Understanding drug resistance in ovarian cancer and in multiple myeloma to identify effective new therapeutic approaches
The DNA Damage and Cancer Therapy Laboratory investigates two areas of cancer research: the blood cancer multiple myeloma and ovarian cancer. Our research team is seeking new combination treatment approaches to overcome drug resistance in multiple myeloma and ovarian cancer.
The second most common blood cancer, multiple myeloma can be treated, but patients commonly relapse, and the cancer becomes more resistant to treatment over time. While new drugs have emerged to treat this disease, treatment resistance remains an urgent challenge. Almost seven Australians are diagnosed with multiple myeloma every day – most commonly men aged 60 or older.
Among the many types of cancers, ovarian cancer remains an insidious disease that threatens both survival and the quality of life for thousands of women globally. Each day, five Australian women are diagnosed with ovarian cancer, and three will die from the disease. Our studies will provide an understanding of the biology of resistant multiple myeloma and ovarian cancer, identify novel therapeutic targets in resistant disease 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 blood and ovarian cancer models. Our studies are focused on identifying optimal CX-5461 combination therapies and biomarkers of response to this novel 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.
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.
Multiple myeloma (MM) is the second most common haematological malignancy, characterised by recurrent relapse with shorter duration of response to the standard of care therapies with each subsequent treatment. Proteasome inhibitors (PIs) have emerged as an important class of therapy for the treatment of MM. However, resistance to PIs is inevitable and represents an urgent clinical challenge.
Resistance to PIs is linked to pro-survival pathways that protect cancer cells from cell death. We propose that the combination of PIs with therapies that target the ribosome, the “molecular machinery” responsible for protein synthesis, will improve therapeutic efficacy through inhibition of protein synthesis of pro-survival factors. The selective inhibitor of ribosome synthesis CX-5461 has recently demonstrated promising antitumor activity in heavily-treated MM patients in an early Phase I clinical study. We propose that combining PIs with CX-5461 will be an effective therapeutic strategy in MM that can delay or overcome the onset of resistance.
In this project, we will assess the effectiveness of targeting the ribosome in combination with the PIs in a MM mouse model. We will also characterise global protein signatures as well as signatures at the single cell level of the cellular pathways that mediate resistance to PIs. Our findings will also enable the identification of new therapeutic opportunities in targeting cellular pathways that are altered in resistant MM cells.