Verbesserung des Therapieerfolgs von Cisplatin- und/oder Strahlen-Behandlungen - Einsatz von AZ-1775 zur Sensibilisierung von HPV+ und HPV- HNSCC
Zusammenfassung der Projektergebnisse
The cure rate for patients with aggressive head and neck tumors remains poor due to resistance to the traditional treatment regimens using chemotherapy and radiation. TP53, the gene that encodes the p53 protein, is the most commonly mutated gene in this type of cancer and is, in turn, associated with treatment failure and poor survival outcomes. Therefore, more effective therapies are urgently needed. Abrogating the G2 checkpoint in head and neck squamous cell carcinoma (HNSCC) could be an effective therapeutic strategy in P53-deficient tumor cells. Inhibition of WEE1 kinase abrogates the G2 cell cycle arrest and to exploit G1 checkpoint deficiency of p53 deficient tumor cells, and thereby enhancing their apoptotic response to DNA damage. The small molecule inhibitor AZD1775 is a potent and specific inhibitor of WEE1. AZD1775 induces cell death in combination with chemotherapy and specially sensitizes TP53-deficient tumor cell lines to various anticancer agents. HNSCC cells expressing high-risk p53 mutations are significantly sensitized to cisplatin therapy by AZD1775. AZD1775, also significantly potentiates cisplatin response and produces suppressive effects on HPV+ head and neck tumor growth. The vulnerability of HNSCC to the HDAC inhibitor vorinostat and AZD1775 through induction of replication stress is associated with decreased Rad51-mediated homologous recombination. This provides preclinical foundation for initiation of clinical trials using combination of HDACs and WEE1 inhibitors, particularly for patients with advanced and recurrent metastatic HNSCC tumors. Recent data demonstrate, combination of the Rad51 inhibitor B02 and AZD1775 displays synergism in HNSCC lines both in vitro and in vivo in orthotopic mouse model of oral cancer. The drugs appear to exert synergism through modulation of replication stress and recombination homology repair markers associated with significant apoptosis. This is a very promising combination which is currently under further investigation.
Projektbezogene Publikationen (Auswahl)
- Replication stress leading to apoptosis within the S-phase contributes to synergism between vorinostat and AZD1775 in HNSCC harboring high risk TP53 mutation. Clin Cancer Res. 2017 Aug 8
Tanaka N, Patel AA, Tang L, Silver NL, Lindemann A, Takahashi H, Jaksik R, Rao X, Kalu NN, Chen TC, Wang J, Frederick MJ, Johnson FM, Gleber-Netto F, Fu S, Kimmel M, Wang J, Hittelman WN, Pickering CR, Myers JN, Osman AA
(Siehe online unter https://doi.org/10.1158/1078-0432.CCR-17-0947)
