Research report 2007 – Rhabdoid Tumour Study

Dr Algar presented the following report for the Spring 2006 Newsletter.

Investigators: Associate Professor David Ashley. Dr Elizabeth Algar and Andrea Muscat.

Childhood Rhabdoid Tumours (RT) are a rare but increasingly recognised tumour occurring in infants. These tumours occur in renal tissue and the central nervous system where they are also termed Atypical Teratoid Rhabdoid Tumours (AT/RT). Despite aggressive treatment with chemotherapy and radiation, the majority of children with these tumours die within one year of diagnosis. Recently it has been shown that rhabdoid tumors are associated with loss or mutations of the INI1 (SMARCB1) gene. INI1 is a core subunit of the SWI/SNF complex, a large protein complex that plays an important role in maintaining the stability of chromosomes in cells. We have hypothesized that INI1 might achieve this by maintaining the correct patterns of chemical modification on DNA and on its associated proteins. These chemical modifications include methylation and acetylation. When INI1 loss occurs in rhabdoid tumour, these modifications will be altered, however we believe it might be possible to restore normal patterns of chromosome methylation and acetytation, and thereby inhibit tumor growth, by using a class of chemical reagents called HDAC inhibitors or HDACi.

To demonstrate proof of principle we have shown that putting INI1 back into a rhabdoid tumor cell line, G401, causes the cells to stop growing. One of the HDACi we have tested so far also causes rhabdoid tumor cells to stop growing. We are presently analysing what happens to the patterns of acetylation and methylation in some important chromosome regions in these cells, both those that have had INI1 put back into them and those that have been treated with HDACi. We are also testing the effects of additional classes of HDACi and of INI1 on other rhabdoid tumor cells lines that we have acquired through a collaboration with scientists at the Children’s Hospital of Philadelphia and at the Peter MacCallum Cancer Institute. Our aim is to see whether certain HDACi treatments have the same specific biological effects as putting back INI1 into these cells. If we can show that HDACi treatment reverses the effects of loss of INI1, then we will explore the possibility that HDACi (also known as an epigenetic therapy) might be a promising agent in the treatment of rhabdoid tumor.

We are very grateful for the support that CIKA has provided for this project to date as it has enabled us to generate some interesting and important preliminary data. We are now in a position to build upon this and progress the project further.

Elizabeth Algar PhD.

A progress report on this project was published in the Christmas 2007 CIKA Newsletter.

This study was conducted under the direction of Dr Elizabeth Algar of the Molecular Oncology Laboratory. Rhabdoid tumours are rare, and have a very high mortality rate. This research was conducted in collaboration with other hospitals here and abroad.

Significant progress was made with this project during the year ended 30 June 2007. The studies have provided evidence that supports the hypothesis of the changes in the chromosomes within the affected cells. The studies also identified a possible way to at least partly restore some of the normal genetic and metabolic pathways in rhabdoid tumor cells. The findings have been published in peer-reviewed scientific literature, and will form the basis to support funding applications to the NHMRC. Dr. Algar has presented the study findings in Australia and overseas.