Epigenetics Research at UCLA

The Noreen Fraser Foundation is providing funding to establish a lab at UCLA which will collaborate with researchers at Johns Hopkins to test a cutting-edge new type of breast cancer drug that works by reversing epigenetic changes in cancer cells. The new type of treatment may be effective in the treatment of ovarian cancers as well. The DNA of human cells contains approximately 30,000 protein-encoding genes. Which genes are active in an individual cell, for instance, in the heart or the kidney, determines the appearance, behavior and function of the cells in each organ; control of gene expression therefore allows for organ specialization, growth and replacement of tissues and wound repair and is central to multicellular life. Human cancer cells differ from their non-malignant counterparts in which genes they express; this difference in gene expression is the essence of cancer. Much more recently, it has been recognized that mutations, which are simply changes in the sequence of bases in the DNA molecules that make up our genes, are not the whole cancer story. It turns out that changes in gene expression in a cell can be caused by mechanisms other than changes in the DNA base sequences inherited from parents; these changes are called “epigenetic” changes and occur normally as we age. There are two main mechanisms for epigenetic change: 1) addition of simple single carbon methyl groups to the DNA molecule and 2) simple chemical changes in the protective proteins that coat DNA and help to regulate folding of delicate chromosomes; these proteins are called histones. It is now clear that DNA methylation and histone modification are especially prevalent in human cancer cells. It has already become part of clinical practice to administer agents that remove DNA methyl groups to treat myelodysplastic syndrome, a previously untreatable early form of leukemia. It is now becoming clear that epigenetic events during the evolution of human cancers may play a major role both in producing the cancer gene expression phenotype and in resistance to rationally targeted cancer therapies. This is very important because, unlike mutations in DNA, epigenetic changes can be reversed. The laboratory work funded by NFF will be supervised by Dr. Ramin Nazarian, PhD. Dr. Nazarian will work with Dr. John Glaspy in the design and interpretation of experiments aimed at developing sufficient pre-clinical data to justify a much larger grant application and at supporting the initiation of a phase I clinical trial within 18 months. Preliminary data generated in a collaboration between Johns Hopkins and UCLA indicate that epigenetic changes are very important in the biology of human ovarian and breast cancers, including their evolution to more aggressive and treatment- resistant pehnotypes. Researchers believe that therapies that reverse epigenetic changes (hypomethylating agents and/or histone deacetylase inhibitors) are potentially very powerful tools in the treatment of breast and ovarian cancers. There are two classes of drugs that require study. The hypomethylating agents, of which azacytidine will be the agent of choice, and the HDAC inhibitors, of which entinostat will be the most promising agent. For ER+ breast cancers, the researchers will test the entire bank of cell lines for: 1) effects of estrogen deprivation alone on growth inhibition (control) 2) comparative effects of pre-treatment with azacytidine alone on the growth inhibition in these cell lines 3) comparative effects of pre-treatment with entinostat alone on the growth inhibition in these cell lines 4) Comparative effects of azacytidine combined with entinostat on the growth inhibition in these cell lines Although estrogen receptor expressing (ER+) human breast cancer is often initially controllable with estrogen blocking therapy, these tumors usually become resistant to this treatment and develop the ability to grow in the absence of estrogen. Despite several very effective estrogen-interdicting available therapies, ER+ breast cancer continues to result in more annual breast cancer deaths than any other subtype of this disease. The researchers hypothesize that pre-treatment with azacytidine will make ER+ breast cancer more dependent on estrogen, by reversing the epigenetic changes that decrease estrogen sensitivity over time. The preclinical experiments may support this hypothesis and if they do, can also define the duration of exposure necessary to have this effect. It is possible that entinostat plus azacytidine will be more effective in these preclinical models. When the scientists have these data in hand, they will be in a position to launch a proof of concept clinical trial in women with ER+ metastatic breast cancer that have had progression on estrogen-directed therapy. This trial would utilize either azacytidine alone or the combination of entinostat and azacytidine, depending upon our data.