The Aurora kinases play essential roles in cell proliferation and are involved in the mitotic process. Three human Aurora kinases – A, B and C – are known, each with specific actions.
Aurora kinase A is of particular interest in cancer, and the gene that encodes for it is often amplified in several different tumour types, including head and neck, colorectal, breast and bladder cancers, and also glioma. In these cases the prognosis is poor. The kinase itself is overexpressed in various other tumour types.
ENMD-2076 is an Aurora kinase A inhibitor being investigated by EntreMed.1,2 It has activity against several other kinase types, notably the tyrosine kinases VEGFR-2, JAK2, and others.
In a Phase I trial, 67 patients with advanced solid tumours were given continuous daily oral doses of 60, 80, 120, 160 and 200mg/m2.3 Two had grade 3 hypertension at the highest dose, and 160mg/m2 once a day was determined to be the maximum tolerated dose. The most common adverse events were hypertension, nausea, vomiting and fatigue. A partial response was achieved by two patients with platinum refractory or resistant ovarian cancer.
It is also being investigated in blood cancers. A total of 15 heavily pre-treated patients with acute myeloid leukaemia were given oral doses of 225, 325 or 375mg/day.4 Drug related side-effects included dizziness, fatigue, diarrhoea, nausea, oesophageal reflux and hypertension. One of the 13 evaluable patients achieved a leukaemia free state, and two others had a significant reduction in bone marrow blast counts. The drug is currently being tested in a Phase II trial in patients with platinum resistant ovarian cancer.
references
1. R.M. Bray et al. Blood, 2006, 108 (11), Abst 1377
2. G.C. Fletcher et al. Mol. Cancer Ther. 2011, 10, 126
3. J.R. Diamond et al. Clin. Cancer Res. 2011, 17, 849
4. K.W. Yee et al. AACR-NCI-EORTC Int. Conf. Mol Targets Cancer Ther. (Nov 15-19, Boston) 2009, Abst A106
