TRAIL apoptotic pathway-targeted therapies for NSCLC
Department of Pathology & Laboratory Medicine, Winship Cancer Institute, Emory University School of Medicine, 1365-C Clifton Road
NE, Atlanta, GA 30322, USA
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Cite this article as: Bellail AC, Hao C. TRAIL apoptotic
pathway-targeted therapies for NSCLC. Transl Lung Cancer Res
2012;1(2):155-157. DOI: 10.3978/j.issn.2218-6751.2012.02.02
Editorial
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Transl Lung Cancer Res Mar 4, 2012. DOI: 10.3978/j.issn.2218-6751.2012.02.02
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The global burden of lung cancer is a death every 4 seconds,
round the clock, 365 days a year, with a global incidence
estimated at 1,350,000 in 2002 (1). Lung cancers are
classified into two major types: Small cell lung cancer and
non-small cell lung cancer (NSCLC). NSCLC constitutes
75% of primary lung cancers and the prognosis for patients
with NSCLC is poor. Less than 25% of new NSCLC cases
present with local stage I or II disease treatable by surgical
resection and chemotherapies; however, up to 50% of these
stage I and II cases develop recurrence regardless of the
treatments (2). The first-generation chemotherapy agents,
doxorubicin, methotrexate and vincristine developed in the
1970s are essentially ineffective in treating NSCLC. Based
on the experience with the second-generation agents (i.e.,
cisplatin, etoposide, mitomycin, vindesine, vinblastine) in
the 1980s, cisplatin-based combination was recommended
for the treatment of advanced NSCLC (3). With the thirdgeneration
agents (i.e., paclitaxel, docetaxel, gemcitabine,
taxane) approved in the 1990s, cisplatin-based combination of
the third-generation agents is used worldwide for the treatment
of advanced NSCLC, despite the fact that the therapy only
modestly improves patient survival (4). This grim reality
demands better understanding of the molecular basis of
NSCLC and requires innovative therapeutic strategies in order
to achieve substantially improved treatment outcomes.
In the last decade, a new generation of target agents have been
developed targeting cancer specific signaling pathways. Gefitinib
(Iressa, AstraZeneca), for instance, is the first target agent to be
approved for the treatment of patients with advanced NSCLC
(5). Gefitinib is a small molecule that targets the mutated
tyrosine-kinase domain of epidermal growth factor receptor
(EGFR), which results in substantial clinical responses in 10% to
18% patients with advanced NSCLC harboring EGFR mutations
(6,7). Gefitinib, however, only improves patient survival for a
few months and the cancer eventually starts growing due to the
development of acquired resistance in part due to concurrent
EGFR mutations (8), raising an issue of the cancer resistance to
target agents. To improve the response, first-line gefitinib therapy
was therefore suggested in a genotype-directed clinical approach
to patients with advanced NSCLC that harbors EGFR mutations
(9). The experience with gefitinib provides a tantalizing preview
of what we hope will be a genotype-directed targeted therapy for
the treatment of advanced NSCLC.
Recently, tumor necrosis factor-related apoptosis-inducing
ligand (TRAIL; also termed Apo2 ligand, Apo2L) has been
emerging as a target agent for the treatment of NSCLC.
TRAIL was identified in the middle 1900s (10,11) and soon
recombinant human TRAIL (rhTRAIL) was generated and
shown to be able to induce apoptosis in cancer cells and inhibit
the growth of cancer xenografts, without causing damage to
normal cells (12,13). Physiological studies further established
the role of TRAIL in the innate and adaptive immunity against
cancer and, therefore, TRAIL is considered as a natural
cancer killer (14). Several lines of evidence in preclinical
studies suggest that TRAIL could serve as a target agent in the
treatment of advanced NSCLC, in particular in combination
with chemotherapy: (I) TRAIL receptor 1 (TRAIL-R1; death
receptor 4, DR4) and TRAIL-R2 (DR5) were detected in human
NSCLC tissues (15); (II) rhTRAIL is capable of inducing
apoptosis in NSCLC cell lines in vitro (16) and inhibiting
NSCLC xenograft growth in vivo (13,17); and (III) combination
of rhTRAIL with chemotherapy can overcome the TRAIL
resistance in NSCLC cells (18).
Based on the preclinical studies, clinical trials of rhTRAIL
was launched and the first phase I trial of rhTRAIL (rhApo2L/
TRAIL, dulanermin), co-developed by Amgen and Genentech,
were released at the 2006 American Society of Clinical Oncology
(ASCO) Annual Meeting, showing that the monotherapy of rhTRAIL was well-tolerated and associated with partial response
in patients with advanced solid cancer (19). The phase Ib trial
then revealed that the combination of rhTRAIL with paclitaxel,
carboplatin, and bevacizumab (PCB) improved the progressionfree
survival of patients with advanced NSCLC (20). In
contrast, however, the data from phase II trial of rhTRAIL
was disappointings. Published in the November 2011 issue of
Journal of Clinical Oncology, the phase II trial of 213 patients with
advanced NSCLC revealed that the addition of PCB to rhTRAIL
did not improve the progression-free survival of patients (21).
While the factors such as small sample size and lack of control
in the phase Ib may explain the difference between the phase Ib
and II trials, the phase II trial in a large group of patients have
indicated that advanced NSCLCs are resistant to the treatment
of rhTRAIL.
TRAIL apoptotic pathway has also been targeted by its
agonistic monoclonal antibody (MAb) against DR4 and
DR5. At the 2002 American Association of Cancer Research
(AACR) Annual Meeting, Human Genome Sciences reported
for the first time the generation of a fully human agonistic MAb
against DR4 (HGS-ETR1, mapatumumab) and DR5 (HGSETR2,
lexatumumab). Phase I trials have successfully evaluated
the safety and pharmacokinetics of HGS-ETR1, HGS-ERT2
and PRO95780 (drozitumab), a fully human DR5 MAb
developed by Genentech (22-24). At the 2010 ASCO Annual
Meeting, however, the results from two phase II trials in two
large groups of patients revealed that the addition of PCB or
PC (paclitaxel, carboplatin) to PRO95780 and HGS-ERT1
did not improve the response rates in patients with advanced
cancer. Together with the phase II trial of rhTRAIL, these
phase II trials of DR4 and DR5 MAb have demonstrated the
resistance of advanced NSCLCs to the treatment of the TRAIL
target agents.
In the last decade, a tremendous amount of preclinical
and clinical efforts has led to the genesis of this new class of
apoptosis target agents. Unfortunately, the data from phase
II trials have also demonstrated the resistance of human
cancers including NSCLC to the treatment of the TRAIL
target agents. A number of molecular models of TRAIL
resistance have been reported mainly from studies of cancer
cell lines, arranging from the genetic loss and mutation of
TRAIL apoptotic elements to the overexpression of apoptosis
inhibitory proteins and posttranslational modification of
proteins (25). In contrast, however, a few studies have been
carried out in patients’ cancer tissues and the tissues-derived
cell models such as cancer stem cells and the cell-derived
xenografts. It is vital for us to understand the mechanisms of
TRAIL resistance in patients’ cancers and therefore develop
the combination therapy that can overcome the resistance
of TRAIL target agents for the effective clinical treatment of
patients with advanced NSCLC.
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References
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