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DNA damage & cancer therapy

Understanding drug resistance in ovarian cancer to identify effective combination therapies

Relapsed ovarian cancer kills 3 women every day in Australia. Women with the most common type of ovarian cancer, high-grade serous, initially respond to chemotherapy. This is usually followed by cancer relapse and the development of drug resistance. Our studies will provide an understanding of the biology of resistant ovarian cancer, identify novel therapeutic targets in ovarian cancer and test new therapies including the novel drug CX-5461.

CX-5461 has shown promising activity in early phase clinical trials in blood and solid cancers and our pre-clinical studies demonstrate significant efficacy for CX-5461 in ovarian cancer models. Our studies are focused on identifying optimal CX-5461 combination therapies and biomarker of response to this novel therapy. With this work we hope to identify effective treatment options for the 300,000 women around the world diagnosed with ovarian cancer each year.

Honours and PhD projects

  • Characterisation of the nucleolar DNA damage response
  • Identifying novel modulators of DNA replication stress
  • Examining deregulation of mRNA translation in ovarian cancer

If you are interested in applying for a PhD or Honours in the DNA Damage and Cancer Therapy Lab at St Vincent’s Institute, please contact Dr Elaine Sanij (email: [email protected]) for further details.

Research Themes

The nucleolar DNA damage response- A novel non-genotoxic approach to ovarian cancer therapy

Most women with high-grade serous ovarian cancer (HGSOC) will not survive for more than 5 years due to intrinsic resistance to chemotherapy or the rapid development of acquired resistance. Defects in homologous recombination (HR) DNA repair in 50% of HGSOC cases are key determinants of sensitivity to chemotherapy and PARP inhibitors (PARPi). Acquired resistance is associated with varied mechanisms including restoration of HR activity and stabilisation of stalled DNA replication forks (fork protection).

We have shown that CX-5461, the novel inhibitor of RNA polymerase I (Pol I) transcription, exhibits therapeutic efficacy in HGSOC models. CX-5461 has shown promising activity in Phase I clinical trials in blood and solid cancers. Our studies demonstrate CX-5461 induces a localised DNA damage response (DDR) within the nucleoli, the site of Pol I transcription. This unique nucleolar DDR (n-DDR) is distinct to DDR initiated by DNA damaging agents. n-DDR causes global replication stress via destabilising replication forks leading to activation of cell cycle checkpoints (Sanij et al., Nature Comms 2020). How activation of n-DDR leads to destabilisation of replication forks remains an unresolved question. We hypothesise that characterising mediators of n-DDR will identify biomarkers of response to CX-5461 and can uncover a novel class of DDR therapeutics with improved efficacy and reduced toxicity compared to DNA damaging chemotherapies.

Our research aims are to characterise early n-DDR factors and to understand how n-DDR leads to global replication stress. This project will aid the discovery of novel targets and treatment strategies for relapsed ovarian cancer.

Reprogramming of mRNA translation as a driver of drug resistance in ovarian cancer

Most women with high-grade serous ovarian cancer (HGSOC) will not survive for more than 5 years due to intrinsic resistance to the standard therapy or the rapid development of acquired resistance.

Chemotherapy are PARP inhibitors (PARPi), the standard of care therapy in HGSOC, have been recently discovered to also act through deregulation of ribosome synthesis (ribosome stress) via inhibition of ribosomal RNA (rRNA) synthesis and ribosome biogenesis. In this study we will investigate reprogramming of mRNA translation in response to chronic ribosome stress as a driver of drug resistance in HGSOC. We propose delineating the mRNA translation landscape of resistant HGSOC will enable the identification of novel therapeutic vulnerabilities. 

The first-in-class inhibitor of rRNA synthesis CX-5461 shows significant therapeutic efficacy in chemotherapy- and PARPi-resistant HGSOC models (Sanij et al., Nature Comms 2020). CX-5461 is showing promising clinical activity in Phase I trials in blood and solid cancers. Our recent work has shown cancer cells' response to CX-5461 involves alterations in mRNA translation and protein synthesis (Kusnadi et al 2020 EMBO J). We propose that acute translational reprogramming is a mode of action of ribosome targeting therapies including cisplatin and PARPi and that defining the networks associated with dynamic response will enable the identification of novel vulnerabilities in HGSOC.

In this study, we will characterise reprogramming of mRNA translation that mediates intrinsic and acquired resistance to chemotherapy and PARPi in clinically relevant models of HGSOC. We will also examine alterations in mRNA translation that mediate response to cisplatin, PARPi and CX-5461 in HGSOC. This project will aid in the discovery of novel therapeutic targets and the design of more effective and durable therapies that will have significant impact for women with relapsed ovarian cancer.

Student Projects

  • Visit this page for a list of all student projects currently offered at SVI

Staff

  • Dr Elaine Sanij
  • Diannita Kwang, Research Assistant
  • Kezia Gitareja, Honours student
  • Anthony Xuan, PhD student

Publication Highlights

  1. Yan S., Xuan J., Brajanovski N., Tancock M., Madhamshettiwar P., Simpson K., Ellis S., Kang J., Cullinane C., Sheppard K. E., Hannan K. M, Hannan R. D., Sanij E. *, Pearson R. B. * and Chan K*. The RNA polymerase I transcription inhibitor CX-5461 cooperates with topoisomerase 1 inhibition by enhancing the DNA damage response in homologous recombination-proficient high-grade serous ovarian cancer. British Journal of Cancer (2021); Feb;124(3):616-627. * co-senior author
  2. Sanij E.*,#, Hannan K. M.*, Xuan J., Brajanovski N., Ahern J., Yan S., Chan K. T., Son J., Kondrashova O., Lieschke E., Wakefield M., Trigos A., Frank D., Cullinane C., Poortinga G., Khanna K., Andrew J. Deans, Mileshkin L., McArthur G. A., Soong J., Berns E., Hannan R. D., Scott C., Sheppard K. E. and Pearson R. B#. CX-5461 activates the DNA damage response and demonstrates therapeutic efficacy in high-grade serous ovarian cancer. Nature Communications (2020) May 11(1):2641. *co-first author, # co-corresponding authors
    This study shows the Pol I transcription inhibitor CX-5461 is a promising therapy in ovarian cancer utilizing HGSOC-PDX models
  3. Kusnadi E., Trigos A. Cullinane C., Goode D., Larsson O., Devlin J., Chan K., De Souza D., McConville M., McArthur., G., Thomas G., Sanij E., Poortinga G., Hannan R., Hannan K., Kang J and Pearson R. Reprogrammed mRNA translation drives metabolic response to therapeutic targeting of the ribosome biogenesis. EMBO J (2020) Nov 2; 39(21): e105111.
  4. Son J., Hannan K. M., Poortinga G., Hein N., Cameron D., Ganley A. R., Sheppard K. E., Pearson R. B., Hannan R.D. * and Sanij E*.  rDNA chromatin activity status as a biomarker of sensitivity to the RNA polymerase I transcription inhibitor CX-5461. Frontiers in Cell Developmental Biology (2020) 2020; 8: 568. * co-senior author
  5. Khot A., Brajanovski N., Cameron D.P., Hein N., Maclachlan K.H., Sanij E., Lim J., Soong J., Link E., Blombery P., Thompson ER., Fellowes a., Sheppard KE., McArthur GA., Pearson RB., Hannan RD., Porrtinga G and Harrison SJ. 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 Discovery (2019) 9 (8), 1036-1049.
    Significance: Critical paper describing the first-in-human clinical trial of the first-in-class Pol I inhibitor CX-5461, demonstrating CX-5461 has single-agent anti-tumour activity against advanced hematological cancers. 
  6. Udugama M.*, Sanij E.*, Voon H. P., Son J., Hii L., Henson J., Chan F., Chang F. T. M., Liu Y., Pearson R. B., Kalitsis P., Mann J. R., Collas P., Hannan R. D.  and Wong L. H. Ribosomal DNA copy loss and repeat instability in ATRX-mutated cancers. Proceedings of the National Academy of Sciences (PNAS) (2018) May 1;115(18):4737-4742. co-first author.
    Significance: This paper demonstrates a role for alpha thalassemia/mental retardation X-linked (ATRX) in mediating rRNA gene loci stability. ATRX is mutated in various cancers including brain cancers, pancreatic neuroendocrine tumours and osteosarcoma. This paper demonstrates evidence that ATRX-mutated cancers exhibit rRNA gene loci instability providing therapeutic potential of targeting Pol I transcription inhibition by CX-5461 in a wide range of ATRX-mutated cancers.
  7. Yan S., Frank D., Son J., Hannan M.,
 Hannan D., Chan K., Pearson R and Sanij E. The potential of targeting ribosome biogenesis in high-grade serous ovarian cancer. International Journal Molecular Science (2017):18(1), 210; doi:10.3390.
  8. Quin J., Chan T.K, Devlin J.R, Cameron D.P, Diesch J, Cullinane C, Ahern J, Khot A, Hein N, George A.J, Hannan K.M, Poortinga G, Sheppard E, Khanna K, Johnstone R.W, Drygin D, McArthur G.A, Pearson R.B, Sanij E*. Hannan R.D*. Inhibition of RNA Polymerase I transcription initiation activates non-canonical ATM/ATR Signalling. Oncotarget (2016) 7(31): 49800-49818. *co-senior author 
    Significance: In this paper, we showed that CX-5461 activates DNA damage signalling pathways within the nucleoli and sensitizes cells to DNA damaging agents. We demonstrated that the combination of CX-5461 and a drug targeting ATM/ATR signalling improved therapeutic efficacy in vivo thus extending the utility of both classes of drugs.
  9. Sanij E.*, Diesch J., Lesmana A., Poortinga G., Hein N., Lidgerwood G., Cameron D.P., Ellul J., Goodall G.J., Wong L.H., Dhillon A.S., Hamdane N., Rothblum L.I., Pearson R.B., Haviv. I., Moss T. and Hannan, R.D*. A novel role for the Pol I transcription factor UBTF in maintaining genome stability through the regulation of highly transcribed Pol II genes. Genome Research (2015); 5(2):201-212. *Corresponding authors
    Significance: In this paper, we reported a novel role the Pol I-transcription factor UBTF in regulating the expression of highly transcribed Pol II genes critical for chromatin packaging and DNA repair. The coordinated regulation of these processes emphasizes the therapeutic opportunities of targeting Pol I transcription for cancer therapy.
  10. Hein N., Hannan K.M., George A.J., Sanij E.*, Hannan R*. The Nucleolus: an emerging target for cancer therapy. Trends In Molecular Medicine (2013); 19(11):643-54. (*co-senior) 
    Significance: This was an invited review following the publication of Bywater et al., Cancer Cell paper in 2012. The review highlighted the potential of targeting Pol I transcription as an exciting novel target for cancer therapy.
  11. Bywater M., Poortinga G., Sanij E., Hein N., Peck a., Cullinane C., Wall M., Cluse L., Drygin D., Anderes K., Huser N., Proffitt C., Bliesath J., Haddach M., Schwaebe M., Ryckman D.M. Rice W.G., Lowe S.W., Johnstone R.W., Pearson R.B., McArthur G.A., Hannan R. Inhibition of RNA Polymerase I as a therapeutic strategy to promote cancer-specific activation of p53. Cancer Cell (2012); 22(1):51-65.
    Significance: Critical and high-profile paper demonstrating that dysregulated Pol I transcription can be targeted in vivo to selectively kill cancer cells. Resulted in the initiation of clinical trial of CX-5461 targeting patients with haematological malignancies at Peter Mac.
  12. Sanij E., Poortinga G., Sharkey K., Hung S., Holloway T., Quin J., Robb E., Wong L., Thomas W., Stefanovsky V., Moss T., Rothblum L., McArthur G., Pearson R. and Hannan R. UBF levels determine the number of active ribosomal RNA genes in mammals. Journal of Cellular Biology (2008);183: 1259-1274. [IF: 8.89]
    Significance: This paper demonstrated that UBTF determines a dynamic transition between active and inactive ribosomal RNA gene states. This study is fundamental to our current understanding of how CX-5461 induces a defect in ribosomal RNA gene chromatin that activates DNA damage signalling, which can be targeted to improve therapeutic efficacy. This article was highlighted in Science magazine as the editor’s choice of recent literature highlights in molecular biology, Pickersgill, Science (2008) 323, 5913, pp.439.