A translational research story from Australia- The first-in-class drug CX-5461
This research story comes from the Peter MacCallum Cancer Centre (Peter Mac) in Melbourne, Australia. Not only research advances in Australia are exciting, but the outdoor lifestyle, the weather and the scenery are also supreme!
The experimental drug CX-5461 is the result of over 15 years of basic and pre-clinical laboratory research, performed at Peter Mac in collaboration with Senhwa Biosciences and scientists at the John Curtin School of Medical Research.
Sixteen Peter Mac patients with various refractory blood cancers were involved in the first-in-human Phase I study, led by clinicians Dr Amit Khot and Assoc Prof Simon Harrison. In this study, CX-5461 was able to stall cancer progression in a third of trial participants1.
CX-5461 is considered first in a potential new class of anti-cancer drugs that directly target a critical part of the ribosome-making machinery - RNA Polymerase I transcription of ribosomal RNA genes. Blocking this critical step in ribosome biogenesis causes stress levels inside cancer cells to skyrocket, stalling DNA replication and leading to growth arrest and cancer cell death2.
We reported CX-5461’s efficacy as an anti-cancer agent in pre-clinical models of MYC-driven lymphoma and acute myeloid leukaemia3, 4, 5, and we predicted CX-5461 would be most effective in cancers with activated growth signalling pathways and/or defects in DNA repair such as ovarian cancer.
50% of high grade serous ovarian cancer (HGSOC) cases, the most common type of ovarian cancer, harbour defects in homologous recombination (HR) DNA repair genes most commonly BRCA1/2, key determinants of sensitivity to the standard of care chemotherapy and Poly-(ADP-ribose) polymerase inhibitors (PARPi)6. Sadly, cancer relapse due to the development of drug resistance is common leading to incurable disease7, 8.
In a recent study published in Nature Communications, we showed CX-5461 has a distinct mode of action in activating the DNA damage response (DDR), is synthetic lethal with HR deficiency and enhances the therapeutic efficacy of PARPi in HR deficient HGSOC models. The combination of CX-5461 and PARPi resulted in dramatic and durable tumour regression in vivo. We propose CX-5461 and PARPi therapy will provide a more effective therapy in HR deficient ovarian cancer than single agent treatment.
CX-5461 was also effective even in an ‘incurable’ model of HGSOC that had previously developed resistance to chemotherapy and PARPi. Our data demonstrate CX-5461-induced DDR overcomes fork protection, a well-characterised mechanism of resistance to PARPi and chemotherapeutics in BRCA-deficient cancer cells9, 10.
We identified CX-5461-sensitivity signatures in primary and relapsed ovarian tumour samples. We propose that CX-5461 has exciting potential as a treatment option for patients with ovarian cancer harbouring HR deficiency, unstable replication forks or high MYC activity who typically have poor clinical outcome. We speculate CX-5461's activity may extend to a wide range of cancers with aberrations in DDR genes such as, breast, prostate and pancreatic cancers, melanoma and myeloma. We also believe that the development of predictive biomarkers of response and optimal combination approaches is essential for the success of future clinical trials.
- Khot A, et al. First-in-Human RNA Polymerase I Transcription Inhibitor CX-5461 in Patients with Advanced Hematological Cancers: Results of a Phase I Dose Escalation Study. Cancer Discov, (2019).
- Quin J, et al. Inhibition of RNA polymerase I transcription initiation by CX-5461 activates non-canonical ATM/ATR signaling. Oncotarget, (2016).
- Bywater MJ, et al. Inhibition of RNA polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell 22, 51-65 (2012).
- Devlin JR, et al. Combination Therapy Targeting Ribosome Biogenesis and mRNA Translation Synergistically Extends Survival in MYC-Driven Lymphoma. Cancer Discov 6, 59-70 (2016).
- Hein N, et al. Inhibition of Pol I transcription treats murine and human AML by targeting the leukemia-initiating cell population. Blood, (2017).
- Konstantinopoulos PA, Ceccaldi R, Shapiro GI, D'Andrea AD. Homologous Recombination Deficiency: Exploiting the Fundamental Vulnerability of Ovarian Cancer. Cancer Discov 5, 1137-1154 (2015).
- Bowtell DD, et al. Rethinking ovarian cancer II: reducing mortality from high-grade serous ovarian cancer. Nat Rev Cancer 15, 668-679 (2015).
- Wakefield MJ, Nesic K, Kondrashova O, Scott CL. Diverse mechanisms of PARP inhibitor resistance in ovarian cancer. Biochim Biophys Acta Rev Cancer 1872, 188307 (2019).
- Chaudhuri AR, et al. Erratum: Replication fork stability confers chemoresistance in BRCA-deficient cells. Nature 539, 456 (2016).
- Yazinski SA, et al. ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells. Genes Dev 31, 318-332 (2017).