Cancer Cell Group Current Research
Project One: The Cancer Stem Cell as a Target for Cancer Treatment
Like the stem cells that shape the development, repair and replacement of various tissues and organs in our body, cancer stem cells or tumour-initiating cells also self-renew and differentiate into other tumour cell types, and can divide indefinitely.
We are attempting to model the glioblastoma multiforme (GBM) cancer stem cell. GBM is the most common brain cancer and patients with the disease have a very poor prognosis.
The goal of this research is to establish cell lines that mimic the complex nature of GBM stem cells and can be used to screen for compounds that compromise their survival. We also plan to use cancer stem cells isolated from immortalised cell lines and GBM tumours as antigen sources for the generation of cancer vaccines. This is being undertaken in collaboration with Dr Ian Hermans and Wellington Hospital neurosurgeon Mr Martin Hunn.
We have shown that we can generate neurospheres from tumour cell lines and glioblastoma tissue and that these spheres contain stem cell-like cells that can form tumours in immunocompromised murine models.
Molecular profiling of these spheres has revealed a significant elevation of self-renewal genes relative to serum-grown cells that do not form spheres, supporting the presence of cancer stem cells in neurospheres.
Project Two: Immunotherapeutic Targeting of Melanoma Stem Cells
In July 2008, a global collaborative Melanoma Research Alliance programme was initiated by Prof Jonathan Cebon, Ludwig Institute, Melbourne with the aim of defining melanoma stem cell markers that will be useful for vaccination or immunotherapy.
For several years now, we have been developing cancer stem cell models for drug targeting and were one of the first groups in the world to show the presence of germ cell markers on stem cells. This collaborative research programme builds on the observations that the germ cell markers called CT antigens re-emerge in a small number of melanoma cells, and that these markers can be targeted by the patient's own immune system resulting in tumour-free survival.
Because very few melanoma cells express these antigens, the results suggest that melanoma is populated by a small population of rogue ‘stem cells'.
Although still in the early stages of this project, human melanoma cell lines have now been established and the stem cell marker, CD133, used to sort and subsequently culture cells. We are also establishing tumour growth and serial passage in immunocompromised NOD/SCID mice to investigate the stem cell properties of these cells.
Project Three: Drug Targets on Tumour Cells & Immune Cells
One of the main objectives of this research is to develop novel anti-cancer drugs that interfere with PMET. In collaboration with Prof Rob Smith, we have designed and tested more than 20 compounds, with lipophilic cations being the most potent inhibitors of PMET and tumour cell proliferation. A promising drug target of this pathway is the plasma membrane NADH oxidase enzyme. We are currently profiling the various splice variants of this enzyme on tumour cells to establish their drug sensitivity. We are also working with Novogen's anticancer drug phenoxodiol, which is thought to induce apoptosis in cancer cells by blocking the function of a cell surface NADH oxidase. We have shown that while phenoxodiol does inhibit PMET and cancer cell proliferation, it is highly immunosuppressive, suggesting a target molecule is also present on T cells.
Project Four: Acute Responses to Reductive Stress & the Regulation of Gene Expression
SIRT1 is a member of the sirtuin family of NAD+-dependent deacetylases that plays a critical role in regulating a number of intracellular processes in response to changes in NAD+ levels. We have examined the interplay between SIRT1 and PMET in various cancer cell lines following knock-down of SIRT1 expression and have shown that loss of SIRT1 affects the cytotoxicity of PMET inhibitors. This work is currently being prepared for publication.
Collaborators
Prof Aldo Andreani, Prof Laura Landi & Dr Cecilia Prata, University of Bologna, Italy
Dr David Brown, Novogen Inc, Sydney University, Australia
Prof Jonathan Cebon, Ludwig Institute, Melbourne, Australia
Prof Alison Downard, Chemistry Dept, University of Canterbury, New Zealand
Dr Patries Herst, Department of Radiation Therapy, University of Otago, Wellington, New Zealand
Prof David Ritchie, Peter macCullum Cancer Institute, Melbourne, Australia
Assoc. Prof John Miller and Assoc. Prof Peter Northcote, Centre for Biodiscovery, Victoria University of Wellington
Funding Sources
Genesis Oncology Trust
Melanoma Research Alliance
The Royal Society of NZ Marsden Fund
Child Health Research Foundation
Breast Cancer Research Trust
NZ LAM Trust and LAM Australasia Research Alliance
