Platinum-based chemotherapy induces DNA damage in rapidly proliferating cells, such as cancer cells. However, tumor cells keep proliferating despite DNA damage if checkpoint inhibitors, such as p53, a major G1 checkpoint regulator, are deficient. Additionally, DNA repair proteins can limit the impact of chemotherapeutic drugs in tumor cells. One option is to inhibit DNA repair enzymes so that DNA damage remains unrepaired and induces cell death in checkpoint regulator-deficient cancer cells. For example, inhibition of WEE1 tyrosine kinase prevents phosphorylation of the cyclin-dependent kinase CDC2 and impairs the G2 DNA damage checkpoint, blocking further cell cycle progression. As such, WEE1 inhibition selectively sensitizes p53-deficient tumor cells, which are dependent on the G2 checkpoint, to DNA damage induced by chemotherapy.
A study from the late Dr. Eduardo Mendez, in collaboration with Dr. Laura Chow (Clinical Research Division), demonstrated that AZD1775, an inhibitor of WEE1, administered in combination with the chemotherapeutic drugs cisplatin and docetaxel was safe and efficient in patients with head and neck squamous cell carcinoma (HNSCC). The results of this phase I clinical trial were recently published in the journal Clinical Cancer Research.
Previously untreated patients with histologically confirmed HNSCC and borderline resectable or unresectable tumors were enrolled in the study. AZD1775 was first administered as a single agent twice daily for the first week followed by a combination with cisplatin and docetaxel (another cytotoxic cancer drug), which were administered once weekly for three weeks. The four week cycles of treatment were repeated three times, with increasing dosage of AZD1775 at each cycle to determine the maximum tolerated dose.
Out of the twelve enrolled patients, ten could be evaluated for treatment efficacy. In one case, the disease progressed after two weeks of treatment and the patient died. Five patients presented a partial response, while four remained stable. No grade 4 adverse events was observed during the study at the maximum tolerated dose established at 150mg of AZD1775 administered orally twice a day for 2.5 days. Patients with significant tumor size reduction were able to undergo surgery for mass removal.
The patients were classified into two groups: responders and non-responders. Responders were patients presenting a 30% decrease in tumor size and a histological response above 90% as defined by cellularity and tumor necrosis in tumor biopsy. Immunohistochemistry and immunofluorescence analyses of biopsy specimens collected before and after treatment demonstrated a decrease in CDC2 tyrosine 15 phosphorylation, indicating a loss of cell cycle progression associated with an increase in cleaved caspase 3 apoptotic marker. This observation was specific to the responder patients. RPA32, a marker of stress replication associated with DNA damages, also increased in responder patients as early as one week after treatment initiation, when AZD1775 was used as single agent. This result suggests that AZD1775 alone might impact DNA integrity independently of chemotherapy. The patients enrolled generally presented similar genetic alterations in tumor suppressor genes besides p53, such as CDKN2A or PI3K, which can be associated with genomic instabilities and impaired cell cycle. These mutations may have contributed to the increased sensitivity of some patients to AZD1775.
These promising results warrant further studies in patients. AZD1775 has also been evaluated in ovarian, lung or colorectal cancer patients, suggesting myriad potential applications. Dr. Chow added, “the responses were impressive and of great interest – however, further development of this trial would involve changing the standard of care and this would be difficult without large numbers and funding. The AZD1775/chemotherapy combination is less active in the metastatic setting but could certainly be assessed. Also, it would be interesting to assess this in the context of the anti-PD-1 therapies that are now available and how this may combine or add to immunotherapy, but this is challenging as Eddie is no longer here to champion or move this forward”. Dr. Mendez passed away in January of this year.
Funding for this study was provided by the National Cancer Institute, the American Cancer Society and internal funds from University of Washington/Seattle Cancer Care Alliance, Fred Hutch, and AstraZeneca.
Research reported in the publication is a collaboration between Cancer Consortium members Eduardo Mendez, Laura Chow, Renato Martins, (UW, Fred Hutch) and Neal Futran, Cristina Rodriguez and Rafael Santana-Davila (UW).
Mendez E, Rodriguez CP, Kao M, Raju SC, Diab A, Harbison RA, Konnick EQ, Mugundu G, Santana-Davila R, Martins R, Futran ND, Chow LQM. 2018. A Phase I Clinical Trial of AZD1775 in Combination With Neoadjuvant Weekly Docetaxel and Cisplatin Before Definitive Therapy in Head and Neck Squamous Cell Carcinoma. Clinical Cancer Research. [Epub ahead of print].