259Epizyme Inc is focused on discovering novel, small molecule drugs that act as
selective inhibitors of key epigenetic enzymes. The selective addition of methyl
groups to specifi c sites on the histones is controlled by the action of a unique class
of enzymes known as the histone methyltransferases (HMTs). Once the methyl
group has been deposited on the histone site, the affected genes continue to be regu-
lated (turned on or off) until this chemical unit is removed by other enzymes, known
as histone demethylases. In a like manner, other enzyme classes can decorate DNA
and histones with other chemical species and still other enzymes can remove these
species to provide temporal control of gene regulation. The strategy at Epizyme Inc
is to target the HMTs as a family of S-adenosyl methionine-utilizing enzymes, mak-
ing full use of lessons learned from kinases as drug targets and exploiting techno-
logical platforms that allow parallel processing of multiple enzymes of similar
mechanism. Two programs at Epizyme are based on epigenetics: DOT1L targeting
for the treatment of mixed lineage leukemia and EZH2 targeting for the treatment of
certain non-Hodgkin’s lymphomas and breast cancer subtypes. Both of these pro-
grams are at subclinical stage.
Aberrant epigenetic modifi cations are frequently associated with distinct cancer
types and have potential utility as biomarkers. The development of DNA methyla-
tion biomarkers that are predictive of a response to chemotherapy, however, is still
in its infancy. Several studies have reported associations between DNA methylation
biomarkers and response to chemotherapy.
Selective Destruction of Cancer Cells While Sparing
Normal Cells
A problem with conventional chemotherapy or radiotherapy is that damage is not
limited to cancer cells but involves normal cells as well. It is easy to kill cells in vitro
and many new anticancer drugs are being discovered. However, it is diffi cult to
selectively kill cancer cells in vivo without harming normal cells. Even though some
success is achieved in animal experiments, it is diffi cult to translate these fi ndings
into practical management of cancer patients. Strategies for selective destruction of
cancer in vivo are:
- Drugs for selective disruption of cancer metabolism: sphingolipids
- Hyperbaric oxygen as adjunct to radiotherapy
- Genetically engineered bacteria for selective destruction of cancer
- Use of MAbs to selectively target anticancer agents to receptors on cancer cells
- Targeting response to transformation-induced oxidative stress
- Targeting enzymes to prevent proliferation of cancer cells: CFI-400945
Design of Future Personalized Cancer Therapies