AZD-1775 inhibitedp53-mutant HNSCC tumor growth by 66% compared with placebo. The addition of AZD-1775 to a cisplatin treatment regimen significantly enhanced tumor regression, reaching 80% for cisplatin + AZD-1775 compared with 66% for cisplatin alone (P= .003).

The kinaseWee1functions by regulating the G2-M cell-cycle transition, arresting mitotic entry when DNA repair is needed. With AZD-1775, Wee1 inhibition caused HNSCC cells to initiate unscheduled mitotic entry, leading to apoptotic cell death. Asp53plays a critical role in the G1 checkpoint,p53-mutant tumors rely solely on the G2 checkpoint, further sensitizing them to DNA damage.

These findings are of great interest to the field of head and neck cancer, as the addition of AZD-1775 to chemotherapy “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,” the authors concluded.¹

Based on their findings, an early-stage clinical trial of AZD-1775 for HNSCC will begin this fall at the Seattle Cancer Care Alliance.

Overall, the investigators identified several kinases required for HNSCC cell survival, including those involved in G2-M transition, as well as the phosphatidylinositol, focal adhesion, and Src signaling pathways.

“Discovery and development of multiple targets may prove to be a useful strategy, as tumors frequently develop resistance to single agents,” the authors noted. “Targeting multiple vulnerabilities simultaneously may be required to achieve long-term remission [of HNSCC].”¹

References:

1. Moser R, Xu C, Kao M, et al. Functional kinomics identifies candidate therapeutic targets in head and neck cancer.Clin Cancer Res. 2014;20(16):4274-4288.
2. DrBicuspid.com. New hope for patients with hard-to-treat head and neck cancers.http://www.drbicuspid.com/index.aspx?sec=ser&sub=def&pag=dis&ItemID=316267. Accessed September 24, 2014.

Clinical Pearls

• The protein kinase, Wee1, has been identified as a novel therapeutic target for p53-mutant HNSCC.
• These findings were published in the August 15, 2014 issue of Clinical Cancer Research.
• Over 50% of HNSCC cases are associated with mutations in tumor-suppressor gene, p53, which increases risk of metastasis, therapy resistance, and poor clinical outcome.
• With a cross-species comparison of human and mouse kinome-wide screens, researchers identified 38 candidates required for the survival of HNSCC cells.
• The researchers reasoned that these evolutionarily conserved kinases might represent more robust therapeutic targets.
• Additional validation was performed to remove those that caused excess toxicity, and select for those influencing cancer cell viability in both primary and recurrent HNSCC tumors, as well as those with mutations in p53.
• Knockdown of the kinases Wee1, Nek4, and AURKA, for instance, reduced cell viability and increased apoptosis in over 75% of HNSCC cell lines tested.