Epigenetics: A way to fight disease?

Spring 2011

What is Epigenetics?
The most used definition, the study of heritable changes in genome function that occur without a change in DNA sequence The NIH will invest more than $190 million over the next five years to accelerate this emerging field of biomedical research (2008). The overall hypothesis of the NIH Roadmap Epigenomics Program is that the origins of health and susceptibility to disease are, in part, the result of epigenetic regulation of the genetic blueprint NIH Director Elias A. Zerhouni, M.D. (2008) stated, "Epigenomics-based research is now a central issue in biology

Spring 2011

Epigenetics, a way to fight disease?

Epigenetics approach to treating disease is gaining ground This method relies on the modification of genetic controls in cells that do not directly alter DNA sequences Most research articles focus on two types of genetic control modifications DNA methylation and histone acetylation Both are chromatin modifications that impact gene transcription Transcriptional repression caused by chromatin compaction has been linked with DNA hypermethylation of CpG in gene promoters as well as histone deacetylation

It should be noted that methylation is dominant to histone deacetylation, so transcription cannot occur without first inhibiting methylation (Baylin, 2005).
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Histone Deacetylase (HDACs)

18 known HDAC enzymes in humans Class I, II, and IV are zinc-dependent Class III enzymes are HDACs in yeast and include the SIRTs (silent information regulator of transcription, NAD-dependent histone deacetylase, also called sirtuins) Inhibition of HDACs leads to changes in the expression of genes involved in the regulation of apoptosis, proliferation, and the cell cycle.

Spring 2011

Histone deacetylase inhibitors (HDACis)

Most HDACis block substrate access Almost all induce cell cycle arrest, differentiation or apoptosis in vitro Many have potent anti-tumor activities in vivo Some have antiangiogenic properties

Spring 2011

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Epigenetic Therapies
Epigenetic cancer therapies under commercial development (either in safety and efficacy trials or approved) Drug Sponsor Indication Clinical status DNMT inhibitors 5-Aza-CdR (Dacogen) Eisai (Tokyo) MDS Approved May 2006 AML Phase 3 in 480 patients 5-Aza-CR (Vidaza) Celgene (Summit, NJ, USA) MDS AML HDAC inhibitors Vorinostat (Zolinza; suberoylanilide hydroxamic acid, SAHA) Merck (Whitehouse Station, NJ, USA) Vorinostat + bortezomib (Velcade) Panobinostat (LBH589; hydroxamate analog) Novartis (Basel) Panobinostat + bortezomib + dexamethasone Approved May 2004 Phase 3 targeting 480 patients

CTCL Mesothelioma Multiple myeloma

Approved October 2006 Phase 3 targeting 660 patients Phase 2 and 3 targeting 742 patients

Hodgkin's lymphoma CML, AML and MDS Multiple myeloma

Phase 3 in 367 patients Phase 2/3 Phase 3 targeting 676 patients

CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CTCL, cutaneous T-cell lymphoma; NHL, nonHodgkin's lymphoma; NSCLC, non.small-cell lung cancer. Sources: BioMedTracker, Thomsen Pharma Partnering and

Spring 2011

What are the phases of clinical trials?

In Phase I trials, researchers test an experimental drug or treatment in a small group of people (20-80) for the first time to evaluate its safety, determine a safe dosage range, and identify side effects. In Phase II trials, the experimental study drug or treatment is given to a larger group of people (100-300) to see if it is effective and to further evaluate its safety. In Phase III trials, the experimental study drug or treatment is given to large groups of people (1,000-3,000) to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the experimental drug or treatment to be used safely. In Phase IV trials, post marketing studies explain additional information including the drug's risks, benefits, and optimal use.
Spring 2011

http://clinicaltrials.gov/ct2/info/understand

Findings

Spring 2011

 miRNA Therapeutics

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MethylGene?
MethylGene has designed inhibitors of histone deacetylases (HDACs) Deacetylation of histone proteins results in DNA becoming tightly wound and cannot be transcribed Inhibiting HDACs prevents removal of acetyl groups from histones resulting in the loosening of DNA thus allowing the reactivation of genes that normally suppress tumor growth MethylGene combines its HDAC inhibitors with demethylation agents to further improve cancer therapy Vidaza is a DNA hypomethylation drug that restores functioning of genes that are critical for normal cell differentiation and growth Vidaza was tested with MethylGenes lead HDAC inhibitor MGCD0103 (Mocetinostat)

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MethylGenes Findings
Results 53% clinical response rate at the 90 mg dose in all patients with myelodysplastic syndromes (bone marrow disease such as leukemia) FDA designated MGCD0103 as an orphan drug for treating acute myeloid leukemia and Relapsed/Refractory Hodgkins lymphoma Scientists observed that just 4 of 11 HDAC isoforms are strongly related to cancer Their HDAC inhibitors specifically target this subset of four isoforms This may have advantages in efficacy or reduced side effects

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MethylGenes Future
Created a library of 4,000 to 5,000 compounds based on understanding mechanistic enzymology and inhibiting catalytic domains

Plans for MGCD0103 to be tested with other drugs in Phase 1,2, and 3 trials for treating other varieties of cancer
Potential treatments for autoimmune disorders, inflammatory diseases, diabetes, neurodegenerative illnesses, and fungal infections

A new HDAC inhibitor compound in their library, MGCD290, turns off the fungal drug-resistance mechanism and makes drugs for fungal infections more potent
Other isoform-specific inhibitors in their library hold promise for treating Huntingtons, Alzheimers, and other neurodegenerative disorders

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