Biotechnology is enjoying another banner year on Wall Street. Currently, there are at least 39 companies queued for an IPO. This led us at the WEEKLY to wonder: what is the actual science behind each company’s promise that leads public markets to invest billions of dollars? This week and next, we are popping open the hood and checking out what exactly merits such a milestone.
First up is Syndax (Waltham, MA), a biopharmaceutical company pumping out a new epigenetic therapy for cancers resistant to treatment, which pique our interest because of the novelty of their approach. In this issue, we will get behind the wheel and go for a ride to examine epigenetics and its potential for future therapies.
TERM OF THE WEEK: GENE EXPRESSION
Genes are the actual DNA sequence encoding for a protein that confers a particular trait and genetics is the study of how genes determine an organism’s characteristics.
Gene expression is the process cells use to read genetic information to make proteins. Because each cell in our body has the same genetic information, it is the differences in gene expression that determine what proteins a cell will end up producing. Gene expression is the reason a heart cell is different from a liver cell.
Gene expression differences are also associated with disease. For example, a type of cell or tissue may make too much or too little of a particular protein, which is the basis for many genetic disorders.
BEYOND GENETICS: EPIGENETICS
Epigenetics are changes to DNA that do not alter the actual gene sequence, but rather are chemical modifications to the DNA itself. These changes typically affect gene expression, or how the gene is read by the cells. Epigenetic modification can occur either directly to the nucleotide bases themselves (A, C, G, or T) or to the histones, which are small proteins that package and order DNA.
The above image illustrates how histones are tiny spheres in which DNA wraps itself.
One of the most common types of epigenetic modification is methylation—the addition of a methyl (CH3) group to cytosine (C) nucleotides. The result: methylation reduces or even blocks gene expression.
A second type of modification is called acetylation—the addition of an acetyl group (CH3 CO) to the histones. Acetylation loosens the association of the DNA with the histones, making the DNA more accessible to the enzymes used in gene expression, ultimately increasing protein production.
Deacetylation—the removal of an acetyl group—increases the association or “grip” of the DNA around the histone proteins. Deacetylation makes the DNA less accessible to enzymes used in gene expression, thereby decreasing the production of proteins.
CLINICAL TRIALS: ENTINOSTAT
Syndax’s new drug, Entinostat, is a histone deacetylase (HDAC) inhibitor. HDACs are enzymes that increase the expression of certain genes by deacetylation, or the removal of acetyl groups from histone proteins.
Entinostat’s goal is to target HDACs overexpressed in a variety of cancers, potentially leading to the shutdown of uncontrolled cell growth. Entinostat targets a common mechanism; perhaps it could one day be used in a range of different cancers if shown to be effective.
Currently, there are ongoing Phase II trials studying the effect of Entinostat combined with Roche’s Tarceva on Hodgkin’s lymphoma and metastatic lung cancer. In addition, Phase III trials are underway for studying advanced breast cancer, where Entinostat is combined with Pfizer’s Aromasin. Notably, Entinostat combined with Aromasin has received the FDA’s “New Breakthrough Therapy” designation for breast cancer.
THE FUTURE OF HDACS
HDACS are associated with more diseases than cancer, and Acetylon Pharmaceuticals (Boston, MA) is in preclinical development for HDAC inhibitors—potentially treating autoimmunity, neurodegeneration, cardiac disorders, stroke, diabetes, and depression. Their HDAC inhibitor-based myeloma therapy is also in development.
As the field of epigenetics flourishes, an increasing number of therapeutics targeting this mechanism are expected to gain ground. Enzymes involved in epigenetic modification appear to play a role in a range of different disorders. The true challenge will be in developing targeted inhibitors for each subset of enzyme.
