The transcription of the 45S ribosomal RNA (rRNA) genes by RNA Polymerase I (Pol I) is a major rate limiting step for ribosomal biogenesis, and consequently for cell growth and proliferation. Dysregulation of
Pol I transcription of the rRNA genes is an almost universal feature
of cell transformation and cancer, and work from our laboratory has shown that targeting this process is a promising new approach for cancer therapy. We have shown recently used the small molecule inhibitor of Pol-1 transcription CX-5461 to selectively kill B-lymphoma cells in a genetic model of spontaneous lymphoma while maintaining
a viable wild type B-cell population. The therapeutic effect is a direct consequence of rapid activation of p53-dependent apoptotic signaling (Bywater et al., Cancer Cell 2012). We are currently commencing
the first clinical trial in humans with CX-5461 to treat patients with heamatologic malignancies.
In addition, we have recently identified a novel p53-independent cell cycle checkpoint in response to inhibition of Pol I transcription in human primary fibroblasts, which display a proliferation defect arising from both G1 and G2 cell cycle arrest. These phenotypes are associated with a DNA damage – like response.
This project aims to identify the key mechanisms by which cells respond to acute inhibition of Pol I transcription, which will enable us to predict which malignancies will respond to this novel treatment strategy.