Research Projects

Lung Cancer Research – Dr Paula Sommer

Lung Cancer Research – Dr Paula Sommer

Dr Paula Sommer

Title of the project

Epigenetic silencing of the glucocorticoid receptor in small cell lung cancer

Highlights of the Project:

Small cell lung cancer (SCLC) is an aggressive disease with a very poor prognosis, demanding novel advances in treatment. Many cancers silence the expression of tumour suppressor genes by epigenetic modification such as DNA methylation. We have recently shown (Kay et al 2011) that the glucocorticoid receptor (GR), a normally ubiquitously expressed gene, is silenced by methylation and that removal of the methyl marks using a DNA methyltransferase inhibitor allowed endogenous reexpression of the GR, driving the cancer cells to apoptosis. The discovery of a novel and endogenous mechanism to specifically induce apoptosis of SCLC may contribute to the design of more tailored therapy for this deadly disease.

Non-Scientific Progress Report:

Lung cancer is the major cause of cancer death world-wide and remains a significant problem in South Africa, particularly among the male population but is worryingly on the rise in the female population. This is exacerbated by the fact that HIV-infected individuals experience elevated risks of lung cancer. Small cell lung cancer (SCLC) is a highly aggressive disease characterised by wide-spread metastases. Initially the disease responds well to chemotherapy but have a very poor long term survival rate of less than 5% after 5 years due to relapse with chemoresistant disease. Despite significant advances in early diagnosis and therapy, long term survival remains rare and novel, alternative therapies are  demanded.

It is now generally accepted that during the early stages of carcinogenesis, many cancers suppress the expression of unwanted genes such as tumour suppressor genes by the placement of large methyl groups on the promoters of these genes. These methyl groups sterically prevent gene expression and so the genes are silenced.

We have shown that the gene coding for the glucocorticoid receptor (GR) is silenced in this way in SCLC cells. If the GR is re-expressed in these cells, the cells undergo cell death by apoptosis. This suggests that the GR is a novel tumour  suppressor gene for SCLC.  Therefore, the discovery of a mechanism whereby the GR is specifically activated in SCLC may be a successful adjunct to existing chemotherapy regimens.

Congress abstracts:

  • KM Houston and P Sommer. 2011. Epigenetic silencing of the glucocorticoid receptor in small cell lung cancer. 39th Conference of the Physiology  Society of Southern Africa (PSSA), 29 -31 August 2011.
  • N Singh and P Sommer, Expression of glucocorticoid receptor promoters in small cell lung cancer. 39th Conference of the Physiology Society of Southern Africa (PSSA), 29 -31 August 2011.

Publications:

Paul Kay, George Schlossmacher, Laura Matthews, Paula Sommer, Dave Singh, Anne White, David Ray. 2011. Loss of glucocorticoid receptor expression by DNA methylation prevents glucocorticoid induced apoptosis in human small cell lung cancer cells. PLoS ONE: Research Article, published 03 Oct 2011 10.1371/journal.pone.0024839

Please summarise how you believe this project is of value in the struggle against cancer:

Small cell lung cancer (SCLC) is a highly aggressive cancer that initially responds well to chemotherapy but disseminates rapidly and develops resistance to anti-cancer drugs, leading to very poor long term survival rates. Despite considerable advances in the diagnosis and treatment of SCLC over the past 10 years, long term survival remains rare, and thus novel approaches to treatment are demanded to reduce its impact on the global health burden.

Previously we showed that silencing of the glucocorticoid receptor confers a survival advantage to small cell lung cancer cells. We now show that the glucocorticoid receptor is silenced by methylation which, unlike mutations, is a reversible event. The identification of a novel, endogenous mechanism that specifically induces apoptosis of SCLC cells offers great promise of the development of targeted therapeutics for the treatment of this deadly disease.


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