The sole function of RNA Polymerase I (Pol I) is to transcribe the 47S pre-rRNA gene in distinct sub-nuclear regions called nucleoli. The resulting transcript is cleaved into three of the rRNA molecule required for ribosome biogenesis. Since this process is frequently elevated in cancer, it was postulated that it may represent a form of oncogenic addiction and hence could be target therapeutically. Indeed, our lab showed that by inhibiting rRNA transcription with CX-5461, a novel Pol I inhibitor provided by Senhwa Biosciences1, it was possible to selectively kill tumour cells while leaving normal cells unharmed despite seeing a similar level of Pol I inhibition across all cells2.
In light of this encouraging pre-clinical data and positive toxicology results, the Peter MacCallum Cancer Institute began enrolling patients into a Phase I clinical trial for CX-5461 in July 2013. As of January 2014, five patients have been treated and enrolments are ongoing. While the primary objective of the trial is to determine the maximum tolerated dose for intravenously administered CX-5461, we have also designed a range of correlative studies to evaluate the mechanism of action and to identify predictive biomarkers of efficacy of CX-5461 in haematologic cancers. These methods will complement the clinical data gathered from the trial and fast-track the development of CX-5461 into further Phase II/III studies. These tools could also be used in future trials for CX-5461 in different cancer types and for future second-generation Pol I inhibitors.