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Epigenetics Now Goes Far Beyond HDAC Inhibitors

By Anette Breindl
Science Editor

WASHINGTON – Several presentations at the American Association for Cancer Research's (AACR) Annual Meeting this week underscored the size of the epigenetic space. Targeting epigenetic alterations has gone far beyond histone deacetylase (HDAC) and DNA methyltransferase (DNMT) inhibitors, which are the two classes of epigenetic enzymes that have approved drugs targeting them.

HDAC inhibitors on the market are Istodax (romidepsin, Celgene Corp.) and Zolinza (vorinostat, Merck & Co Inc.). There are also two DNMT inhibitors currently approved: Vidaza (azacitadine, Celgene Corp.) and Dacogen (decitabine, Astex Pharmaceuticals Inc.).

But epigenetics can be classified in several different ways, and companies are branching out beyond HDAC and DNMT to target other parts of the methylation machinery.

At a Saturday session on "Targeting Epigenetics: An Epicenter of Oncology Drug Discovery?", Novartis Inc.'s Ho Man Chan defined epigenetic changes as "heritable gene expression patterns not encoded in DNA."

Epigenetic changes can be due to modifications of the DNA itself in the form of, for example, methyl or acetyl groups, or the histones that package DNA, thus affecting how it is seen, and how accessible it is, to the cell's transcription machinery.

The interplay between epigenetic and genetic changes is a two-way street. Some epigenetic alterations lead to the silencing of DNA repair genes, which increases the mutation rate of tumors with such changes. On the other hand, many changes in epigenetic patterns have genetic mutations of the responsible enzymes as their root cause.

There are several possibilities for how epigenetic changes might lead to cancer, Massachusetts General Hospital's Russell Ryan told the audience at Saturday's session. One is that changes in the epigenetic state could lock in, for example, a stem cell-like state. On the other hand, their widespread effects may be a red herring. Ryan said it is possible that one or a few of the many pathways they affect are the key to their role in cancer, and that identifying those few will be the key to developing successful epigenetic therapies.

But whatever the mechanisms, the system is of the sort that is likely to be druggable: "It's an enzyme-rich system," Ryan said, making it an appealing target to drug developers.

And going after epigenetic enzymes could render targets druggable by proxy: If an oncoprotein, for example, cannot be targeted, maybe the epigenetic enzymes that affect it can.

At a Monday plenary session on epigenetics, James Bradner described one such way to expand the druggable genome: using bromodomain inhibitors to target the oncoprotein myc.

Data on Mutations is 'Alarming'

Bradner, who is at the Dana Farber Institute, described himself as a discovery chemist – and told the audience that from his perspective, the cancer genome data on mutations are "alarming." The numbers indicate there are more than half a million recurrent mutations affecting almost 25,000 proteins – in other words, "almost all of them."

About 500 of those are known to contribute to pathogenesis, and there are approved direct-acting therapeutics for a paltry 15 of those mutations.

To top it off, by and large, those mutations are not the ones that show up again and again in different cancers. P53, the most frequently mutated gene in human cancer, still has no therapeutics directed at it. The same is true for myc, though Bradner said that successfully targeting this frequently amplified oncogene would provide "true one-stop shopping" in fighting the hallmarks of cancer.

Myc, and many of cancer's big league players, are hard to drug for a variety of reasons. But Bradner's work has shown that in addition to rare cancers with bromodomain fusion proteins, myc-amplified cells are uniquely sensitive to bromodomain inhibition. Swiss OncoEthix SA is furthest along in bringing BET inhibitors to the clinic for cancer. The company is in Phase I trials with bromodomain inhibitor OTX015.

Bradner is co-founder of Cambridge, Mass.-based Tensha Therapeutics, which is developing bromodomain inhibitors preclinically, as are GlaxoSmith-Kline plc and Constellation Pharmaceuticals Inc., whose chief scientific officer is chairing a session on "Therapies Targeting Epigenetic Mechanisms" on Tuesday.

Canadian Resverlogix Corp., which is in Phase II trials with a BET inhibitor RVX-208 in other indications, announced it is spinning out its discovery platform into an independent entity, RVX Therapeutics Inc., which will have cancer as one area of focus. Resverlogix Corp is testing RVX-208 in other indications, while Bradner's academic lab is looking at BET inhibitors as potential male fertility treatments. (See BioWorld Today, Sept. 13, 2011, Jan. 17, 2012, and Aug. 29, 2012.)

Chairing Monday's plenary session, as well as presenting at it, was Epizyme Inc.'s Robert Copeland, who gave an update on the company's programs targeting two protein methyltransferases, DOT1L and EZH2, for different blood cancers. While DNMTs add epigenetic marks to DNA, the protein methyltransferases that Epizyme targets add them to proteins – mostly, though not exclusively, histones. (See BioWorld Today, Nov. 24, 2010, and April 26, 2012.)

Another enzyme that appears to straddle epigenetics and metabolism is isocitrate dehydrogenase (IDH), an enzyme with two sub forms, IDH1 and IDH2. IDH1 leads to the demethylation of certain lysines through its effects on the 2-hydroxyglutarate. Agios Pharmaceuticals Inc. published data in preclinical data on its IDH inhibitors in Science last week.

For now, the bulk of clinical trials targeting epigenetic mechanisms is still at an early stage. But Epizyme's Copeland told BioWorld Today that it is exciting to see the field move forward. Those clinical trials, he said, will be "the ultimate test of the whole hypothesis."

In other news from the AACR:

• Ariad Pharmaceuticals Inc., of Cambridge, Mass., presented data from two preclinical studies showing that ponatinib (Iclusig) potently inhibits RET, an oncogenic driver of medullary thyroid cancer (MTC) and non-small-cell lung cancer (NSCLC), and FGFR, commonly mutated in endometrial, lung and other cancers. The RET study showed that ponatinib inhibited naturally occurring activating mutants of RET found in MTC and NSCLC at clinically achievable plasma concentrations, with greater potency than that of other approved tyrosine kinase inhibitors with RET activity. The FGFR study evaluated the ability of ponatinib to inhibit a broad panel of naturally occurring mutant variants of FGFR1, 2, 3 and 4, demonstrating that ponatinib blocked a variety of mutant variants of FGFR, with particularly promising activity against mutant variants of FGFR2 observed in endometrial and squamous cell carcinomas of the lung. The FDA approved the pan BCR-ABL inhibitor in December 2012. (See BioWorld Today, Dec. 17, 2012.)

• Arno Therapeutics Inc., of Flemington, N.J., presented data examining onapristone's effect on preclinical models of breast cancer, using a biomarker that has the potential to identify patients with certain cancers that may best respond to onapristone therapy. Findings showed inhibitory effects in cell lines with activated progesterone receptors, and researchers concluded that the immunohistochemistry technique developed to identify activated progesterone receptors in tumors may be applicable in the clinical setting. Phase I studies of onapristone are set to start in the second half of this year.

• Celldex Therapeutics Inc., of Needham, Mass., reported results of an in vitro study analyzing the activation of human T cells with CDX-1127, a monoclonal antibody that binds CD27 and is designed to activate patients' immune cells against their cancer. Consistent with earlier work, results confirmed the mechanism of action of CDX-1127, showing that it elicits potent activation of T cells by inducing their proliferation and release of immune-modulating cytokines.

• Immunomedics Inc., of Morris Plains, N.J., reported that its humanized antibody, clivatuzumab, is specifically reactive with pancreatic ductal adenocarcinoma (PDAC) and does not react with chronic pancreatitis tissues. The company said those data have implications for the clivatuzumab-based blood test, suggesting that subjects diagnosed with chronic pancreatitis who are found to be positive for the blood test may actually have cancer and should be followed for further indications of PDAC.

• Merrimack Pharmaceuticals Inc., of Cambridge, Mass., reported findings showing that preclinical candidate MM-121 restored tumor sensitivity and delayed the onset of resistance to the aromatase inhibitor, letrozole, in an ER+ breast cancer model. The fully human monoclonal antibody targets ErbB3, a cell surface receptor implicated in tumor growth and survival. In 2009, Merrimack signed a potential $530 million exclusive global license and collaboration agreement with Sanofi SA, of Paris, to develop MM-121 in several cancer types. (See BioWorld Today, Oct. 2, 2009.)

• MethylGene Inc., of Montreal, reported preclinical data showing kinase inhibitor MG516 possesses inhibitory activity against a spectrum of tyrosine kinase receptor targets, including Eph receptors and RET as well as MET, AXL and VEGF-R family members. The study incorporated data from in vitro kinase and cell-based analyses. MG516 also reversed resistance to the VEGF-R inhibitor sunitinib in an in vivo preclinical tumor model.

• Nektar Therapeutics Inc., of San Francisco, presented preclinical data showing that cancer immunotherapeutic NKTR-214 targets the IL-2 receptor complex through selective receptor binding to the IL2Rβ subtype, activating destruction of the tumor by the body's immune system. NKTR-214 represents the first application of the company's polymer conjugate technology platform to target a receptor subtype in the tumor microenvironment while avoiding the unwanted effects from off-target receptor binding. NKTR-214 also has improved pharmacokinetics and enhanced tumor penetration, allowing for a 10-fold reduction in overall dosing.

• NewGen Therapeutics Inc., of Menlo Park, Calif., reported preclinical data showing high potency, pharmacokinetics and single-agent activity of NT-113, an irreversible pan-ErbB tyrosine kinase inhibitor. Results showed the compound potently inhibited ErbB subtypes, including EGFR, HER2 and ErbB4 in a panel of more than 100 tyrosine kinases and was highly active against Tarceva- (erlotinib, Astellas Inc.) and Iressa- (gefitinib, AstraZeneca plc) resistant cancer cells with EGFR mutations, including T790M, L858R and d-746-750. Potent anticancer activity was demonstrated in T790M mutant non-small-cell lung cancer and HER2-positive gastric cancer xenograft models, while pharmacokinetic data showed excellent bioavailability, a long half-life and the ability to penetrate the blood barrier at therapeutic concentrations.

• NewLink Genetics Corp., of Ames, Iowa, presented preclinical data for NLG919, an indoleamine-(2,3)-dioxygenase (IDO) pathway inhibitor. Findings reported in a poster presentation showed that NLG919 inhibited the IDO pathway in vitro and in cell based assays, blocked IDO-induced antigen-specific T-cell suppression and restored T-cell responses, demonstrated single agent antitumor activity and showed synergistic T-cell activation and antitumor activities with indoximod (NLG8189 or D1-MT). Findings also showed that NLG919 is orally bioavailable and has a favorable pharmacokinetic and toxicity profile.

• Pharmacyclics Inc., of Sunnyvale, Calif., reported Phase II data showing that oral agent ibrutinib demonstrated rapid and sustained disease control as a monotherapy in untreated, relapsed and refractory chronic lymphocytic leukemia patients, irrespective of characteristics that predict poor outcomes to chemoimmunotherapy. The study also tested in vivo effects of the Bruton's kinase inhibitor using blood and tissue samples collected before and during treatments, with results showing a rapid and sustained disease control in blood, lymph nodes, spleen and bone marrow with ibrutinib. After six months, 95 percent of patients experienced a reduction in lymph node size and all showed a reduction in spleen enlargement, with a median reduction of 55 percent. In 26 patients for whom a bone marrow biopsy was done, tumor infiltration decreased by 82 percent.

• Spirogen Ltd., of London, and BioAtla LLC, of San Diego, reported data on the use of pyrrolobenzodiazepine (PBD) dimers as warheads in antibody drug conjugates (ADCs). The study evaluated the efficacy of five ADCs against solid and hematological cancer targets, with the hematological target antibody engineered using BioAtla's CIAO and BioAcceleration technologies and conjugated to Spirogen's cytotoxic PBD dimers. Trastuzumab ADCs were tested against HER2-expressing human breast cancer in vivo. In both tumor types, data showed the ADCs achieved durable complete regression and tumor-free survival. The PBD dimers were not found to be cross-resistant with widely used chemotherapeutic agents.