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Various cell signalling and centromere proteins whose function is perturbed and/or upregulated in human tumours require the addition of a farnesyl pyrophosphate molecule for normal function. Farnesyl transferase (FTase) inhibitors block this step, reduce the function of these oncogenic proteins, and inhibit the growth of a variety of human tumour cell lines. FTase inhibitors are well tolerated, but previous monotherapy cancer trials have had disappointing outcomes. Further work on cancer cell lines has shown that FTase inhibitors act synergistically with cytotoxic drugs (particularly taxanes) and positively influence tumour resistance; combination trials have been proposed.
The authors studied the combination of the oral FTase inhibitor lonafarnib and paclitaxel in 33 patients with advanced stage IIIb/IV non-small cell lung cancer (NSCLC) who had progressive disease despite recent taxane based chemotherapy. Open label treatment consisted of 3 week cycles with continuous lonafarnib 100 mg twice daily and paclitaxel 175 mg/m2 given on day 8. The disease was evaluated following each cycle and treatment stopped if there was disease progression. This preliminary study was restricted to patients who had no cerebral metastases, had good performance status, no major co-morbidity, and no significant persistent toxicities from previous treatment.
Fourteen patients had a partial response or stable disease on trial therapy (which is impressive given that all patients had taxane resistant/refractory disease when enrolled). The treatment was well tolerated. These encouraging results have prompted the authors to begin a larger phase III trial (with carboplatin, paclitaxel and lonafarnib) for the first line treatment of patients with NSCLC.
Although the results reported here are preliminary and directly applicable to only a small subset of patients with NSCLC, it is hoped that FTase inhibitors will prove to be useful.