Anticancer agent - AEG-35156
A failure of apoptosis is a characteristic of cancer, as it enables malignant cells to proliferate
A failure of apoptosis is a characteristic of cancer, as it enables malignant cells to proliferate. One factor involved is X-linked inhibitor of apoptosis protein, or XIAP, which is overexpressed in numerous types of tumour. This is being investigated as a potential target in anticancer treatment, as downregulating XIAP induces apoptosis and also sensitises tumour cells to both radiotherapy and cytotoxic drugs. AEgera Therapeutics has designed an antisense oligonucleotide, which is undergoing clinical trials,1 that has both high potency and high selectivity for XIAP.
A Phase I open label, dose escalation study was carried out in 38 patients with advanced refractory malignant tumours.2 The drug was given by continuous intravenous infusion over either three or seven days of a 21-day treatment cycle, with doses starting at 48mg/m2/day and escalating until a consistent dose limiting toxicity was observed. The maximum tolerated dose was found at 125mg/m2/day in the seven-day cycle, and 213mg/m2/day in the three-day cycle. Peak plasma concentration increased proportionally with dose, and maximum suppression of XIAP mRNA levels was observed at 72 hours, with a mean suppression of 21%. This also coincided with a dramatic decrease in circulating tumour cells in one patient with non-Hodgkin's lymphoma. It was well tolerated, and showed some antitumour activity in refractory lymphoma, melanoma and breast cancer.
It is also being investigated in combination with other drugs in patients with breast, non-small cell lung and pancreatic cancers, acute myeloid leukaemia and lymphoma, and also solid tumours that can be treated with docetaxel. In a Phase I/II trial in patients with relapsed or primary refractory AML3 a total of 24 patients were given escalating doses of 12-250mg/m2 as an intravenous solution over two hours, and a further 32 given the highest planned dose of 350mg/m2, both in combination with idarubicin and high dose cytarabine reinduction chemotherapy. XIAP mRNA levels reduced as the dose increased, and all patients given the high dose had at least 30% knockdown, with a median maximal knockdown of 90%. In the 350mg/m2 dose group 15 of the 32 patients achieved a complete response, compared with just one of the 24 given 250mg/m2. Other than two incidences of peripheral neuropathy, the drug was well tolerated. Trials continue.
References
1. Y. Hu et al. Clin. Cancer Res. 2003, 9, 2826
2. E. Dean et al. J. Clin. Oncol. 2009, 27, 1660
3. A.D. Schimmer et al. J. Clin. Oncol. 2009, 27, 4741
