Anticancer agent – imetelstat
US biotech company Geron is looking to inhibit the activity of telomerase as an anticancer strategy, using imetelstat
The function of the enzyme telomerase is to lengthen the telomeres at the end of DNA strands; in normal cells, these shorten with every cell division, regulating their lifespan. In cancer cells, this pathway is frequently activated and enables the cells to carry on dividing indefinitely, greatly facilitating proliferation.
US biotech company Geron is looking to inhibit the activity of telomerase as an anticancer strategy, using imetelstat, a lipid-conjugated 13-mer nucleotide that has a high affinity for telomerase’s RNA template.1
One potential indication is non-small cell lung cancer. In a randomised Phase II trial, 114 patients with advanced NSCLC whose disease had not progressed after completing 4–6 cycles of platinum based chemotherapy were randomised to receive 9.4mg/kg on days 1 and 8 or a 21-day cycle, or placebo, either with or without bevacizumab, as maintenance therapy.2
There was an improvement in overall survival in both imetelstat-only and bevacizumab groups; however, this was not statistically significant. But in a sub-group analysis in patients whose tumours had short telomeres, there was a trend towards increased progression-free survival.3
A trial has also been carried out in patients with myelofibrosis, in which abnormal haematopoietic cells progenitor cells within the bone marrow proliferate, leading to fibrosis.4 A total of 33 patients were given 9.4mg/kg of the drug via a two-hour intravenous infusion every three weeks, or weekly for the first three weeks, followed by three-weekly doses.2 An initial analysis of the first 18 patients was carried out, and at the median follow-up time of 3.2 months, all bar two remained on the treatment.
In the group of 11 given just three-weekly doses, there were no grade 4 adverse events, with three experiencing grade 3 thrombo-cytopoenia, and one patient grade 3 anaemia. Two in the second group had grade 4 thrombocytopoenia. Two patients also required a reduced dosage because of myelosuppression.
The overall response rate was 44%, including four who met the criteria for a complete response, including a reversal of fibrosis. A fifth patient had a partial response. The company is now planning further trials in this indication, and it is also being investigated in other haematologic myeloid malignancies, including myelofibrosis patients whose disease has transformed to acute myeloid leukaemia.
References
1. A. Roth et al. Recent Results Cancer Res. 2010, 184, 221
2. A. Chiappori et al. Amer. Assoc. Cancer Res. Ann. Meet. 2013 (6-10 April, Washington DC), Abst. 4660
3. A. Chiappori et al. Amer. Assoc. Cancer Res. Ann. Meet. 2013 (6-10 April, Washington DC), Abst. 2376
4. A. Tefferi et al. 55th Amer. Soc. Hematol. Ann. Meet. 2013 (7–10 December, New Orleans), Antibodies. 662
