12:58 PM
Sep 21, 2017
 |  BC Innovations  |  Tools & Techniques

On your marks

How the slowly-progressing epigenetics field is moving away from cancer

With less fanfare than the first two waves, a quiet rise in activity is driving a revival of interest in epigenetics, despite little progress in solving the fundamental challenges that have dogged the field from the start.

Although a host of new chromatin-regulators have been identified over the last five years, few of the targets have been touched by drug developers. Instead, preclinical innovation has been springboarding off positive clinical data by devising workarounds to selectively hit validated targets and explore uses for them beyond cancer (see "New Epigenetic Targets").

And while companies may be missing opportunities by not jumping on the new targets, preclinical progress in the field has clearly been sufficient to sustain enthusiasm among investors, who have been steadily backing new opportunities created out of the earlier waves.

In the last five years, at least 12 epigenetic companies have been formed, raising more than $428.5 million between them. Of those, nine are going after epigenetic targets already in the clinic, including HDACs and BET bromodomain proteins. Two have not disclosed targets and one is working on diagnostics based on epigenetic profiles (see "New Epigenetic Companies").

Approval of the first pan-HDAC inhibitor in 2006 launched the initial era of epigenetics; since then seven more pan-HDAC inhibitors have been approved and at least 30 more are in clinical development, along with the first isoform-selective versions, which should have less widespread effects across the genome.

The second epigenetics surge kicked off five years ago when BET bromodomain inhibitors were shown to have exceptional clinical efficacy in NUT midline carcinoma -- a rare genetic disease caused by rearrangement of the NUT gene that often results in generation of BRD-NUT fusion proteins. At least 11 BET inhibitors are now in the clinic for various cancers.

The advent of HDACs, and then BET bromodomain proteins, was met with broad enthusiasm, but the idea that regulating the agents that regulate gene expression could make major inroads into treating cancer proved harder than anticipated to realize.

In 2013, a collection of epigenetic experts at BioCentury’s SciBX Summit on Innovation in Drug Discovery & Development highlighted three key challenges for the field: determining which patients will respond to an epigenetic modulator, developing therapeutics selective for individual proteins within a family, and creating the tools that will help compile the mechanistic and biological information needed to solve the other two problems.

Those problems have not gone away. But rather than battle the preclinical limitations, researchers have been implementing bedside-to-bench translation, using clinical data to provide mechanistic insights, and exploiting new technologies to drive innovation in and beyond cancer.

“We’ve seen an epigenetics Renaissance over the last few years with the discovery of new enzymes, and more importantly, an understanding of the more complex roles of HDACs. The next two major leaps we’re seeing are using epigenetics in non-oncology situations, and using it to enhance activity of some of the newer immuno-oncology agents,” said Simon Jones, president and CEO of Regenacy Pharmaceuticals LLC.


"The next two major leaps we're seeing are using epigenetics in non-oncology situations, and using it to enhance activity of some of the newer immuno-oncology agents."

Simon Jones, Regenacy


Table: New epigenetic targets

Select therapeutic epigenetic targets. At least 16 new targets involved in chromatin modulation and gene expression have been described in the BioCentury Innovations Distillery since 2012. The new targets include methyltransferase, acetyltransferase and demethylase enzymes, as well as transcriptional activators, repressors and enhancers. Disease areas and standard indications with translational potential for each target were identified from preclinical research papers highlighted in the Distillery. While most epigenetic modulators in the clinic are being developed for cancer, 11 of the 16 new targets have translational potential in non-cancer indications. Commercial programs have been disclosed against only one of the new targets, protein arginine methyltransferase 5 (PRMT5). Source: BioCentury Archives; BCIQ: BioCentury Online Intelligence

Epigenetic categoryTargetDisease area(s)Indication(s)Description
MethyltransferaseDNA (cytosine-5-)-methyltransferase 3 α (DNMT3A)CancerAcute myelogenous leukemia (AML); colorectal cancerEliminating proleukemia cells expressing DNMT3A could help treat AML; a DNMT3A inhibitor could help treat colorectal cancer
PRMT5CancerMantle cell lymphoma (MCL); colorectal cancer; chronic myelogenous leukemia (CML)Inhibiting PRMT5 could help treat MCL, colorectal cancer and CML
Histone acetyltransferaseK(lysine) acetyltransferase 2B (KAT2B; PCAF)Cancer; endocrine / metabolicBrain cancer; diabetesInhibiting KAT2B could help treat brain cancer; KAT2B antagonists could help treat Type II diabetes
K(lysine) acetyltransferase 5 (KAT5)InfectiousChikungunya virusInhibitors of KAT5 could help treat Chikungunya viral infection
Histone lysine demethylaseJumonji/ARID domain containing...

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