Kinases carry out a wide range of signalling and other functions within a cell, and blocking their activity can lead to inhibition of the cancer cell growth and replication, and even apoptosis
Kinases have proved a very fruitful area in recent years in the hunt for new and promising targets for treating cancer. These proteins carry out a wide range of signalling and other functions within the cell, and blocking their activity can lead to inhibition of the cancer cell growth and replication, and even apoptosis.
The polo-like kinase family is involved in the regulation of the cell cycle, playing a role in the formation of the mitotic spindle as cells divide, and activate CDK/cyclin complexes during that mitotic phase of the cell cycle. There are at least four members of this family of kinases, with polo-like kinase 1, or PLK1, being the best characterised. Boehringer Ingelheim is developing the small molecule drug volasertib,1 which acts as an inhibitor of PLK1, and has recently been granted orphan drug status by both the FDA and EMA for the treatment of acute myeloid leukaemia.
This designation was granted in the light of positive results of a Phase I/II clinical trial in elderly patients with AML, given in combination with low dose cytarabine. After the Phase I part of the trial determined the maximum tolerated dose of volasertib in this combination to be 350mg, and also demonstrated promise in patients with relapsed or refractory disease, 87 patients were given the drug via intravenous infusion in combination with subcutaneous low-dose cytarabine, or the cytarabine alone.2 A significantly larger proportion – about three times as many – of those given the combination achieved an objective response of complete remission, either with or without incomplete blood count recovery than those given cytarabine alone. A Phase III trial in this indication is now under way.
The drug’s potential in treating solid tumours is also being assessed. For example, in an open label, single arm Phase III trial in patients with locally advanced or metastatic urothelial cancer, 50 subjects who had previously received platinum therapy and progressed within two years of one prior chemotherapy regimen were given 300mg intravenous doses every three weeks, rising to 350mg if the dose was well tolerated in the first cycle.3 Seven patients achieved a partial response, 13 had stable disease, and the remainder progressed within six weeks. Median progression-free survival was 1.4 months, and the median overall survival 8.5 months. The most common serious side effects were neutropoenia, thrombocytopoenia and anaemia. This was determined to be insufficient activity for further evaluation as monotherapy.
More promise was seen in a trial comparing volasertib to chemo-therapy in platinum resistant or refractory ovarian cancer.4 Volasertib was given as third or fourth line therapy, with 109 patients randomised to receive the drug or the investigator’s choice of single-agent chemotherapy, which could be pegylated liposomal doxorubicin, topotecan, paclitaxel or gemcitabine, until progression or intolerance occurred. One year after randomisation, six volasertib patients and no chemotherapy patients were ongoing for progression-free survival. Similar levels of partial response and stable disease were achieved in the two arms, with a lower side-effect profile in the volasertib group.
The drug is also being evaluated as part of a combination regimen with other kinase inhibitors in advanced solid tumours, including afatinib5 and nintedanib.6
1. D. Rudolph et al. Clin. Cancer Res. 2009, 15, 3094
2. J. Maertens et al. Blood 2012, 120, Abst. 411
3. W.M. Stadler et al. Cancer 2014, 120, 976
4. E. Pujade-Lauraine et al. J. Clin. Oncol. 2013, 31 (suppl.), Abst. 5504
5. M. Peeters et al. J. Clin. Oncol. 2013, 31 (suppl.), Abst. 2521
6. F.G. De Braud et al. J. Clin. Oncol. 2013, 31 (suppl.), Abst. 2556