Dr P Raninga
No more applications being accepted
Competition Funded PhD Project (Students Worldwide)
About the Project
Triple negative breast cancers (TNBCs) account for 15-20% of all diagnosed breast cancers (BCs), and are the most aggressive form of BC, spontaneously metastasize to lungs and brain, and exhibit poor prognosis. Due to the lack of hormone receptors, anti-hormonal therapies are not effective in treating TNBC patients. Therefore, chemotherapy and radiotherapy remains a mainstay of treatment. Although TNBC patients initially respond to the chemotherapies, they eventually develop resistance. Hence, novel and more effective therapies are needed for TNBC patients. The proteasome pathway is enriched in TNBC cells and therefore, represents an attractive therapeutic target. However, current FDA approved proteasome inhibitors (PrtIs) (bortezomib and carfilzomib) showed no significant clinical efficacy for TNBC patients. This may be due to the weaker proteasome inhibitory activity of these PrtIs or due to the presence of persistent clones that are intrinsically resistant to PrtIs. Several studies have reported the role of such persistent clones in developing chemoresistance in multiple cancers including TNBCs. We hypothesize that using a potent proteasome inhibitor may exert a significant anti-cancer activity in TNBCs. Moreover, isolating such persistent clones following PrtIs treatment and mapping their transcriptomic and proteomic profile will identify the proteins or pathways responsible for PrtIs resistance.
Aims:
1. Evaluating the anti-cancer activity of novel and potent proteasome inhibitors on primary and metastatic TNBCs.
2. Performing transcriptomic and proteomic analysis in persistent TNBC clones to identify molecular determinant for PrtI resistance.
3. Developing novel therapies targeting candidate proteins/pathways and to evaluate its efficacy in overcoming PrtI resistance using in vitro and in vivo models for TNBCs.
Approaches:
We will examine the anti-tumour activity of a novel proteasome inhibitor on primary and metastatic TNBCs in vitro and in vivo. We will use syngeneic murine model of TNBC, human cell line-xenografts, and patient-derived tumour xenograft models. To decipher the resistance mechanism, we will initially isolate PrtIs resistant clones by exposing TNBC cells to the maximum tolerated dose of PrtIs and selecting the residual cells that represent the persistent cells. We will perform RNA sequencing and proteomic analysis to map the genetic and protein profiles of persistent clones. Based on these experiments, we will rank the proteins or signalling pathways that may be involved in PrtI resistance in TNBC cells. We will perform functional validation on top 20 candidates using RNA interference (shRNA and CRISPR-Cas9) technique. Based on these experiments we will identify the protein or pathway responsible for drug resistance and use specific pharmacological inhibitors to analyse the effect of inhibiting candidate protein/pathway on overcoming PrtI resistance. We will also analyse the effect of PrtIs alone and in novel combination therapies on lung and brain metastatic TNBC using state-of-the-art metastatic mouse models of TNBCs.
For more information about this research group: http://www.qimrberghofer.edu.au/lab/signal-transduction/
Funding Notes
QIMR Berghofer is offering a limited number of PhD Scholarships for top applicants. For details, eligibility criteria and to apply: http://www.qimrberghofer.edu.au/students/university-students/phd-scholarships/
Do not apply for the QIMR Berghofer scholarship without making contact with the supervisor first. Provide an academic CV and transcripts in your introduction email.
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