The Combination of Etoposide and Histone Deacetylases applied to Cancers with high levels of c-MYC and c-FOS gene expression

The Combination of Etoposide and Histone Deacetylases applied to Cancers with high levels of c-MYC and c-FOS gene expression:

This research project investigates the possibility of combining Etoposide with Histone Deacetylases in the treatment of cancers that display a significant expression of te c-Myc and c-Fos gene.  The drugs proposed for this trial are Etoposide and Histone Deacetylases.

Etoposide was first synthesized in 1966 and is a drug widely used in chemotherapy since 1983 when it obtained  FDA approval. Etoposide forms a ternary complex with DNA and the topoisomerase II enzyme which participates in the unwinding of DNA, hence prevents the rwligation of the DNA strands, and by doing so causes DNA strands to break. This action then  leads to DNA synthesis errors and subsequently to cell death. Etoposide has, however, some reported side effects such as low blood pressure, hair loss, pain or burning at the injection site .

Histone deacetylation has been an effective treatment for various types of cancers. By the removal of acetyl groups from histones, histone deacetylases create a non-permissive chromatin conformation that prevents the transcription of genes that regulate the expression of proteins involved in tumor development such as c-FOS. In addition to histones, histone deacetylases deacetylate a variety of other proteins including transcription factors and other abundant cellular proteins involved  in the regulation of cell growth, differentiation and cell death. Histone Deacetylases are among the most promising therapeutic targets for cancer treatment, and they have inspired researchers to study and develop HDAC inhibitors worldwide.

The present research project consists in computerized and laboratory testing of the efficacy of combining these two treatments in cases of observed overexpression of both the c-MYC and c-FOS gene.  Although the two drugs already exist and are used in cancer therapy, the interaction of  the two drugs when used in combination needs to be examined. This can be achieved by using a mouse model bearing specified tumors to be done at the University of Texas at El Paso (UTEP). Preliminary testing should be conducted by implanting cancer cells in the skin of mice. The combined treatment should then be applied indiscriminately to mice presenting high expression of c-Myc and c-FOS, and to those with low expression of these genes. The response to the treatment will be monitored to evaluate the efficacy of the treatment in mice with high c-Myc and c-FOS expression as compared to the control group with low c-Myc and low c-FOS expression. In a later phase, testing would be conducted  in cancer patients presenting high expression of c-Myc and c-FOS, especially for patients treated for triple negative breast cancer, but also for ovarian cancer and other types of cancer with an overexpression of c-MYC.

The combination of Etoposide with Histone Deacetylases represents de facto a novelty in cancer treatment, especially in the case of triple negative breast cancer that is until today associated with a worse prognosis than other breast cancer types. It has a characteristic recurrence pattern with the peak risk of recurrence and the majority of deaths occurring in the first 3 and 5 years after the initial treatment, respectively.