The epigenetics approach to treating cancer is gaining ground. This method relies on the modification of genetic controls in cells that do not directly alter DNA sequences. A chief target is chromatin, the packaging material that blankets chromosomes. When methyl groups attach to cytosine nucleotides on chromatin, gene transcription is prevented. Another chromatin modification, histone acetylation, also impacts gene transcription.
MethylGene (www.methylgene.com) exploits both these options. The company is designing inhibitors of histone deacetylases (HDACs), a class of enzymes that removes acetyl groups from histones, thereby allowing the reactivation of genes that normally suppress tumor growth. MethylGene combines its HDAC inhibitors with demethylation agents to further improve cancer therapy.
Drugs that remove methyl groups from DNA in chromatin were first developed to treat a group of blood disorders called myelodysplastic syndromes. Pharmion (www.pharmion.com; now owned by Celgene) developed Vidaza, the first demethylating agent approved by the FDA in 2004. Vidaza acts by causing hypomethylation of DNA. It thus restores normal function to genes that are critical for normal cell differentiation and growth.
In 2006, MethylGene partnered with Pharmion to test Vidaza in combination with MGCD0103, MethylGene’s lead HDAC inhibitor. The partnership adds drug development skills to MethylGene’s rational drug design expertise. “It’s a nice marriage,” says Donald Corcoran, president and CEO of MethylGene. “We’re good at research and early-stage development, and Pharmion does a good job at commercializing and marketing drugs.”
The MGCD0103-Vidaza combination showed a 36% clinical response rate in all patients with myelodysplastic syndromes and acute myeloid leukemia (AML) and a 53% response rate at the 90 mg dose, which will be used in future studies. (See the February 1 issue of GEN, “DNA Methylation Bolsters Cancer Research,” for more on the MethylGene-Pharmion collaboration.)
In February, the FDA designated MGCD0103 as an orphan drug for the treatment of AML. The compound also has orphan drug status for refractory Hodgkin’s lymphoma. There have been no newly approved therapies for relapsed/refractory Hodgkin’s lymphoma for decades.
Corcoran helped to found MethylGene 12 years ago as a spin-off from Hybridon (now Idera) to advance DNA methyl transferase technology licensed from McGill University. The company’s first technology platform used antisense oligonucleotides, but it did not prove successful.
While working in Quebec, Corcoran was struck by the number of well-trained medicinal chemists coming out of local universities who left Canada to find jobs in the U.S. To slow the brain drain, “we diversified into a medicinal chemistry company to build oral small molecule enzyme inhibitors,” says Corcoran.
Now the company’s team of 30 medicinal chemists focuses on creating novel oncology compounds that inhibit not only HDACs but also kinases, sirtuins, and methyl transferases, all enzymes involved in cancer and other diseases. Farthest along is MGCD0103, an oral isotype-selective HDAC inhibitor that activates genes turned off by epigenetic silencing. When histone proteins are acetylated, the DNA becomes tightly wound and cannot be transcribed. HDAC inhibitors loosen DNA and reverse the gene silencing.
MethylGene’s scientists observed that just 4 of 11 HDAC isoforms are strongly related to cancer. “Inhibiting the others does not appear to make a difference,” says Corcoran. The company’s HDAC inhibitors specifically target this subset of four isoforms.
In contrast competing HDAC inhibitors like Merck’s Zolinza are known as pan inhibitors because they hit all 11 HDAC isoforms. “We took the time to learn what HDAC isoforms are involved in cancer and were the first to design an HDAC inhibitor to be specific,” according to Corcoran. This emphasis on isoform specificity “is one of the hallmarks that differentiates us from many others,” and may have advantages in efficacy or reduced side effects, he adds.
MethylGene plans to start a Phase III trial of MGCD0103 early in 2009. The compound is also in a Phase I trial in combination with Taxotere for solid tumors, in a Phase I/II study in combination with Gemzar for pancreatic cancer, and in five Phase II trials for a variety of hematological cancers.
Solid tumors also harbor HDAC abnormalities, and MethylGene’s pipeline contains oral tyrosine kinase inhibitors that target c-Met and VEGF receptors, known to promote angiogenesis and tumor metastasis. MGCD265 will soon be evaluated in Phase I trials in a variety of solid tumors in refractory patients.
Through rational drug design, researchers at MethylGene have made a library of 4,000 to 5,000 compounds based on understanding mechanistic enzymology and inhibiting catalytic domains. As more and more HDACs are found to contribute to other indications such as autoimmune disorders, inflammatory diseases, diabetes, neurodegenerative illnesses, and fungal infections, the library will offer possible new treatments.
A new target is hospital-acquired fungal infections that attack immunocompromised patients including those with HIV and cancer. Azoles, the staple drugs for fungal infections, are becoming less effective due to resistance controlled by fungal HDACs.
A compound in MethylGene’s library, dubbed MGCD290, targets only fungal HDACs but not human HDACs. Preclinical studies show that MGCD290 turns off the fungal drug-resistance mechanism and makes azoles more potent. The company expects to file an IND application for MGCD290 in the third quarter.
Other isoform-specific inhibitors in MethylGene’s library hold promise for treating Huntington’s, Alzheimer’s, and other neurodegenerative disorders.