Bowel Cancer Research
‘Development of Innovative Chemotherapeutics that Target ATP- Binding Casette (ABC) Family Proteins Expressing Cancers to Overcome Multidrug Drug Resistance’
University of Sydney, NSW
Co-funded by Rotary District 9675
‘The Heather Newbould PhD Scholarship’
“We aim to develop this agent to be orally active and can be administered as tablets. We believe this will significantly improve patient compliance and the ease of use.”
Lionel Leck is a first year Ph.D candidate in Medicine at the department of Pathology University of Sydney. His main research interest is on cancer multidrug resistance, specifically in the family of ATP-binding cassette (ABC) proteins of substrate transporters such as P-glycoprotein (Pgp) and Multidrug resistance protein 1 (MRP1).
The ABC transporters plays a crucial role in clinically acquired multidrug resistance and its overexpression is directly correlated with highly advanced metastatic cancers. Lionel’s Ph.D thesis focuses on the elucidation of the complex molecular pathways and the functional roles of these ABC transporters in order to develop a novel combinational chemotherapeutics that would target these ABC pumps to overcome multidrug resistance.
The news of drugs being ineffective is devastating to patients. Multidrug resistance (MDR) affects patients with a wide variety of solid tumours, advanced and metastatic cancers such as bowel cancer. Poor response to chemotherapy in numerous advanced cancer types are directly linked to the presence of substrates transporter pumps, p-glycoprotein (Pgp) and multidrug resistance proteins (MRPs) located the surface of cells. In the context of normal healthy tissues, its main function is to protect the body from toxic substances by transporting them out of the cells. However, in cancer cells, they have been found to transport numerous forms of chemotherapeutic agents out the cells, thereby reducing efficacy and effectiveness of the drugs, and leading to MDR. These transporters are normally found in healthy non-cancer cells but their levels are significantly increased in these advanced cancer cells.
My supervisor, Dr Patric Jansson was the first demonstrate, a unique alternative functions of the Pgp transporter. Notably, it was shown that Pgp transporters are not only found on the outer membrane of the cell but they are also found within the intracellular compartment of cells. Hence, we aimed to utilize these alternate functions to develop a frontier drug design strategy and combinational novel agent that would enable us to “trick” these transporter pumps, by taking advantage of the characteristics and features that are often found in cancer cells (i.e. elevated level of transporters pumps and copper level) to induce cell death and overcome MDR.
Supervisors: Dr Patric Jansson, Dr Angelica Merlot & Prof Des Richardson