Oncology takes lead in exploring potential of epigenetics

Latest breakthroughs help create array of powerful drugs

The past five years have been a golden age in cancer genetics. The cost of gene sequencing has fallen low enough for researchers to read the genomes of many thousands of patients — comparing the DNA of diseased and healthy tissues to find the mutations associated with tumour formation and growth.

The results confirm clinicians’ longstanding view of cancer as a genetic disease. They demonstrate the huge complexity of the rapid genetic changes that take place as a tumour starts growing and later metastasises to other sites. A patient with advanced disease is likely to have many different genetic profiles, as various lineages of cancer cells develop in a Darwinian process somewhat like the evolution of plants or animals in ecological niches.

The myriad mutations in cancer DNA are only the start of the genetic complexity associated with the disease. The processes that regulate genes, turning them on or off according to circumstances, introduce a further level of complexity, by the name of epigenetics.

Epigenetics applies throughout biology, from the development of different organs within an embryo in which all cells share the same DNA. Its implications for medicine are enormous. Auto-immune and neurological diseases, for instance, involve abnormalities in epigenetic regulation. Oncology is the discipline embracing epigenetics with the greatest enthusiasm, as a potential diagnostic and therapeutic tool.

“Epigenetic breakthroughs are quietly creating a toolbox of powerful drugs to treat cancer,” says Andrew Baum, Citigroup pharmaceuticals analyst, in a recent report. “We conservatively estimate that oncology . . . alone will generate $10bn [a year] by 2025.” Companies with the most advanced epigenetic drug pipelines are GlaxoSmithKline, Celgene, Otsuka and Epizyme.

Tony Kouzarides, professor of cancer biology at Cambridge university, says the epigenetic changes of most significance in oncology fall into two classes. Simplest to understand is direct molecular tagging of DNA itself. Chemical markers attach to genes and switch them on or off; most common is methylation (attachment of a methyl group).

The other, more complicated process is indirect and involves histones — beadlike proteins around which DNA is wrapped inside the cell nucleus to form a “chromatin” complex. Chemical modification of histone affects the activity of the DNA inside.

“In both cases, we can affect the epigenetic process, through drugs that hit the enzymes that modify the DNA or histone,” says Prof Kouzarides. By inhibiting the appropriate enzyme, it is possible to inactivate a cancer-associated gene. His lab has found an inhibitor called i-Bet that is effective against the epigenetic pathways leading to “mixed lineage leukaemia”, an aggressive blood cancer that occurs mainly in children.

Mr Baum foresees four waves of commercial success for epigenetic drugs in cancer. The first will treat lymphoma and lung cancer; the second will overcome acquired resistance to oral cancer drugs by inhibiting the c-myc oncogene; the third will eliminate the stubborn “cancer stem cells” that can lead to relapse after successful treatment; the fourth will improve patients’ response to immunotherapy — the most exciting innovation of all in cancer treatment — by epigenetic priming of the tumour.

An emerging cancer diagnostics area is based on the detection of epigenetic biomarkers associated with cancer. The German company Epigenomics identifies cancer by detecting methylation of cancer-associated genes in blood samples. Its first product is a blood-based screening test for the early detection of colorectal cancer. Others that use DNA methylation for diagnosis include MDXHealth and Exact Sciences of the US.

Cambridge Epigenetix, a Cambridge university spin-off, takes a different approach focusing on the “epigenetic code” of different tags that control DNA activity. Its co-founder is chemistry professor Shankar Balasubramanian, whose previous company Solexa devised the world’s leading technology for reading the sequence of DNA itself. He refers to how “underprovided” epigenetics research was with “good tools and reagents” and that Cambridge Epigenetix aims to go beyond DNA methylation and develop tests for other epigenetic modifications implicated in disease. These include the addition of hydroxymethyl and formyl groups.

Academic and industrial research networks associated with epigenetics are growing. One, EpiGeneSys, is funded by the EU and encompasses 170 labs across Europe. “We want to foster an open, collaborative research environment that nurtures bright young scientific minds and creates a culture where members can share ideas and advance critical thinking,” says Genevieve Almouzni of EpiGeneSys and a senior researcher at the Institut Curie in Paris.

According to Prof Balasubramanian it is hard to overstate the significance of epigenetics. “While our core DNA is largely fixed, epigenetics will enable us to assess and measure how our living system changes in response to disease and the environment,” he says. “That is going to be immensely powerful in medicine and beyond.”

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