Anticancer agent - tosedostat
The aminopeptidase enzyme system catalyses the hydrolysis of amino acids at the amine terminus. Myeloma cells are dependent on the response of the unfolded protein to assemble folded immunoglobulins correctly. Thus interfering with the aminopeptidase system may have therapeutic applications in cancers such as myeloma by affecting tumour regulation.
The aminopeptidase enzyme system catalyses the hydrolysis of amino acids at the amine terminus. Myeloma cells are dependent on the response of the unfolded protein to assemble folded immunoglobulins correctly. Thus interfering with the aminopeptidase system may have therapeutic applications in cancers such as myeloma by affecting tumour regulation.
Chroma Therapeutics is developing CHR-2797, or tosedostat - a prodrug for an active metabolite that has potent, selective anti-proliferative effects in both haematopoietic and epithelial tumour cell lines in the lab.1 The active is formed in the body by the cleavage of the cyclopentyl ester to the free acid, and is an inhibitor of Zn2+ dependent aminopeptidases. It generates signs of amino acid deprivation in sensitive cells, decreases protein synthesis, and increases the level of the pro-apoptotic protein NOXA.
In an open label, single agent, dose escalating Phase I salvage study in 16 elderly and treatment refractory patients with multiple myeloma, myelodysplastic syndrome or acute myeloid leukaemia, subjects were given escalating oral doses of the drug once a day.2 The doses ranged from 60 to 180mg, and treatment continued for up to 84 days, or until progressive disease occurred. Thirteen patients completed the 28 day dose finding phase, and six reached the full 84 days of treatment. It was well tolerated, although two patients on the highest dose developed a 75% reduction in platelet count that was considered drug related. Five AML patients died in the first three months or within four weeks of discontinuing treatment, three because of disease progression, and two as a result of a non-drug related myocardial infarction. Three of the 12 AML patients achieved complete response after one to three months.
A Phase II trial has also been carried out, in elderly or previously treated patients with AML or MDS.3 Again, it was an open label, single agent trial, and subjects were given 130mg oral doses once a day for up to 84 days, and the treatment could be continued if the investigator believed it was still beneficial. A total of 41 patients were involved in the trial. Ten of the 38 AML patients responded to treatment, of whom two were receiving the drug as a salvage therapy. Three achieved a complete response, and the remission was durable for two of these. Two of the three MDS patients also responded, and had stable disease for six months. The median overall survival in AML patients was 130 days, and adverse events were fatigue, thrombocytopoenia, pyrexia, peripheral oedema and diarrhoea.