Download Opportunities for Students with Prof Anna Nowak

Opportunities for Students with Dr Cleo Robinson
Chemoprevention of Mesothelioma
Mesotheliomas typically occur many years after exposure to asbestos. This long latency offers an opportunity for
chemoprevention. In the 1990s the Wittenoom workforce cohort was invited to participate in a program of vitamin A (carotene or retinol), assistance to quit smoking, and dietary advice. The rate of mesothelioma between groups was not
statistically different overall, but the study showed the potential for intervention.
The aim of this project is to screen the Clinical Compound Library (JHCCL, Version 1) consisting of 1514 approved drugs
available as 37 x 96-well plates each for activity against a number of established mesothelioma cell lines. We plan to
select candidate drugs for preclinical verification in the MexTAg transgenic mesothelioma model. In these mice SV40
(Simian Virus 40) large T antigen (TAg) is expressed by the mesothelium. After exposure to asbestos, mesothelioma
develops in all MexTAg mice compared to 20-30% of wild type mice. After intraperitoneal asbestos injection, the mice
predictably develop mesothelioma (mostly sarcomatoid) with median survival of 24 weeks, compared with 56 weeks for
asbestos injected wild-type mice. Plasma levels of drug or intermediate metabolite will be measured in tail vein blood at
suitable intervals to assess adequacy of administration and dosing. Initially, each of four candidate drugs will be
administered to thirty-two MexTAg mice and placebo to a control group of thirty-two MexTAg mice. Two outcome
measures are of interest 1) difference in mesothelioma rates over the follow-up period between asbestos injected control
MexTAg animals and asbestos injected MexTAg animals treated with a chemopreventive candidate, and 2) differences in
median survival time between these two experimental arms.
Investigating Tolerance Using a SV40 Large T Antigen Transgenic Mouse Model of
Mesothelioma
Cancer develops from host cells and is therefore immunologically likely to be mostly self. Self-reactivity is controlled by
several mechanisms which result in immunological tolerance; essentially the ability of the immune system to discriminate
appropriately and minimize autoimmunity. The degree of tolerance to an antigen is affected by both its anatomical
location and the amount of antigen expressed. So to develop a cancer vaccine a suitable target must be found that is
predominantly expressed on cancerous cells with limited or weak expression by normal tissues. Such a vaccine could
prevent disease from developing in susceptible people and may have therapeutic value. A unique opportunity is available
to investigate immunological tolerance in SV40 large T antigen transgenic mice that are susceptible to mesothelioma; the
MexTAg model.
The project will investigate immunological tolerance to SV40 TAg in MexTAg mouse strains. By investigating the ability of
cancer cell lines expressing different levels of TAg, to grow in the four different MexTAg mouse lines, tolerance can be
assessed. A high copy tumour cell line (299h) does not grow in a wild type mouse because the TAg makes the cells an
immunological target. A single TAg copy mice (266s) grows, but appears much later and grows slower than non TAg
tumours. With four lines of mice that express between 1 and 100 copies of TAg we can map vaccine efficacy to the
degree of tolerance.
Last Updated: 08/07/2010