Anticancer agent - enzastaurin

Many different kinases are involved in the processes by which cells reproduce and grow.

In particular, there are at least 11 isoforms of protein kinase C that are implicated in cell proliferation and differentiation, gene transcription, tumour growth and angiogenesis. They each have different tissue expression, subcellular location and specificities, and the overexpression of several types is directly linked to a number of cancers, such as kidney, liver, breast, colon, non-small cell lung and prostate, and various specific protein kinase C isozyme inhibitors have been developed to target various specific intracellular pathways as anticancer agents.

One that has attracted interest from drug developers is protein kinase C ß, which is thought to be involved in several different cancers, and is also thought to be involved in vascular endothelial growth factor induced tumour development and angiogenesis, and also in the phosphatidyl-inositol 3-kinase pathway that regulates apoptosis. A number are under development, including Eli Lilly's enzastaurin,¹ which had potent anticancer activity in a variety of preclinical cancer models.

As well as several Phase I trials, numerous later stage studies have been carried out. It has been investigated in 53 patients with late stage or metastatic non-small cell lung cancer who had failed at least one previous therapy.² Subjects were given 500mg of the drug once a day every 28 days, and while no partial or complete responses were seen, 18 patients achieved stable disease. The mean progression free survival was 1.8 months, and the progression-free survival rate at six months was 10.4%.

It has also been investigated in relapsed diffuse large B-cell lymphoma.³ A total of 55 patients were given at least one 500mg dose, and 12 were alive and progression free after two cycles of treatment. One achieved a complete response, and five a minor response, with three patients remaining progression free for at least 12 cycles of treatment.

In another trial, oral doses of 500mg a day in a six week cycle were given to patients with recurrent high grade gliomas, with a total of 85 patients being given 500mg a day in a six week cycle.⁴ Of these, 13 achieved stable disease for at least three months, and 14 had an objective radiographic response, one of which was a complete response.

A fourth trial has been carried out in 60 patients with relapsed or refractory CD20+ mantle cell lymphoma, who had received at most four prior chemotherapies.⁵ Subjects were given 500mg of the drug in oral doses. No objective tumour responses were seen, but 22 of the patients remained progression free for at least three cycles, and six of these had stable disease for up to 22 months.