We recently have discovered a frontier strategy for overcoming drug resistance mediated by P-glycoprotein (Pgp) in the lysosome. Identifying new targets for resistant cancers are crucial, as current therapies have limited efficacy and Pgp-mediated drug resistance remains a common and intractable problem in a variety of advanced cancers. We have discovered an innovative new mechanism for taking advantage of elevated Pgp and Cu in resistant tumours by ‘tricking' Pgp within the lysosomal membrane. This strategy represents an exciting new paradigm for utilising Pgp against itself to kill drug resistant tumours. By using this strategy, my team has been involved in the development of agents that are entered clinical trials. Thus, our broad expertise will be fully utilised in this project to develop effective new drugs that potently overcome resistance. The marked productivity of this team in high quality international journals and long expertise in this field shows our capacity to deliver high impact, innovative research that will successfully lead to translatable outcomes.
This project describes an innovative new mechanism for targeting drug-resistant cancers. This research utilises novel metal binding agents that take advantage of the elevated levels of P-glycoprotein (Pgp) and copper, which are found in high amounts in drug-resistant cancers. This strategy represents an exciting new paradigm in which the activity of the lysosomal detoxifying drug pump, Pgp, is directly utilised to transport our agents into lysosomes to target the resistant tumour itself. Thus, this innovative strategy will target the most drug-resistant cancers that are currently a major intractable problem. Specifically, this research exploits and "tricks" the most common drug-detoxifying pump (Pgp) that tumours utilise to protect themselves against chemotherapeutics. Significantly, we showed that Pgp, is not only expressed in the plasma membrane, but is also found in lysosomes, and acts to transport and sequester chemotherapeutics into this organelle to mediate drug-resistance. This mechanism can be exploited by anti-cancer agents that target and damage lysosomes. The novelty of this new tumour targeting strategy has enable and agent by our team to enter multi-centre clinical trials for advanced cancer. Importantly, these agents are safe/tolerable, which was also shown in vivo. Hence, this mechanism and drug development strategy is translatable from "bench to bedside".Despite its marked efficacy against many types of cancer, the agents were not optimised for overcoming Pgp-mediated resistance, and only partially accumulated in the lysosomal target. Thus, its activity is far from optimal, and this project will develop a new optimised library of agents that are derived from knowledge utilising our current established agents to increase targeting of drug-resistant cancers [Jansson et al., Cancer Res, 2011;71:5871; Jansson et al., JBC, 2015;290:9588; Jansson et al., J.Med.Chem., 2016;59:8601; Jansson et al., JBC, 2016;291:3796, Jansson et al., JBC, 2018;293:3562]. Specifically, this project will: (1) identify the best agent to overcome resistance; (2) maintain the other highly optimised properties of these agents e.g., efficacy, safety, tolerability, etc.; and (3) enhance established lysosomotropic and Pgp-substrate properties that has been demonstrated to be crucial for lysosomal-targeting. [Jansson et al., Cancer.Res.2011;71:5871; Jansson et al., JBC.2015;290:9588, Jansson et al., J.Med.Chem.2016;59:8601; Jansson et al., JBC.2016;291:3796; Jansson et al., Cell.Death.Dis.2016;7:e2510; Jansson et al., JBC,2018;293:3562].Overall, this research is crucial in order to develop breakthrough pharmaceuticals that directly target Pgp-resistant cancers by an innovative strategy and will increase patient-survival rates.
This is an exciting opportunity to participate in the development of a novel treatment strategy for highly drug resistant cancers, which are currently almost untreatable. This are a highly productive and successful team with an excellent track record in both research (>61 publications in this field over last 10 years) and supervision (>15 Honours and PhD students). We are looking for an enthusiastic and motivated PhD student to join us on this project. A background in biochemistry and molecular cell biology is desired, but not essential. Training of all experimental techniques will be provided and student will be closely supervised by Dr. Jansson and his team, with regular face-to-face meetings and guidance.
The opportunity ID for this research opportunity is 2428