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Report on progress to date for Nicola Murray Foundation 2

10th January 2014

Professor Charlie Gourley

 Previously we screened a panel of ovarian cancer cell lines (cells that have been made immortal and which grow in culture on plastic dishes in the laboratory) in order to identify those which lacked expression of HNPCC genes and as such may represent the situation in patients who carry HNPCC gene mutations. We found three such cell lines and returned the missing gene to these cell lines in order to investigate the effect that this has on the characteristics of the cancer cell. In 2013 we found that returning the missing gene had no effect on the growth of the cancer cells (in short term culture) or on their sensitivity to standard chemotherapy agents. We also discovered that two of the cell lines silenced the added gene during long term culture suggesting that loss of this gene was required for them to continue behaving like cancer cells.

 

Data from these (and other) cell line models combined with data from a panel of 600 human ovarian cancers have suggested that the levels of some of the mismatch repair proteins are controlled together in a pairwise fashion. The cellular mechanisms responsible for this phenomenon are currently under intense investigation in the hope that they can shed light on potential new therapies in HNPCC-deficient ovarian cancer.

 

Much of the work performed in the last year has been creating the correct models and identifying the correct cells to use in a large drug screen which will be performed in February 2014. This experiment will compare the growth of pairs of cancer cell line clones which are identical except for the presence or absence of a particular functional HNPCC gene. These pairs of cancer cells will be exposed to approximately 400 new cancer drugs which target important processes in the cancer cell. In this way we hope to find which pathways are critical in ovarian cancer patients with HNPCC gene defects and which drugs are likely to be most effective in these patients.

 

In 2013 we also wrote and published a review of the role of the HNPCC genes in ovarian cancer. Hopefully this will increase the awareness of this important but under-investigated subject. 

 

We are extremely grateful to the Nicola Murray Foundation and their fundraisers for continuing to support our work.

 

 

Report on progress to date for Nicola Murray Foundation 1

31st January 2013

Professor Charlie Gourley

Despite the fact that HNPCC (Hereditary Non-Polyposis Colorectal Cancer) is the second most common hereditary ovarian cancer syndrome, the effect of this genetic condition on ovarian cancer behaviour has been under-investigated.

The Nicola Murray Foundation support work to investigate the role of HNPCC in ovarian cancer development and behaviour in the laboratory of Professor Charlie Gourley at the University of Edinburgh Cancer Research Centre. Jessie Xue is the Nicola-Murray Foundation funded PhD student who is performing this work.

The hypothesis of our study is that HNPCC-deficient ovarian cancer is a distinct subgroup with different underlying biology and also different sensitivity to anticancer therapies.

In the first part of our study we have grown a panel of 20 ovarian cell lines (tissues that grow in dishes in the laboratory; 18 of these were taken from ovarian cancers and two of these were taken from normal ovaries). We have screened these 20 cell lines to identify those in which any of the seven HNPCC genes have been inactivated. This screen identified three cell lines which had no expression of one or more of the HNPCC genes.

We have now taken these three cell lines into the next stage of our work and we have restored the HNPCC genes that were missing in some representatives of each of these three cell lines. This will allow us to compare the behaviour of the same cell line that contains or does not contain a particular HNPCC gene. This model system will allow us to determine the role that each gene has in the biology of the cancer and importantly whether it affects the sensitivity of the ovarian cancer to both conventional and novel cancer therapies.

As a separate piece of work we have investigated the level to which the HNPCC genes were switched on in a panel of 590 ovarian tumours from patients treated in South East Scotland over the last 20 years. We found that certain subtypes of ovarian cancer were more likely to have these genes switched off than other subtypes of ovarian cancer. We also identified other genes that were likely to be switched off at the same time, shedding light on genes that work together in patients who have defective copies of the HNPCC genes.

We are extremely grateful to the Nicola Murray Foundation for the funding that has allowed us to complete the work to date and for the ongoing funding which we hope will enable us to use the models that we have created to identify specific treatments for patients with HNPCC-deficient ovarian cancer.






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