In the past two decades, epigenetics has grown from an obscure concept applicable mainly to X chromosomal inactivation to
one of the dominant driving forces in pharmaceutical R&D (1). Briefly stated, the epigenetic model of regulatory control is
based on the observation that half of the structural genes of higher organisms are preceded by CpG islands, clusters of cytosines
alternating with guanadines that constitute signaling points that respond to epigenetic signals (2). Modification of these
sites through a methylation reaction blocks the transcription of linked genes. Whereas numerous pathological conditions demonstrate
an epigenetic connection, progress has been most notable in the field of cancer biology.
K. John Morrow, Jr., PhD
Evidence linking epigenetic modi-fications to the activation of oncogenes or the inactivation of onco-suppressor genes is
rapidly coalescing (3). Researchers currently propose a dynamically interactive model by which the genome and epigenome feed
back on one another, driving the growth or the involution of tumors (4–6).
This complex model of regulatory control offers many opportunities for a more nuanced understanding of the cancer cell and
how it spans the transformation from normal to various stages of malignancy. The new knowledge base opens up possibilities
for early diagnosis, because subclinical tumors may release DNA molecules into the circulation that bear highly specific epigenetic
modifications defining the type and stage of malignancy of a particular tumor type. These markers can be methylated sites
in target genes, and as such, provide a specific and sensitive target. Currently, numerous diagnostic tests for these markers
are under development (7).
By the same token, an epigenetic-based therapeutic attack on cancer has been launched. There are a number of basic science
teams working with industry to define new epitherapeutics for a range of different cancers.
These changes, affecting both the diagnostic and the therapeutic aspects of oncology, demand a restructuring of our strategies
for attacking this disease. There is much interest in other diseases that may have an epigenetic basis, but cancer-based investigation
is far advanced over other diseases, so for the next few years this will no doubt be the prime focus of epi-drug development.
New targets call for new strategies for synthesis and production. This may influence the relative balance between small molecules
and biological drugs, decisions that will affect the allocation of resources for large-scale production in the coming years.
Companies have made decisions in the past reflecting their projected bioprocessing needs, with serious implications for cash
flow, so it is crucial that these allocations be assigned on the basis of the best information available.