The Translational Research Unit, though recently formed, has members with vast experience in pre-clinical studies and in clinical trials. The organisation of this unit is purposely overlapping with both clinical research units within the Departments of Medical Oncology and Radiation Oncology and both Departments are actively involved in many international and national and clinical trials. They are the coordinating centre for a substantial number of these and have a professional data managers unit to collect, maintain and analyse the data.
The Translational Research Unit also is integrated with the Laboratories’ research programs. It is currently involved in pre-clinical studies of the antiangiogenic compounds Pi88 and thalidomide. The translational research unit and the Medical Research unit are also currently involved in a clinical trial of thalidomide in the treatment of malignant mesothelioma.
Any pre-clinical or clinical trial requiring laboratory support in the way of laboratory based analyses, can be easily organised. All trials are approved by the NSH Research Ethics Committee.
This cell model has been developed in collaboration with Dr Mary Davey, Cell and Molecular Biology, UTS.
For details see the Drug & Radiation Resistance Program.
they have similar levels of multidrug resistance, they have the same background as they were derived form the same drug sensitive CCRF-CEM parental cell line and they have not been genetically manipulated.
The CEM/VLB100 and CEM/E1000 cells provide a simple way of screening compounds for their potential interactions with either P-glycoprotein or MRP1. This is achieved by comparing the cytotoxicity of the test compound in the CEM/VLB100 and CEM/E1000 cells relative to that in the sensitive CCRF-CEM cells. Increased resistance (higher IC50) in the CEM/VLB100 cells indicates an interaction with P-glycoprotein while a higher IC50 in the CEM/E1000 cells indicates an interaction with MRP1. Confirmation of these interactions is achieved by using inhibitors of P-glycoprotein (such as SDZ-PSC-833) and MRP1 (such as buthionine sulphoximine) that should specifically reverse any resistance. For some compounds their effect on the cellular accumulation of the fluorescent drug daunorubicin (transported by P-glycoprotein and MRP1) can be determined in competition studies using flow cytometry.
We have used the human leukaemia cell lines HL60, K562 and U937, and the small cell lung cancer cell lines H69 and H82 to develop clinically relevant cellular models of drug and radiation resistance. These were developed in collaboration with Dr Mary Davey, Cell & Molecular Biology Department, UTS. For details see the Drug & Radiation Resistance Program. These all show low level but broad cross resistance, they are stable and do not require any further drug treatment to maintain the resistance phenotype and they often express increased levels of MRP1. A subline with increased resistance to radiation and drugs has also been generated by treating with fractionated radiation. Because these resistant sublines reflect the resistance encountered in the treatment of cancer, they provide a convenient way to screen compounds for their potential to circumvent resistance. Several conventional chemotherapeutic drugs that target tubulin, have been identified for their ability to reverse resistance (for details see the Drug & Radiation Resistance Program) .
Screening of compounds for their ability to reverse resistance is performed by firstly determining the IC50 of the test compound in the sensitive and resistant cells. Cells are exposed to an IC50 dose for 1 hr and after 24 hr, their level of resistance to conventional chemotherapeutic drugs is determined. This screening schedule has proven to be the most sensitive at detecting reversal of resistance. Other schedules are available that test for compound/drug interactions that produce resistance reversal.
Cellular models provide the concepts for new treatment strategies. Although they are very important in establishing the cellular and molecular mechanisms involved in a potential new treatment and they tell us what is possible, they only provide part of the story.
To progress an idea for a new treatment into clinical trial, it must first be tested in an animal model. This step is an essential part of testing. It provides valuable information on the effectiveness of the new treatment in a whole body setting. We have developed several rat tumour models in which to test new treatments:
The Animal Care and Ethics Committee of NSH help us plan and approve all in vivo experiments.
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Commercial
research opportunities
We consider commercial research opportunities that are contractual or collaborative
Programs of Commercial Interest:
Structured to provide a bench to bed platform
The Bill Walsh Cancer Research
Laboratories is within the Department of Medical Oncology, Royal North Shore
Hospital. Our research is mainly laboratory-based cancer research with expertise
in molecular and cellular biology, cellular response pathways, animal tumour
models, angiogenesis biology and experimental drug design and testing using
our cellular and animal model systems.
The Department of Medical Oncology and the Bill Walsh Cancer Research Laboratories
have established the OncologyTranslational Research Unit to fast-track the
laboratory research outcomes into clinical trial and clinical practice and
to have practical input into the laboratory research programs. This organisational
structure ensures that the Laboratories’ research programs remain focused
on improving cancer treatment. In turn, the Translational Research Unit provides
the preclinical and clinical trials capacity to extend the laboratories’ findings
into a clinical context. The integration of laboratory, preclinical and clinical
research provides a platform for the development and testing of new treatment
strategies in all phases from molecular, through cellular and animal models,
into preclinical and through to clinical trials testing. There are few organisations
that can offer such an integrated program for developing and testing new cancer
treatment strategies.
We have developed the highly multidrug resistant CCRF-CEM/E1000 subline (CEM/E1000) by treatment with epirubicin. CEM/E1000 cells overexpress the multidrug resistance associated protein, MRP1 as a result of amplification of the MRP1 gene on chromosome 16p13.1. These cells have retained their resistance for over 12 months in culture without further treatment. The drug cross resistance profile of the CEM/E1000 cells is typical of that attributed to MRP1 overexpression. Their level of drug resistance is similar to that of the classical CEM/VLB100 subline that overexpresses the multidrug resistance transporter, P-glycoprotein (P-gp) as a result of the MDR1 gene on chromosome 7 being amplified. The CEM/VLB100 cells are also stably resistant for periods of over 6 months growth without drug treatment. The CEM/VLB100 and CEM/E1000 sublines are therefore ideal for comparing P-glycoprotein mediated and MRP1-mediated drug resistance because they are stable,