Exploration of a xenograft model of human prostate cancer to predict patient treatment response

• Main Author: Beekharry, Ramprakash
• Published: University of Hull 2014
• Subjects: 610; Medicine
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.679629

For several years, docetaxel was the only treatment to improve survival of patients with metastatic prostate cancer. There are now many novel agents available but the optimal sequence of treatments remains undefined. The emergence of prostate cancer stem cells has brought a new way to elucidate the molecular mechanisms behind treatment failure and recurrence. Traditionally cell lines have been used in preclinical studies but recently ‘near patient’ derived xenografts (PDX), have been suggested to be a better way to investigate new therapies and investigate pathways in metastatic spread. First we used a subcutaneous and an orthotopic PDX model to determine which is most feasible in looking at the differences in the expression of basal and luminal cell markers. We then looked at the effect of docetaxel on hormone naïve and castrate resistant PDXs specifically measuring changes in the numbers of basal and luminal cells determining docetaxel resistance. Finally we tried labelling and fluorescent cell sorting PDX cells to track metastatic spread and monitor chemotherapy effects. The mouse prostate microenvironment did not drastically change cellular phenotypes, allowing us to use the simpler subcutaneous method to assess chemotherapy effects on PDX. In fact the subcutaneous xenografts retained basal and luminal cells maintaining the clinical heterogeneity present in prostate cancers. In the docetaxel studies, alteration in AR expression and high levels of basal-like cells from the outset appeared to confer resistance. Although docetaxel had an overall detrimental effect, there was a typical decrease in the number of basal cells in both hormone naïve and resistant tumours. No trends were seen in the luminal populations. Side effects affecting continuation of treatment were evident. Lentiviral transduction was successful in PC3 cells where they maintained high levels of fluorescent (RFP) reporter expression. Transduction of PDX cells proved more challenging and requires further optimisation. In the evolving area of new prostate cancer treatments, docetaxel chemotherapy continues to play an important role and could be given in hormone naïve cancers. This can also increase the chances of benefitting from the whole variety of new drugs. However, not all tumours are sensitive and resistance mechanisms remain unclear.