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Combination therapy shows potential in TP53-mutated head and neck cancers
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Yale Cancer Center researchers have identified a potential combination therapy that appears promising for patients with TP53-mutated head and neck cancers.
“Head and neck cancers can be extraordinarily devastating, even for people who are cured,” Barbara A. Burtness, MD, professor of medicine in the department of medical oncology and co-leader of the developmental therapeutics research program at Yale Cancer Center, and a HemOnc Today Editorial Board Member, said in a press release. “The disease can impact people’s appearance and their ability to speak and to eat with others.”
The researchers evaluated treatment with the Aurora kinase A inhibitor alisertib (MLN8237, Takeda/Millennium) and the small molecule inhibitor of the tyrosine kinase WEE1 adavosertib (AZD1775, AstraZeneca), alone or in combination, using in vitro and in vivo head and neck squamous cell carcinoma models.
Results showed increased levels of Aurora kinase A were associated with worse survival outcomes among patients with p16-negative head and neck squamous cell carcinoma.
“We also uncovered the broad reason that [Aurora kinase A] inhibitors have been failing in the clinic,” Burtness said. “Unfortunately, they put the cell into cell cycle arrest, which is probably a temporary effect. When the [Aurora kinase A] inhibitor levels go back up, then the cell can divide, and the cancer can continue growing. ... We hope that this [combination therapy] approach might have a much broader effect beyond head and neck cancer, because TP53 is the holy grail of undruggable targets in human tumors.”
HemOnc Today spoke with Burtness about the research and what additional studies are planned.
Question: What is the need for new, effective therapies for this patient population?
Answer: This is a group of patients for which we see some responses with chemotherapy, and we do cure some patients. We also now see some responses with immunotherapy. However, the rates for recurrence and death remain high. Beyond cetuximab (Erbitux, Eli Lilly), no targeted therapy has ever shown to be effective in this patient population. The predominant genomic abnormality among patients with head and neck cancer is mutation in TP53 — a tumor suppressor gene that cannot be targeted. We were interested in whether there were any other targets within the cell, that a TP53-mutated cancer would be susceptible to, that we could exploit.
My colleagues and I had been studying Aurora kinase A as a potential target in head and neck cancer. There was evidence that Aurora kinase A was overexpressed, and when it was overexpressed, the cancers had a worse prognosis. We knew that Aurora kinase A was regulated by TP53, so it made sense that if a patient had a TP53-mutated cancer, Aurora kinase A expression would be increased.
We participated in a previous early-phase trial evaluating alisertib, and were very disappointed to find that alisertib only had about a 9% response rate in head and neck cancer. The genesis of this work was to find out the cause of resistance to alisertib and how to overcome it. What we found so far was that alisertib actually did inhibit Aurora kinase A. We also found a lot of the abnormalities that one would expect from Aurora kinase A inhibition; however, these changes resulted in phosphorylation of CDK1 and cell cycle arrest. We then wondered if we gave patients another drug that removed phosphorylation from CDK1 and allowed the cell to enter mitosis, even though it had not had time to correct abnormalities, whether this would be more lethal.
Q: How was this research conducted and what did you find?
A: We started with experiments with cell lines and saw marked synergy between alisertib and adavosertib. We saw the same thing in 3-D culture. We then conducted mechanistic studies where we confirmed that adavosertib permitted dephosphorylation of CDK1 and led to formation of bizarre mitotic figures and marked increase in apoptosis. We think that this is a very strong story — we have figured out the intrinsic vulnerability of the Aurora kinase A inhibitor.
Q: What is next for research?
A: We feel this clinical combination is ready for testing in a phase 1 trial. We have extended these findings to other Aurora kinase inhibitors and other pairs of cell cycle acting agents together. We think this is a paradigm that will be worth exploring for a lot of targeted therapies and possibly in other cancer types. We would not be surprised if many were vulnerable to this type of approach. This may be appropriate to test in people with HPV-negative cancer that recurred after platinum therapy or immunotherapy.
Q: Is there anything else that you would like to mention?
A: A lot of the work for this research was done by Jong Woo Lee, MD, PhD, associate research scientist at Yale Cancer Center, and Janaki Parameswaran, MD, who was a fellow in my lab and is now doing early drug development at Bristol-Myers Squibb. Both deserve credit for this work. – by Jennifer Southall
Reference:
Lee JW, et al. Clin Cancer Res. 2019;doi:10.1158/1078-0432.CCR-18-0440.
For more information:
Barbara A. Burtness, MD, can be reached at Yale Cancer Center, PO Box 208028, New Haven, CT 06520; email: barbara.burtness@yale.edu.
Disclosure: Burtness reports no relevant financial disclosures.