Polo-like kinases are overexpressed in a variety of human tumours but not in normal cells, making them a potential target for cancer chemotherapy
Polo-like kinases are enzymes that are involved in cell division and checkpoint regulation of mitosis; they also help maintain DNA integrity. They are overexpressed in a variety of human tumours but not in normal cells, making them a potential target for cancer chemotherapy.
Rigosertib, a small molecule agent designed to target these kinases, is being developed by US biotech company Onconova.1 It remains active against numerous cancer cells that are resistant to other drugs, without affecting normal cells. Trials are furthest advanced in myelo-dysplastic syndrome (MDS). In a Phase I/II trial, patients with the MDS or acute myeloid leukaemia were given the drug by continuous intravenous infusion over a period of 72 to 144 hours every two weeks, for between five and 70 weeks.2 Three achieved a marrow complete response and two a haematological improvement. The five non-responders were the five patients with AML. It was well tolerated.
A shorter dosing period has also been investigated.3 In a Phase I/II trial, 13 patients with MDS were given the drug as a 48hr continuous infusion every week for three weeks of a four week cycle. Ten were given 800mg/m2/day, and the remaining three 1500mg/m2/day. Again it was well tolerated, with the most common adverse events being thrombocytopoenia, neutropoenia, anaemia, fatigue and nausea. Several patients experienced a significant decrease in blast count compared with pre-treatment values, and just two progressed.
The drug also has potential in solid tumours, both as a single agent and in combination with other drugs. In one trial, it was given to 13 patients with advanced solid tumours who had failed previous chemotherapy regimens in combination with oxaliplatin, in doses ranging from 250 to 1250mg/m2 as a 24-hour continuous infusion every week.4 Initial results were a partial response in one patient with refractory ovarian cancer, and stable disease in a further ovarian cancer patient and another with colon cancer.
Another combination is with gemcitabine; 36 patients with advanced pancreatic and other solid tumours were given weekly infusions of gemcitabine plus the new drug as a 2hr infusion twice a week.5 A partial response was seen in two ovarian cancer patients, one with NSCLC achieved stable disease, and there was a partial response in one thymic cancer patient. Of 18 pancreatic cancer patients, seven of the 13 evaluable patients exhibited tumour regression, including one confirmed partial response. Median progression-free survival was 19 weeks, and overall survival 48 weeks.
1. M.V. Reddy et al. J. Med. Chem. 2011, 54, 6254
2. L.R. Silverman et al. Blood 2010, 116, Abst 2944
3. A. Raza et al. Blood 2010, 116, Abst. 3815
4. I. Chaudhary et al. J. Clin. Oncol. 2010, 28 (suppl.), Abst e13133
5. W.W. Ma et al. J. Clin. Oncol. 2010, 28 (suppl.) Abst 2101