apoptosis-inducing agents, which have
entered phase I clinical trials, represent
new avenues for therapeutic intervention
and are expected to enhance
current treatment strategies, said Anthony
Tolcher, MD, director of clinical
research at the Institute for Drug
Development, San Antonio, Texas.
"It's been a lonely world for those
of us who have been pursuing drugs
that target apoptosis, compared to
those that target pathways of proliferation,
such as the epidermal growth
factor receptor, which has been a main
focus at this entire meeting," Dr.
Tolcher commented at the 10th World
Conference on Lung Cancer.
At a session on targeted therapy for
lung cancer, Dr. Tolcher predicted that
although apoptosis-inducing agents
are still in early clinical development,
"they may have a role in 3 to 5 years in
the clinical setting."
Apoptosis is critical for normal
physiologic processes. Elimination of
certain cells (eg, viral-infected cells or
self-reactive T cells that are involved in
autoimmunity) is important to health.
Aberrant and diminished apoptosis is
common to many types of malignancies
and takes many forms, including
altered expression of the tumor necrosis
factor receptor family, overexpression
of bcl-2, altered expression of
DR4 (death receptor 4) and DR5 (death
receptor 5), diminished Bax expression,
PTEN mutations, and more.
Both extrinsic and intrinsic pathways
govern cell death.
"The reduction in cell death goes hand
in hand with mechanisms that increase
cell proliferation," Dr. Tolcher said.
Drugs targeting programmed cell
death, said Dr. Tolcher, are currently
directed primarily at bcl-2 inhibitors
and the TRAIL (tumor necrosis factor
receptor apoptosis-inducing ligand)
receptor family, "a large family of death
receptors" that initiates the external
apoptotic pathway. Subtypes TRAILR1
and TRAIL R2 are considered the
targets for cancer therapies. They are
highly expressed in many tumor cells
and their activation kills tumor cells
Several strategies have been proposed
for TRAIL-receptor activation,
including use of small peptides or recombinant
monoclonal antibody agonists
that bind to the external domain.
Monoclonal antibodies, which have a
long elimination half-life, are ideal
when long exposure to a drug is desired,
therefore this avenue is encouraging,
In experimental studies, agents targeting
DR4 and DR5 have been shown
to induce tumor regression and possibly
yield a long-term "cure" in non-
small-cell lung cancer xenografts. The
drug is given as a single intravenous
dose every 28 days, and no dose-limiting
toxicity has yet been noted in early
These agents are now under clinical
investigation. DR4 is being studied in
the US and Canada, and DR5 is in
clinical trials in Europe.
Bcl-2 as a Target
In the intrinsic pathway, bcl-2 is a
promising target. The bcl-2 protein is
overexpressed in many solid tumors.
Bcl-2 is overexpressed in more than
50% of small-cell lung cancer tumors,
and in 30% of non-small-cell lung
cancers. Overexpression shuts down
the apoptotic pathway, making bcl-2 a
negative prognostic factor, despite current
therapy, clinical studies have
One way to target bcl-2 is with antisense
oligonucleotides, which are
small strands of nucleotides that bind
to messenger RNA. The first-generation
antisense oligonucleotides did not
work because they were unstable in
normal plasma, but newer agents are
stable. The drug at the forefront of this
class is oblimersen (G3139), which
shows dose-dependent reductions in
mRNA and has synergy with a broad
array of chemotherapy agents.
"What led to Aventis licensing this
drug was its effect in non-small cell
lung cancer xenograft H460. There was
modest log cell kill and small change in
tumor growth over controls, but when
given with docetaxel there was significant
tumor control, tumor growth
delay, a greater log cell kill, and complete
responses in 4 out of 7 animals
and long-term survival," he said.
"Bcl-2 may be associated with resistance
to current chemotherapy, but
with an agent such as docetaxel we see
true synergy," Dr. Tolcher said.
The most dramatic performance of
oblimersen has been with chronic lymphocytic
leukemia (CLL). Pivotal studies
with this agent have been completed
in CLL, multiple myeloma, and
melanoma. In non-small-cell lung
cancer, a randomized phase II study is
now comparing docetaxel versus
docetaxel plus oblimersen.
"For our patients, apoptotic-inducing
agents represent a whole new avenue
that has not been explored-cell
death-by targeting bcl-2 and TRAIL,"
Dr. Tolcher said. "These agents may
also enhance our current forms of