Anticancer agent - deforolimus

Various receptor tyrosine kinases are involved in triggering the signal transduction pathways that cause the growth and proliferation of cancer cells.

Many have been the target of drug discovery projects in recent years, and one of these is mTOR, or mammalian target of rapamycin. When activated, this initiates pro-survival signalling and progression of the cell cycle in the tumours. It was discovered when it was noticed that the immunosuppressant macrolide antibiotic rapamycin had potent antiproliferative and proapoptotic activity, and this proved to be a result of its inhibition of what became known as mTOR.

Deforolimus is one of several compounds that are showing promise as mTOR inhibitors.¹ Discovered by Ariad Pharmaceuticals and licensed to Merck & Co, it is a semisynthetic rapamycin analogue that is active against a number of different human tumour models. Numerous trials have been carried out, including an open label Phase II study in 38 patients with taxane-resistant, androgen-dependent prostate cancer.² Subjects were given 50mg of the drug by intravenous infusion once a week on four-week cycles. Most adverse events were mild to moderate, and included fatigue, nausea, diarrhoea, mouth sores and thrombocytopoenia. Sixteen of the patients were evaluable for response, and one had a partial response, 13 achieved stable disease and two had disease progression.

Another Phase II trial was carried out in patients with advanced endometrial cancer.³ Subjects were given 12.5mg doses of the drug by infusion daily for five days every two weeks on 28 day cycles. Again, it was largely well tolerated. Of the 27 patients who were evaluable for response, 14 discontinued before four cycles had been completed because their disease had progressed, three because of non-treatment related adverse events, and one withdrew consent. Nine had a complete or partial response or achieved stable disease.

It has also been investigated as a potential treatment for a variety of advanced sarcomas.⁴ Subjects were given the same regimen as in the previous trial. Half of the 36 patients who were evaluable for response achieved an objective response or long term stable disease.

Another potential use is in haematological malignancies. Twelve patients with relapsed or refractory acute myelogenous or lymphocytic leukaemia, agnogenic myeloid metaplasia or myelodysplasia were given the same drug regimen.⁵ While there were three serious adverse events related to the treatment, of the 11 evaluable patients three had stable disease, and four disease progression after the first cycle.