Poster Presentation 25th Lorne Cancer Conference 2013

Designing molecular biomarkers of therapeutic response to CX-5461, a first-in-class RNA Polymerase I inhibitor, for an upcoming Phase I clinical trial (#131)

Don P Cameron 1 , Megan J Bywater 1 2 , Nadine Hein 1 , Elaine Sanij 1 , Gretchen Poortinga 1 , Denis Drygin 3 , William G Rice 3 , Simon J Harrison 1 , Grant A McArthur 1 , Ross D Hannan 1
  1. Peter MacCallum Cancer Institute, East Melbourne, Vic, Australia
  2. Department of Biochemistry, University of Cambridge, Cambridge, United Kingdom
  3. Cylene Pharmacuticals, San Diego, United States of America

RNA Polymerase I  (Pol I) transcribes the 47S rDNA gene in the nucleolus, which is then processed into three of the four RNA components of the ribosome. Enlarged nucleoli have been observed as a hallmark of tumours for over 100 years, and elevated rRNA synthesis is a common feature of rapidly proliferating cells. We have found it is possible to exploit this oncogenic addiction to rRNA transcription therapeutically with a small molecule Pol I inhibitor CX-5461, developed and characterised in conjunction with Cylene Pharmaceuticals (San Diego). Upon inhibition of Pol I, malignant cells undergo p53-dependent cell cycle arrest and apoptosis while normal cells are spared1. This first-in-class inhibitor will enter Phase I trials at Peter Mac in February 2013.

The incorporation of biomarker analysis and pharmokinetic studies into Phase I clinical trials has become common practice to validate on-target effects and fast-track drug development2. We have designed a number of assays to measure therapeutic response to CX-5461 and to identify potential biomarkers for sensitivity to Pol I inhibition. We have optimised an in situ hybridisation assay for directly measuring levels of rRNA either fluorescently (FISH) or chromogenically (CISH) in fixed suspension cells and solid tumour specimens, with potential for broader use as a pathologic marker for malignant cells. We will also measure other response biomarkers such as nucleolar disruption, activation of the p53 pathway and apoptosis. Finally, we hope to identify further predictive biomarkers in addition to p53 by NGS with the aim of elucidating Pol I mechanism and identifying patients likely to be sensitive to CX-5461 treatment.

  1. Bywater, M.J.; Poortinga, G.; Sanij, E.; Hein, N.; Peck, A.; Cullinane, C.; Wall, M.; Cluse, L.; Drygin, D.; Anderes, K.; et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell 2012, 22, 51-65
  2. Tan, D.S.W.; Thomas, G.V.; Garrett, M.D.; Banerji, U.; de Bono, J.S.; Kaye, S.B.; Workman, P. Biomarker-driven early clinical trials in oncology - a paradigm shift in drug development. The Cancer Journal 2009, 15, 406-420