EPIGENETIC THERAPY FOR LUNG CANCER

Much more widely studied than the modifications themselves
are the enzymes that mediate the decorations of histone tails.
The ability to inhibit HDACs, enzymes that are thought to be
involved in inappropriate gene repression in cancer, has given
rise to a flurry of drug development and preclinical studies using
lung cancer cell lines. 21,128 Many studies report inhibition of
growth and induction of apoptosis by HDACI, and these drugs
are being used in phase I and II in clinical trials. 129,130 Although
gene reactivation is observed in many cases, it is not clear whether
this is an effect of deacetylase inhibitors on histone tails or on
other proteins that are acetylated, such as heat shock protein 90
(HSP90). 129 HDACI LBH589 increased HSP90 acetylation in
lung cancer cells, thereby decreasing HSP90 protein chaperone
ability, an activity that helps EGFR mutant p roteins maintain
functionality. 131 The exciting link in lung cancer between EGFR
signaling and histone deacetylation has been confirmed by several
studies 132–134 and supports the evaluation of combinations
of drugs that target deacetylation and tyrosine kinases in clinical
trials. Of additional interest is the profiling of lung cancer cells
to identify genes that modulate sensitivity to HDACIs 135 and
the combination of standard therapies such as radiation treatment
with HDACIs— approaches that show promise in preclinical
models. 136
One type of drug that forms a logical combination with
HDACIs is DNA methylation inhibitors. A variety of different
DNA methyltransferase inhibitors that work through different
mechanisms is available. 21 Because some of these DNA
methyltransferase inhibitors, such as 5-aza-deoxycytidine
work through incorporation into the DNA (where DNA
methyltransferases are consequently trapped), their efficacy
may be partially related to DNA damage. 21 One study of
human lung cancer cells treated with 5-axa-deoxycytidine
and HDACI indicated that the synergy with HDACIs was
related to DNA damage rather than inhibition of DNA
methylation. 137 Despite our incomplete understanding of
the mechanism of epigenetic therapy, its clinical promise is
high, and phase I and II trials in lung cancer are ongoing
(see http://www.clinicaltrials.gov/). 22,129,130

Powerful tools are being honed for the (epi)genomic analysis of
lung cancer, and these will rapidly increase our understanding
of its molecular underpinnings, as well as provide molecular
markers for detection, diagnosis, prognostication, and monitoring
of recurrence. A key area that will require rapid development
to make the most of these technologies is bioinformatics,
since the staggering amount of data generated must be analyzed
and interpreted. The combination of new (epi)genetic
insights, novel epigenetic drugs, and an emerging understanding
of how these and other drugs function has generated an
aura of hope and excitement in the lung cancer field. The possibility
to build on existing therapies such as EGFR inhibitors
or radiation treatment by combining them with HDACI and
DNA methylation inhibitors opens many new therapeutic avenues.
With progress looming on the fronts of early detection
as well as treatment, it can truly be said that epigenetics has
given new breath to the fight against lung cancer.