Mind Those Histones
“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.