Despite the overwhelming evidence of dysregulated RNA Polymerase I (Pol I) transcription in cancer, only one selective Pol I transcription inhibitor, CX-5461, has completed Phase I/II clinical trials. CX-5461 has recently received FDA approval for the treatment of solid tumors with BRCA1/2 and other homologous recombination gene mutations. However, CX-5461 has additional off-target activities (e.g. Topoisomerase II inhibition and induction of DNA damage) which likely contribute to both its efficacy and toxicity.
To address the need for improved Pol I inhibitors with minimal off-target effects we collaborated with Pimera Inc to develop a selective 2nd-generation Pol I inhibitor, PMR-116. PMR-116 has similar selective Pol I transcription inhibition capability to Cx-5461 with improved bioavailability, toxicology and tissue distribution and does not induce a DNA damage response. PMR-116 also demonstrated significant therapeutic efficacy in preclinical syngeneic models of aggressive acute myeloid leukemia, breast cancer, hepatocellular carcinoma and prostate cancer. These preclinical studies and favourable ADME and toxicity data allowed us to obtain IND registration to undertake a first in human multicentre open-label dose escalation study of PMR-116 treating patients with advanced solid tumours which is ongoing (Peter MacCallum Cancer Centre, Australia ACTRN12620001146987).
To further explore the therapeutic potential of Pol I inhibitors, we screened a library of FDA-approved compounds to identify drugs that can be used in combination with Pol I inhibitors to improve therapeutic efficiency and delay the development of acquired resistance to single agent therapy. We identify the pan-CDK inhibitors Dinaciclib and Flavopiridol as potential drugs for combinatorial therapy with CX-5461. These compounds inhibit RNA Polymerase (Pol II) elongation by preventing the phosphorylation of serine 2 of RPB1 (Pol II C-terminal domain) by CDK9 and have reached Phase 2 clinical trials for haematopoietic malignancies. We show that combinatorial therapy with CX-5461 and both Flavopiridol and Dinaciclib have a synergistic effect in vitro and significantly increase the survival of acute myeloid leukaemia (AML) models in vivo. Our data indicates that inhibition of both Pol I (by CX-5461) and Pol II (by CDK9 inhibitors) can be used in as a therapy to extend survival and reduce acquired resistance.