Epigenetics is the study of processes other than the underlying DNA sequence that affect how genes are expressed. Environmental effects, for example, can cause genes to be activated or inhibited, and such changes can be passed down through multiple generations, affecting overall health and disease progression. Epigenetics is naturally involved in normal human processes also, as demonstrated by the significant variation in cell types—blood cells, neurons, liver cells, etc.—that all contain the exact same DNA. This differentiation is a result of certain genes being turned on (activated) or off (inhibited or silenced).
In an overview published in Nature in 2008, Dr. Danielle Simmons wrote, “Silencing might also explain, in part, why genetic twins are not phenotypically [observably] identical. In addition, epigenetics is important for X-chromosome inactivation in female mammals, which is necessary so that females do not have twice the number of X-chromosome gene products as males.”
Source: MinuteEarth, Nov 18, 2015.
The initial public offering of Cambridge, Massachusetts, based Constellation Pharmaceuticals (proposed Nasdaq: CNST), which is developing therapeutics to treat patients with cancers associated with abnormal gene expression, is expected next week via JP Morgan, Jefferies and BMO. In an amended Form S-1 filed yesterday, the company disclosed terms of its deal: 5.34 million shares between $14 and $16 per share. At the midpoint of the range, it would be an $80 million offering with a post-money market capitalization of $406 million.
Constellation was founded in 2008 and has raised significant capital over the past 10 years, with the most recent Series F bringing in $100 million from new and existing investors in April 2018. The company has an accumulated deficit of $186 million as of March 31, 2018. The largest shareholders now include Column Group (21.7%), Third Rock (12.7%), Venrock (11.1%), University of California (10.0%), Topspin Partners (8.2%) and Cormorant (5.9%).
Epigenetics platform
The company is using its epigenetics platform to generate compounds that selectively regulate gene expression in tumor and immune cells to drive anti-tumor activity. Constellation is focused on three distinct classes of epigenetic regulators:
- Epigenetic writers—enzymes that add chemical modifications on chromatin, which consists of DNA wrapped around an assembly of proteins called histones.
- Epigenetic readers—protein families that recognize and bind to chemical modifications on chromatin
- Epigenetic erasers—enzymes that remove chemical modifications from chromatin.
These different regulators modify chromatin and affect gene expression by either adding, binding to or removing chemical tags on chromatin. While these mechanisms are tightly regulated in normal cells so that genes are activated or silenced appropriately, abnormal cells such as cancer cells can disrupt or take over these mechanisms, ultimately leading to disease.
Source: Constellation Pharmaceuticals website, July 10, 2018.
Constellation is pursuing several cancer types in clinical trials including a Phase 1b/2 trial in metastatic castration-resistant prostate cancer (mCRPC), a Phase 1b/2 trial to treat solid tumors and a Phase 2 trial in myelofibrosis.
Source: Constellation Pharmaceuticals website, July 10, 2018.
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