Mirjam Epping is a PhD student in the research laboratory of Prof. Dr. Rene Bernards. The title of her thesis is: “Functional genetic screens as tools to discover signaling pathways targeted by cancer drugs”. She will defend her thesis at Utrecht University on Tuesday March 18.
A new class of anti-cancer chemotherapeutic drugs (“histone deacetylase inhibitors”) shows clinical effects in some patients, but not in others. Patients with a distinct type of non-Hodgkin lymphoma, referred to as cutaneous T cell lymphoma, often benefit from this class of drugs. Mirjam Epping has investigated which genes can render cells resistant to this class of drugs to get more insight into their mechanisms of action. She introduced a large number of genes in cancer cells and then treated them with the drugs. In the majority of the cells the treatment resulted in growth arrest and cell death. However, a few cells appeared resistant to the treatment due to introduction of the genes and were able to continue to grow. The gene encoding for the retinoic acid receptor was able to cause such drug resistance. Retinoic acid is a natural compound and a derivative of vitamin A. Treatment of normal cells and some cancer cells (eg. leukemias) with retinoic acid causes growth arrest and differentiation of the cells. The results of this research indicate that retinoic acid signaling is involved in the growth arrest induced by this class of anti-cancer drugs.
The second gene that was discovered was, unexpectedly, the tumor gene PRAME. In 88-95% of melanomas (skin cancer), the gene PRAME is known to be hyperactive. In several other types of cancer, PRAME is also hyperactive, but it has been unknown which could be the function of this gene. The research conducted by Mirjam and her colleagues revealed that PRAME inhibits retinoic acid signaling. As a result, melanoma cells with a lot of PRAME are resistant to growth inhibition by retinoic acid. Melanomas are virtually always resistant to treatment with retinoic acid and, unfortunately, these cancers are also resistant to many other chemotherapeutic drugs. By inactivating the gene PRAME in melanomas, Mirjam and her colleagues were able to generate melanoma cells that were sensitive to retinoic acid. The resulting melanoma tumors in experimental animals could be growth arrested by treating the animals with retinoic acid. The investigators also successfully treated experimental animals with combinations of histone deacetylase inhibitors and retinoic acid. A possible implication of this research is that treatment of cancers with histone deacetylase inhibitors combined with retinoic acid may be more effective than treatment with either drug alone.
The public thesis defense will be held in the Academy building at Utrecht University on Tuesday March 18 at 4.15 PM.