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Oct 24, 2013

Epigenetics Targets May Enable Discovery of Novel Drugs

The processes that control epigenomic function are providing new opportunities for deriving new therapeutic strategies.

Epigenetics Targets May Enable Discovery of Novel Drugs

Many companies including Acetylon and Syndax are testing out new HDAC inhibitors. [© fotoliaxrender - Fotolia.com]

  • The epigenome has truly arrived as a drug development target as small biopharma companies and biotech/pharma giants have programs aimed squarely at proteins that operate in the epigenetic space.

    Alterations in the epigenome have gained great attention from scientists as candidates for the development of specific markers for cancer detection, diagnosis, and prognosis. The enzymatic processes that control epigenomic function, such as acetylation or methylation, provide new opportunities for deriving therapeutic strategies designed to reverse transcriptional abnormalities inherent to the cancer epigenome. Aberrant epigenetic mechanisms occur both in chromatin packaging and in localized gene promoter changes that influence transcription of key genes in the cancer process.

    And, scientists now say cancer development not only depends on genetic alterations but on an abnormal cellular memory, or epigenetic changes that convey heritable gene expression patterns critical for neoplastic initiation and progression.

    Epigenetic control systems generally involve three types of proteins: “writers”, “readers”, and “erasers.” Writers attach chemical marks, such as methyl groups (to DNA) or acetyl groups (to the histone proteins that DNA wraps around). So-called “readers” bind to these marks, thereby influencing gene expression; erasers remove the marks.

    The marks are passed down as cells divide, providing a sort of cellular memory to ensure that skin cells, for example, give rise only to other skin cells.

    And understanding chromatin control of gene expression, such as including relationships between histone modifications including acetylation and DNA methylation, may hold a key to understanding the origins of cancer epigenetic changes. This possibility, coupled with the reversible nature of epigenetics, they say, could have enormous significance for the prevention and control of cancer.

  • HDAC Inhibitors

    In pathological situations, where classical histone deactylases (HDACs), the enzymes that remove acetyl groups from chromatin, are overrepresented, histone deacetylase inhibitors (HDIs, or HDAC inhibitors) have emerged as promising cancer therapeutic agents. HDACs normally catalyze removal of acetyl groups from acetylated lysine residues in histones and nonhistone proteins, which helps to regulate gene expression.

    Inhibition of histone deacetylases results in hyperacetylation of histones and modulates gene expression by creating an open chromatin state that leads to expression of previously silenced genes. Although the mechanism of action is not fully understood, inhibiting HDACs has been observed to result in cell cycle arrest and apoptosis of cancer cells.

    Specifically, HDIs catalyze the removal of acetyl groups from the lysine residues of proteins, including histones and transcription factors. Some cancer cells overexpress HDACs, or an aberrant recruitment of HDACs to oncogenic transcription factors causing hypoacetylation of core nucleosomal histones. To date, about 11 HDACs have been described.

    Hypoacetylation of histones, structures associated with chromatin packaging, is associated with a condensed chromatin structure and repression of gene transcription. Inhibition of HDAC activity allows for the accumulation of acetyl groups on the histone lysine residues resulting in an open chromatin structure and transcriptional activation.

    In vitro, vorinostat causes the accumulation of acetylated histones and induces cell cycle arrest and/or apoptosis of some transformed cells.

    Researchers caution that contributions of specific HDACs to a given cancer type remain incompletely understood. Currently approved HDAC inhibitors lack specificity and can cause a broad range of side effects because they impact multiple members of the 11-protein zinc-dependent HDAC family in normal and healthy cells.

    Nonetheless, in 2006, the FDA granted regular approval to vorinostat (Zolinza®, Merck & Co.), an HDI approved for the treatment of cutaneous T-cell lymphoma, a rare immune-cell cancer that affects the skin. In 2009, the HDAC inhibitor romidepsin (Istodax®, Celgene) was approved for the same indication.

  • Novel HDIs on Trial

    Because of mounting evidence that HDIs need to be more specific, companies developing this class of drugs are designing them for more selectivity. Acetylon (Boston, MA), has developed a portfolio of oral, selective HDAC inhibitors targeting oncology, hematology, immunology, and neurologic disease indications. The company presented Phase Ib clinical data regarding its lead candidate, ACY-1215, for the treatment of relapsed or refractory multiple myeloma at the European Hematology Association this past June in Stockholm.

    ACY-1215, an orally administered drug, selectively inhibits HDAC6, an extranuclear member of the HDAC enzyme family. The drug is currently being evaluated in a Phase Ib clinical trial in combination with Celgene’s Revlimid® (lenalidomide) and a Phase I/II trial in combination with Takeda Millennium’s Velcade® (bortezumib) for the treatment of relapsed or refractory multiple myeloma.

    Of those studies, Catherine A. Wheeler, M.D., vice president, clinical development of Acetylon said, “We are encouraged by the number of early clinical responses that have been observed in combination therapy. In the Phase Ib study in combination with Revlimid, eight out of ten evaluable patients to date achieved disease response, including one complete response (with marrow confirmation), two very good partial and four partial responses observed.”

    The company also reported that the drug proved active in heavily pretreated patients in combination with Velcade in the ongoing Phase I/II study, including three partial responses and one minor response to date in thirteen evaluable patients. “Responses in both trials have been durable, with patients remaining on study for up to 11 months.” Dr. Wheeler said.

    She further noted that no dose limiting toxicities or severe adverse events, which are common with previous generation nonselective HDAC inhibitors, have been observed in this trial, and “dose escalation is continuing.”

    Acetylon president and CEO Walter Ogier told GEN, “Ten years ago, people only had a vague idea about the scope of the different HDAC enzymes and were designing nonselective HDAC inhibitors. It’s become more clear what each HDAC enzyme isoform does, and it’s now possible to design small molecule inhibitors that are selective. We have initially focused on inhibition of HDAC6.”

    One downside of epigenetic drug targets, he noted, is their broad effect on fundamental cellular mechanisms, as they target the nuclear histone protein around which DNA is wrapped and have general effects on gene expression. They cause multiple side effects—anorexia, nausea, vomiting, suppression of white blood cells and thrombocytopenia, and profound fatigue, “not unlike those associated with conventional chemotherapy, and which reduce the tolerability of combination drug regimens for cancer, thereby reducing effectiveness.”

    HDAC6, a unique member of the HDAC family, acts outside the nucleus, interfering with the degradation of misfolded proteins similarly to proteasome inhibitors like Velcade. “One of our therapeutic approaches,” he said, “is to combine our inhibitors with Velcade to deal a death blow to cancer cells, which inherently produce large amounts of protein, by choking them on their own waste protein refuse through synergistic proteasome inhibition plus HDAC6 inhibition. We are seeing similar synergy with drugs like Celgene’s Revlimid.”

    Acetylon disclosed last July that it had entered into a strategic collaboration and option agreement with Celgene. The collaboration, the company said, supports the development of Acetylon’s portfolio of oral, selective HDAC inhibitors and includes an exclusive option for the future acquisition of Acetylon by Celgene.

    The collaboration will focus on the continued clinical advancement of Acetylon’s lead candidate, ACY-1215, an oral first-in-class selective HDAC6 inhibitor being developed for hematological malignancies, a second highly selective HDAC6 inhibitor for neurological diseases, and an HDAC1/2 inhibitor for sickle cell disease and beta-thalassemia, the world’s two most prevalent, severe genetic diseases.

    Syndax of Waltham, MA, says it employs epigenetic drugs to selectively target reversible epigenetic changes in cancer cells that lead to the development of drug tolerance to certain targeted therapies. The company’s lead compound, an HDI called entinostat, has shown promising activity in randomized, Phase II clinical trials in combination with the targeted therapies.

    Syndax uses a combination approach with entinostat to epigenetically modulate the development of drug tolerance. Two such drugs include endocrine agents that block the production of estrogen, which drives tumor growth in estrogen receptor-positive postmenopausal women with metastatic breast cancer, and tyrosine kinase inhibitors of the epidermal growth factor receptor, which compete with the growth factor that stimulates tumor proliferation in non-small cell lung cancer. In both cases epigenetic changes in these tumor types—which can be reversed by entinostat, the company says—have been show to correlate with the development of resistance to these drugs in preclinical animal models.

    Currently the company has multiple clinical trials underway, testing entinostat activity in combination with, for example, aromatase inhibitors in breast cancer studies underway. Syndax hopes its epigenetic drug candidate will make the tumor cells vulnerable to aromatase inhibitors again.

    Syndax CEO Arlene Morris says that this would enable women with breast cancer that has spread to continue with more cycles of hormone therapy before shifting to chemotherapy, which has much stronger side effects.

    “The goal is to keep women from going onto chemotherapy as long as possible,” she says.

    In the meantime, the epigenome will continue to provide a wealth of novel drug targets.



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