Lung cancer annually causes more
than 1 million deaths worldwide. Despite efforts aimed at
improving survival, delayed diagnosis and high relapse result in dismal
prognosis. Overall lung cancer 5-year survival rates have only marginally
changed over the past few decades; the current 5-year survival rate is about
15% in the United States and lower in developing countries. Many
of the genetic and epigenetic anomalies found in lung cancer are also present
in normal and preneoplastic tissue, suggesting a multistep process
of epithelial carcinogenesis contemporary to tobacco smoking.
Good examples of the translation of pulmonary molecular events to the clinic
include of the epidermal growth factor receptor (EGFR) tyrosine kinase
inhibitors (TKIs). The growing field of stem cell research is becoming relevant
in the understanding of lung carcinogenesis and to the development of novel
targeted therapies. Identifying
indi-viduals at high risk of lung cancer is crucial, and various biomarkers
such as hypermethylation of certain lung cancer genes are being tested
The Clinical Relevance of the Growth Factor Receptor Tyrosine Kinase
The tyrosine kinase activity of
the EGFR was characterized more than two decades ago.
The EGFR (HER1) is part of a bigger family of transmembrane receptors,
including HER2, HER3, and HER4. They activate the mitogen-activated protein
kinase (MAPK) and the phos-phatidylinositol 3, 4, 5 kinase (PI3k)/protein
kinase B (PKB) signaling pathways, among others; a
disruption of these results in abnormal epithelial development, angiogenesis,
and malignancy in most organs.Moreover, high EGFR protein
levels have been demonstrated in human lung, ovarian, and upper and lower
gastrointestinal cancers. HER1 and HER2 are overexpressed in about 70% and 30% of non-small cell
lung cancers (NSCLCs), respectively. Tobacco-related dysplastic lung tissue has
increased EGFR expression compared to hyperplastic and metaplastic lesions,
suggesting a stage-dependent involvement in lung cancer.
Gefitinib and erlotinib are adenosine triphosphate (ATP) competitive inhibitors
of the EGFR tyrosine kinase domain. Phase I trials of gefitinib demonstrated
benefits in NSCLC. Two large phase II trials, Iressa Dose Evaluation in
Advanced Lung Cancers (IDEALs) 1 and 2 in patients previously treated with
conventional chemotherapy showed response rates in the range of
9%–19%, compared to only 7% for docetaxel. The efficacy of erlotinib in NSCLC
was illustrated in the Br.21 trial by a higher median survival
compared to placebo (6.7 months vs. 4.7 months) as well as a higher 1-year
survival (31.2% vs. 21.5%). Interestingly, two large randomized trials, The
Iressa NSCLC Trial Assessing Combination Treatment (INTACT) 1 and 2, showed
that when gefitinib was used together with a first-line platinum-based agent,
no survival advantage over chemotherapy alone was shown.This
may be explained by the antagonism between the cytotoxic effect of chemotherapy
and the cytostatic (causing G1 arrest) effects of the EGFR-TKI. The
results of trials of sequential chemotherapy and EGFR-TKI will help clarify
this. Combining erlotinib with conventional cytotoxic drugs, as in the case of
gefitinib, did not prove to be useful. However, when erlotinib was combined
with traditional chemotherapy in nonsmokers, a survival benefit was observed. Mutations in the intracellular EGFR (tyrosine kinase) (EGFRTK) domain are
common in never-a-smoker females of East Asian origin responding well to
gefitinib.The frequency of EGFR mutations is thought to be
39% and 48% among Japanese and Taiwanese patients, respectively, and around 3%
to 9% in non-Asian U.S. patients. A new TK domain mutation (substitution of
methionine for threonine at position 790 [T790M]) was found in four out of the
seven patients studied. It is interesting that the
T790M mutation is analogous to a secondary mutation in bcr-abl causing
resistance to imatinib in chronic myeloid leukemia (CML) patients.These examples demonstrate that TKIs play a beneficial role in certain NSCLC
patient subgroups. However, they prompt more genetic and clinical studies to
understand and exploit the heterogeneity of EGFRTK domain mutations to
eventually design more-efficient therapeutic TKIs.
against EGFR tyrosine kinase
Cetuximab has been shown to
confer clinical benefits through disease control in 24.13% of the
EGFR-expressing NSCLC patients treated. Data from phase I and II
trials indicate that cetuximab combined with a first-line platinum-based agent
is well tolerated, with rash being the only side effect. The Lung Cancer Cetuximab Study (LUCAS) trial
suggests that in first-line treatment of advanced NSCLC, the combination of
cetuximab with cisplatin/vinorelbine shows beneficial clinical response with
reasonable safety profiles compared to chemotherapy alone.Such results led in 2004 to a large phase III multicenter trial, the First-Line ErbituX in lung cancer (FLEX) study, evaluating
the efficacy of cetuximab in combination with cisplatin/vinorelbine vs. cisplatin/
vinorelbine alone in patients with advanced untreated NSCLC. Accrual with 1,124
patients was completed in July 2007, and the specific clinical outcomes are
Angiogenesis in lung
Folkman et al.
observed that tumors cannot grow beyond 2 mm without supporting
vascularization.Endothelial cells produce vascular endothelial
cell growth factor (VEGF), a mitogenic factor with a myriad of physiological
functions, both during lung development in early life and during
homeostasis in adulthood. Not surprisingly, abnormalities in the VEGF pathway
can result in acute and chronic lung disease. Various VEGF families have been
characterized: VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental factor.
VEGF ligands upon binding activate three structurally similar type III receptor
tyrosine kinases: VEGF-receptor (VEGFR)-1, VEGFR-2, and VEGFR-3. Alternative
gene splicing leads to several isoforms; these in turn may combine with the
various receptors in a biologically heterogeneous manner. This is being
exploited to develop targeted antiangiogenic therapies with minimal
VEGF is overexpressed in many
cancers, including lung cancer. Its expression in macrophages
in the lung cancer microenvironment correlates to
poor prognosis. Thus modulating angiogenesis in cancer is indeed an attractive
therapeutic strategy. Bevacizumab, a recombi-nant humanized monoclonal VEGF
antibody, has shown a synergistic survival advantage in colorectal cancer.A lung cancer phase II trial studying the synergy of bevaci-zumab and
paclitaxel/carboplatin showed a significant improvement in treatment response:
an overall response rate (ORR) of 31.5% vs. 18.8% in the bevacizumab arm
compared to chemotherapy alone. Furthermore, a longer disease-free interval
(7.4 months vs. 4.2) and overall survival time (17.7 months vs. 14.9)
was seen in the bevacizumab group. The Eastern Cooperative Oncology Group
(ECOG) phase III trial of paclitaxel/carboplatin with or without bevacizumab in
untreated stage IIIB or metastatic NSCLC showed a 27% vs. 10%
response rate for the bevacizumab/chemotherapy group. Progression-free survival
for the former group was 6.4 vs. 4.5 months, and the median survival was
12.5 vs. 10.2 months for the chemotherapy-alone arm. This is ECOG’s gold standard treatment for advanced
NSCLC. Other studies are under way to assess the role of bevacizumab combined
with EGFR TKIs.
The number of molecules under
current clinical investigation include the platelet-derived growth factor
(PDGF), the platelet-derived endothelial cell growth factor (PD-ECGF), various
integrins, angiopoietins, and fibroblast growth factors (FGF)-1 and FGF-2.
Below is a brief description of the ones most relevant to lung cancer.
Aflibercept is a soluble
antiangiogenic decoy receptor composed of segments of extracellular domains
VEGFR-1, VEGFR-2, and placental growth factor (PLGF) fused to the constant
region (Fc) of human immunoglobulin (Ig) G1.
Regeneron and Sanofi-Aventis have commenced an oncology development program to
evaluate afliber-cept with chemotherapy. Efficacy analysis showed evidence of
tumor reduction and prolonged stable disease after aflibercept treatment as a
single agent. Under way is a phase III study of
aflibercept with second-line docetaxel for metastatic NSCLC (Sanofi-Aventis:
FDA-approved sunitinib targets
various TK domains, including those of VEFGR, PDGF receptor (PDGFR), and c-Kit.
SU11248 in NSCLC is being assessed.
This is a low molecular weight
inhibitor of the TK domain of EGFR and VEGFR-2. Its benefit in lung cancer was
shown in a phase I and phase II study in metastatic tumors when used in
conjunction with docetaxel. Further trials will elucidate the
role of ZD6474 either as a single agent or in combination with other
This agent is a potent TKI of
VEGFR-2, VEGFR-3, B-Raf, and PDGFR-β. Several phase III clinical studies are assessing this agent in NSCLC;
under way is a phase III randomized, double-blinded, placebo-controlled study
sponsored by Bayer (NCT00449033) estimated to be concluded in 2010. It aims to
evaluate the efficacy of cis-platin,
gemcitabine, and sorafenib to cisplatin,
gemcitabine, cisplatin, and placebo as first-line therapy for advanced NSCLC
(specifically stage IIIb with pleural effusion and stage IV disease).
is an oral agent against a variety of TKs, such as VEGFR-1, VEGFR-2, VEGFR-3,
c-Kit, and PDGFR-β. A phase I trial in
metastatic NSCLC showed benefits in disease stabilization, and phase II trials
are under way.
Potential of Exploiting Epigenetic Changes in Lung Cancer
About 80 genes are
hypermethylated, often simultaneously within an individual lung tumor.
These epigenetic changes can be translated into practical tools for early
diagnosis. For example, the detection of hypermethylated DNA of
the p16INK4a gene in the sputum of patients with higher risks of developing
lung cancer is useful. Approaches include identifying hypermethylated genes in
lung tumors using a genome-wide strategy to create novel diagnostic and
Table 1. Immunotherapy in lung cancer
Phases I/II ALVAC
(n = 3 lung,
canarypoxvirus expressing both human CEA and the B71 costimulatory molecule.
SD in 3/18
Phase I (n =
to express B7.1
SD in 5 and PR
BLP25 (n = 171 NSCLC)
with lipo some adjuvant.
Phase II trial
(n = 86 NSCLC)
autologous tumor cells with GM-CSF secreting bystander cells.
prolonged remission was seen. No significant tumor response.
Phase II trial
(n = 182 stage Ib/II NSCLC)
double-blinded placebo-controlled study. Efficacy of MAGE-A3
immunotherapeutic as adjuvant therapy in stage IB/ II NSCLC.
clinical benefits; further trials pending.
trial (n = 83 NSCLC)
from three nonrandomized studies. Neisseria meningitides P64k protein
conjugated to a chemical adjuvant and EGF.
benefit of 3.5 months for vaccinated patients compared to nonrandomized
CEA, carcinoembryonic antigen;
SD, stable disease, NSCLC, non-small cell lung cancer; PR, partial response;
BLP, yS-lipoprotein; MUC1, mucin 1; GM-CSF, granulocyte
macrophage colony-stimulating factor; EGF, epidermal growth factor.
The Therapeutic Potential of Exploiting Immunomodulation in Lung Cancer
Two current immunotherapy
strategies focus on active vaccination and adoptive T cell
transfer. A recent phase I and phase II multicenter clinical trial
using granulocyte macrophage colony-stimulating factors in advanced NSCLC
demonstrated promising results that provide not only proof of principle, but
also the basis for further studies. Adoptive T cell
transfer plays a role in the treatment of malignant melanoma; it is a process
that entails the isolation and subsequent in vitro expansion of tumor
infiltrating T cells followed by their reinfusion into
the patient. The challenge relies on the difficulty of
isolating enough tumor-reactive T cells from lung cancer patients.
A summary of clinical trials evaluating the role of immunotherapy in lung
cancer is shown in Table 1.
The Therapeutic Potential of Targeting Wnt in Lung Cancer
Wnt signaling (Fig. 1) is crucial
during the development and homeostasis of the pulmonary tree. Wnt exer ts a regulatory function in the
stem cell compartment of many organs. The clonogenic nature
of human lung cancer was described almost 30 years ago. Clinical lung
adenocarcinomas and small cell lung cancers (SCLC) were found to have a rare
cellular population (< 1.5%) with the capacity to form agar colonies. When
intracranially inoculated into athymic mice, they grew into originating
malignant lesions. There is a link between the high expression of ABC
transporters and drug resistance. Side population (SP) cells isolated by the
efflux of Hoechst 33342 by ABC transporters with stem-cell
characteristics have been demonstrated in both lung cell lines and clinical
NSCLC. These data together with the heterogeneity and regionality of lung
cancer demonstrated in murine models suggest the
involvement of stem cells in the human lung (Fig. 2). The dissection of the
precise molecular mechanisms by which Wnt regulates the initiation, malignant
transformation, and metastatic spread of lung progenitor, or stem-cell like
cells becomes mandatory because of its enormous therapeutic potential.
Fig. 1. The canonical Wnt transduction pathway.
Proteosomal degradation of β-catenin via its phosphorylation occurs
in the absence of Wnt ligands. Downstream, Wnt target genes are maintained
repressed (‘OFF’). Degradation of active β-catenin is reduced upon the binding
of Wnt’s. Accumulation and translocation of β-catenin into the nucleus lead to
binding to T cell factors and activation of target
genes (‘ON’). APC, adenomatous polyposis coli; Dvl, disheveled; GSK, glycogen
synthase kinase; TCF, T cell factor.
Fig. 2. Tissue homeostasis and carcinogenesis through stem cell cycling.
A: Quiescent stem cell (SC) with inactive Wnt.
B: Upon tissue trauma, Wnt transduction leads to activation of homeostatic SCs.
C: These cells produce more pluripotent SCs as well as progenitor cells with limited proliferative power.
D, A: That produces specialized differentiated cells (shown in orange, purple, and blue) to regenerate the tissue. Upon repair, SCs cycle into a quiescent state.
E: Accumulation of oncogenic events may ‘lock’ activated SCs in a permanent Wnt-driven state, leading to cancer stem cells.
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