The DNA Damage & Cancer Therapy Laboratory’s primary research focus is multiple myeloma, with our approach also extended to high-grade serous ovarian cancer. Our research team is developing new therapies targeting ribosome biogenesis and new combination treatment approaches including immunotherapies to overcome drug resistance in both diseases.
Multiple myeloma, the second most common blood cancer, can be treated, but patients commonly relapse and the disease becomes more resistant to treatment over time. Almost seven Australians are diagnosed with multiple myeloma every day- most commonly men aged 60 or older. As Theme Leader of the Myeloma Aetiology Theme at the Barrie Dalgleish Centre for Myeloma and Related Blood Cancers, we lead a multi-site collaboration to accelerate the translation of biomarkers of drug resistance into the clinic.
We are extending this approach to ovarian cancer, an insidious disease that threatens both the survival and quality of life of thousands of women; five Australian women are diagnosed each day, and three will die from the disease.
Our studies use the novel ribosome-targeting drug CX-5461, which has shown promising activity in Phase I clinical trials in blood and solid cancers, and significant efficacy in our pre-clinical models, to identify novel therapeutic targets and biomarkers of response in resistant disease. We are also developing new compounds with selective nucleolar-targeting mechanisms, to expand this class of ribosome-targeting therapeutics.
Current research projects
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Investigating ribosome-targeting therapies for relapsed/refractory multiple myeloma
Altered ribosome synthesis and mRNA translation are increasingly implicated in multiple myeloma (MM) progression and drug resistance. We are testing whether targeting ribosome biogenesis, using our selective Pol I transcription inhibitor CX-5461, and mRNA export/translation, using Selinexor, can overcome resistance in relapsed/refractory MM (RRMM). Genome-wide CRISPR screens have identified mechanisms of sensitivity to these therapies. In patients treated with CX-5461, we observed increased T and NK cell activation and reduced markers of immune exhaustion in bone marrow samples, alongside reduced tumour cell proliferation in pre-clinical models. These findings support combining ribosome-targeting and immune-based therapies to improve outcomes in RRMM.
Translational adaptation mediated by RPL5 deficiency in multiple myelomaMultiple myeloma (MM) cells have exceptionally high rates of protein synthesis, making them highly sensitive to disruption of protein homeostasis. Heterozygous deletion of RPL5, a component of the 60S ribosome subunit, occurs in 20-40% of MM patients and is associated with poorer survival but improved response to the standard therapy proteasome inhibitors. This project investigates how RPL5 deficiency drives translational adaptation to promote MM progression and therapeutic response, and whether ribosome-targeting therapies such as CX-5461 or Selinexor can be more effective in RPL5-deficient MM.
Targeting the nucleoli as a strategy to treat cancerThe nucleolus is the site of ribosome biogenesis, and cancer cells depend on hyperactivated nucleolar function to meet their high demand for protein synthesis. The first-in-class Pol I transcription inhibitor CX-5461 (Pidnarulex) induces nucleolar stress, triggering cell cycle arrest and cell death in various cancer models, and has shown promise in Phase I clinical trials in blood and solid cancers. Using a genome-wide CRISPR-Cas9 screen, we identified five distinct nucleolar stress phenotypes linked to ribosome biogenesis, DNA repair, cell cycle and RNA metabolism, and uncovered a new role for protein phosphatases in regulating Pol I transcription. A complementary high-throughput screen of 24,000 compounds identified CDK and topoisomerase inhibitors as potent inducers of nucleolar stress, highlighting new therapeutic targets for ovarian cancer. This project investigates new approaches to targeting the nucleolus in cancer therapy utilising pre-clinical models of multiple myeloma and ovarian cancer
People
Available for Student Supervision
- Shalini Sundramurthi Chelliah, Research Officer
- Carmelo Cerra, Research Assistant
- Nyree Stojnic, Research Assistant
- Liz Cope, Research Assistant
- Prashanthi Meera Sureshbabu, PhD student
- Kezia Gitareja, PhD student
- Kangni Zou, PhD student
- Yangyi Zhang, PhD student
- Myeongji Ko, Masters student
- Giada Fernandez, Undergraduate student
Student projects
Activation of nucleolar-specific DNA damage response as a therapeutic strategy for ovarian cancer
Lab: DNA Damage & Cancer Therapy
Supervisor(s): Associate Professor Elaine Sanij
Diseases focus: CancerTargeting the nucleoli to treat cancer
Lab: DNA Damage & Cancer Therapy
Supervisor(s): Associate Professor Elaine Sanij Dr Jian Kang
Diseases focus: CancerDefine the role of mRNA translation reprogramming in multiple myeloma progression and response to therapy
Lab: DNA Damage & Cancer Therapy
Supervisor(s): Associate Professor Elaine Sanij Dr Jian Kang
Diseases focus: CancerSelected publications
Liu R., Xuan J., Cerra C., Stojnic N., Pan J., Chelliah S., Mendez S., Dmello R., Cowley K., Zhang Y., Gitareja K., Wakefield M., Deans A., Scott C., Chan K., Simpson K., Kang J. and Sanij E.* RAD54L coordinates the nucleolar DNA damage response to maintain rDNA stability. The EMBO Journal (2026). *senior author
Maclachlan K.H, Gitareja K., Kang J., Cuddihy A., Cao Y., Hein N., Cullinane C., Ang C-S., Brajanovski N., Pearson R.B., Khot A., Sanij E.*#, Hannan R.D.#, Poortinga G.# and Harrison S.J.# Targeting the ribosome to treat multiple myeloma. Molecular Therapy Oncology (2024) 31(1), 200771 * sole communicating author # co-senior author
Behrens K., Brajanovski N., Xu Z., Viney E.M., DiRago L., Hediyeh-Zadeh S., Davis M.J., Pearson R.B., Sanij E., Alexander W. and Ng A. P. ERG and c-MYC Regulate a Critical Gene Network in BCR: ABL1-Driven B-cell Acute Lymphoblastic Leukaemia. Science Advances (2024), 10(10):eadj8803
Kang J., Brajanovski N., Chan T. K., Xuan J., Pearson R. B. and Sanij E. Ribosomal Proteins and Human Diseases: Molecular Mechanisms and Targeted Therapy. Signal Transduction and Targeted Therapy (2021) 6(1), 323
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
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
ORCID profile: https://orcid.org/0000-0002-2063-7813
Scopus profile: https://www.scopus.com/authid/detail.uri?authorId=6507125632
Related News
Funding boost for multiple myeloma research
A four-year grant of $2.9M, announced in June from the Medical Research Future Fund’s Genomics Health Futures Grant will support a multi-centre and multidisciplinary team led by SVI’s Associate Professor Elaine Sanij to identify and validate blood biomarkers to provide early detection of multiple myeloma and to monitor disease progression and response to treatment.
Fellowship fuels search for new ovarian cancer treatments
Thanks to the generosity of the 5point Foundation, SVI researcher Dr Ruofei Liu will continue searching for new solutions for treatment-resistant ovarian cancers as the 2026 recipient of the Christine Martin Fellowship.