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Dec 1, 2012 (Vol. 32, No. 21)

Epigenetics Reshapes the Therapeutic Arena

  • Mind Those Histones

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    Resminostat (the small chemical molecule illustrated by its molecule structure) is shown binding to an HDAC/histone deacetylase enzyme. DNA expression is regulated by acetylation and de-acetylation. Thus, inhibition of an HDAC enzyme (e.g., through resminostat) will result in a more “open” and more “active” state of the histones and the chromatine structure, which will allow better transcription, according to 4SC.

    “At 4SC, our focus is on the interplay between different modifications that occur on histones,” says Bernd Hentsch, Ph.D., CDO at 4SC. Recent years witnessed two major advancements relevant to histone post-translational modifications. In addition to unveiling the contribution of histone deacetylases to regulate additional key players in tumorigenesis, such as p53 and Hsp90, increasing numbers of studies unveiled the complex interplay that exists among different types of histone post-translational modifications.

    “It is therefore important to examine not only direct changes, but the activity of a whole group of modulators of the histone code, and methylation will probably represent the next wave of scientific interest,” says Dr. Hentsch.

    Investigators at 4SC recently revealed a clinical setting where modulating histone acetylation could translate into new and much needed therapeutic applications. One of the acute challenges in oncology is the resistance to therapy that often develops, through a process that involves mutations and, therefore, is not reversible. However, approximately two years ago, an early stage during this process was described and became known as drug tolerance.

    “Tolerance, in contrast to resistance, occurs by epigenetic changes, and it can be reversed when cells are treated with histone deacetylatse or histone demethylase inhibitors,” explains Dr. Hentsch.

    A strategy developed by 4SC scientists is to combine a histone deacetylase inhibitor with an existing therapeutic compound to which the tumor cells are sensitized or re-sensitized.

    In a Phase II 4SC-sponsored Shelter clinical trial for hepatocellular carcinoma that enrolled patients after they had developed tumor resistance to sorafenib, the only first-line treatment available, clinicians co-administered the oral pan-histone deacetylase inhibitor resminostat in addition to sorafenib, and reported an overall median eight-month survival—the longest, to date, among second-line therapies for patients with comparable characteristics.

    “This puts into perspective the fact that epigenetic alterations can revert drug tolerance to a drug sensitive state, where pre-existing regimens can work again,” notes Dr. Hentsch.

    Another epigenetic drug that scientists at 4SC are developing, 4SC-202, is currently in Phase I development. “We have shown that 4SC-202 acts on a broad number of Wnt signaling target molecules, and dysregulation in this pathway is important in a number of malignancies,” says Daniel Vitt, Ph.D., CSO. Additionally, 4SC-202 inhibits protein deacetylation and arrests the cell cycle in the G2/M phase.

    “Resminostat and 4SC-202 interfere with truly important oncogenic characteristics, and it is important to appreciate that even though both are inhibitors of histone deacetylases, they consist of very different chemistries and comprise individual and thus differentiating biological properties. We will, therefore, be able to position these drugs individually in different selected cancers and in different populations,” notes Dr. Hentsch.

  • Colon and Lung Cancer Tests

    “The elegance of epigenetic measurements is that they are incredibly simple and very deployable on platforms commonly used in clinical labs and can be performed on blood specimens,” says Noel Doheny, CEO at Epigenomics.

    Epigenomics has two products, Epi proColon and Epi proLung, available in several European countries, though neither of which is currently available in the U.S. or Canada. Investigators at Epigenomics are in the process of conducting the required clinical trials and seeking regulatory approval in these markets.

    Epi proColon, a noninvasive plasma-based test, relies on detecting septin 9 DNA hypermethylation, a sensitive marker for colorectal cancer. “For this product, the pre-market approval submission in the U.S. is in its later stages,” reveals Doheny. In the U.S., Epigenomics has licensed its septin 9 methylation technology to Quest Diagnostics, ARUP Laboratories, and Companion Dx. “There are tens of thousands of assays that have already been done by these laboratories on patients in the U.S., and the utilization is very encouraging,” says Doheny.

    A recent study revealed that this marker shows comparative sensitivities for detecting tumors on the right and left sides of the colon, for which colonoscopy detection rates differ, particularly in the early stages. The test does not require stool samples or invasive procedures. The firm believes that the availability of this test would encourage and facilitate early detection, at a stage when tumors are easier to monitor, treat, and cure.

    The second test, Epi proLung, which is based on the detection of the methylated SHOX2 gene and at this time is also marketed exclusively in Europe, addresses one of the challenging aspects of lung cancer—the indeterminate results that are often obtained for cytology specimens. In combination with cytology, the Epi proLung assay can provide an immediate answer, which is crucial during the management of this condition, given the urgency for early therapeutic intervention. Early data has shown that this method may be applied in the future to the blood-based screening of lung cancer.

  • Networking and Outsourcing

    “We are a virtual business and, as such, all our experimental research is outsourced to external labs,” explains Anthony Brown, Ph.D., scientific director at CellCentric.

    The main therapeutic area that CellCentric focuses on is cancer. Through a combination of option agreements and consultancies, the company has established contractual relationships with a discovery network comprising over 30 academic laboratories across the world working in the epigenetics field.

    Through its access to unpublished and privileged research information from the participating labs, CellCentric has prioritized over 50 unexplored and underexplored epigenetic targets. It is devoting significant efforts on second-generation enzymes, including developing small molecules that target histone-modifying enzymes. “But we have targets all across the epigenetic space; it is the clinical rationale and opportunity that drives our target selection,” notes Dr. Brown.

    Compounds at various stages of preclinical and clinical development illustrate the promises of recent advances in epigenetics research, and reflect efforts to exploit distinct epigenetic mechanisms. These strides are catalyzing the shift toward newer generations of targets.

    As many epigenetic modifications occur early during disease pathogenesis, their modulation is anticipated to provide, in addition to therapeutic compounds, predictive biomarkers and opportunities for prophylactic interventions, forecasting new perspectives for pharmacology and clinical medicine.

  • Epigenetics Renaissance

    “While the field has been around for a while, recent years have seen a renaissance of epigenetics, partly because we realized that genetics cannot explain everything, and also thanks to the remarkable technological advances that enable us to profile and analyze epigenetic changes in a genome-wide and high-throughput setting,” says Zdenko Herceg, Ph.D., group leader and head of the section of mechanisms or carcinogenesis at the International Agency for Research on Cancer.

    Recent years unveiled the importance of epigenetic modifications in shaping the pathogenesis not only of cancer, but that of other diseases as well, and helped advance ideas for developing more efficient preventive and therapeutic strategies. “The main challenge is to identify the drivers of the functionally important changes and distinguish them from the nonfunctional, passenger ones,” says Dr. Herceg.

    The therapeutic use of epigenetic markers is an area that has witnessed increasing attention, and it is encouraged by the reversibility of epigenetic modifications and by many pieces of evidence pointing to their early occurrence during disease pathogenesis. “The technological revolution in genomics and epigenomics now allows the development of cost-effective and sensitive assays to detect and measure epigenetic markers and their changes in body fluids,” explains Dr. Herceg.


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