RNA polymerase I inhibitors as therapeutics for cancer: Testing combination therapies for haematologic malignancies

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 the rapid activation of p53-dependent apoptotic signalling (Bywater et al., Cancer Cell 2012). We are currently commencing the first clinical trial in humans with CX-5461 to treat patients with haematologic malignancies.

This project will test if we can increase the therapeutic potential of Pol I inhibitors, we will test CX-5461 in combination with standard therapies (eg. cytarabine and/or anthracylines for AML). As CX-5461 induces tumour-specific activation of ATM/CHK2 independent of p53, we will test whether the combination of CX-5461 and CHK2 inhibitors can induce death of p53 null tumour cells via mitotic catastrophe. As we hypothesise that MYC expression predicts sensitivity to CX-5461 we will also test combination therapies with BRD4 inhibitors and PIM kinase inhibitors both of which have been shown to inhibit MYC expression and reduce MYC dependence in.