Current Treatment Options in Oncology (2010) 11:3644

DOI 10.1007/s11864-010-0120-6

Lung Cancer

Exciting New Targets in Lung

Cancer Therapy: ALK, IGF-1R,
HDAC, and Hh
Joel W. Neal, MD, PhD*
Lecia V. Sequist, MD, MPH
Address
*Stanford Cancer Center, 875 Blake Wilbur Drive,
Stanford, CA 94305, USA.
E-mail: jwneal@stanford.edu

Springer Science+Business Media, LLC 2010

Opinion statement
The anaplastic lymphoma kinase (ALK) inhibitor crizotinib will become an integral
addition to the treatment of patients with non-small cell lung cancer (NSCLC) harboring genetic ALK translocations. The insulin-like growth factor receptor (IGF-1R)
monoclonal antibody figitumumab, while initially promising, appears to increase
toxicity and death in combination with chemotherapy in the treatment of patients
with NSCLC of squamous histology; therefore, clinical development of this class of
agents will need to proceed with caution. The histone deacetylation (HDAC) inhibitor
vorinostat did not demonstrate an improvement in overall survival (OS) compared with
placebo in a large randomized trial, but other agents in this class may have greater
selectivity and efficacy. Inhibitors of the hedgehog (Hh) signaling pathways have
some early clinical promise in both NSCLC and small cell lung cancer (SCLC), and larger
studies using these agents are eagerly anticipated.

Introduction
Lung cancer is still the leading cause of cancer-related
death in the United States despite extensive research
efforts and the development of new therapeutic
approaches [1]. However, ongoing research into the
molecular basis of lung cancer has yielded insight into
various molecular pathways that are deregulated during
the process of tumorigenesis. This article summarizes
four signaling pathways of emerging importance in

lung cancer: anaplastic lymphoma kinase (ALK), insulin-like growth factor receptor (IGF-1R), histone
deacetylation (HDAC), and hedgehog (Hh). Inhibitors
targeting these pathways have been used investigationally to treat both non-small cell lung cancer
(NSCLC) and small cell lung cancer (SCLC), and may
lead to novel therapeutic strategies to complement
traditional chemotherapy.

ALK
Anaplastic lymphoma kinase is an orphan member of the insulin
superfamily of receptor tyrosine kinases normally expressed only in
the central nervous system, small intestine, and testis [2, 3]. The
normal function of ALK is poorly understood, but many anaplastic

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37

large cell lymphomas activate ALK oncogenic signaling via genetic

chromosomal translocation, by forming fusion proteins between the
ALK kinase domain and partner proteins such as nucleophosmin
(NPM) [4]. Aberrant ALK expression and signaling have also been
observed in solid tumors, including lung cancers. In a subset of
NSCLC, genetic translocation of two genes in the short arm of chromosome 2 leads to the expression of a fusion protein between the
N-terminal portion of echinoderm microtubule-associated protein-like
4 (EML4) and the C-terminal kinase domain of ALK [5]. This causes
aberrant activation of downstream oncogenic signaling pathways such
as MAP kinase, PI3-Kinase, and STAT, leading to cell proliferation,
invasion, and inhibition of apoptosis [6].
Anaplastic lymphoma kinase translocations in NSCLC were first
detected using a cDNA expression library from an NSCLC tumor to
transform 3T3 fibroblasts [5]. In the initial report, 5 out of 75 Japanese NSCLC tumor samples of unselected histologic subtype contained evidence of an EML4ALK gene fusion. The presence of the
gene fusion was mutually exclusive of mutations in epidermal growth
factor receptor (EGFR) and KRAS, which are other common oncogenic
driving mutations in NSCLC. In a subsequently reported series, tumor
samples that were being screened for EGFR mutations also underwent
ALK screening, resulting in a population weighted toward females,
Asian ethnicity, never/light smoking history, and adenocarcinoma
histology. This study identified 19/141 tumors containing an ALK
translocation (13%) [7], but in an unselected population of patients
with NSCLC, the frequency is likely closer to 35%, since ALK
translocations are associated with light smoking history and adenocarcinoma histologic subtype [8, 9]. However, ALK-mutated tumors
commonly have a unique signet ring cell histologic feature and are
generally less gender-associated than EGFR mutations [8]. Detection
of an ALK tyrosine kinase rearrangement is achieved through a variety
of techniques, including break-apart fluorescence in situ hybridization
(FISH) to detect the genetic translocation [7], multiplexed RT-PCR to
detect the fusion transcript [10], or immunohistochemistry (IHC)
using an antibody to detect aberrant ALK protein expression [11].
The development of tyrosine kinase inhibitors against the ALK kinase
allowed exploration of the hypothesis that tumors harboring the ALK
translocation are oncogene addicted to this signaling pathway. This
term describes the phenomenon in which tumors with an activated
oncogene depend on continued signaling for proliferation and survival. One example of this is in lung cancers harboring activating
mutations in the EGFR tyrosine kinase, in which disruption of EGFR
signaling results in widespread apoptosis of tumor cells [12]. By
analogy, it was believed that ALK-positive tumors may be sensitive to
ALK tyrosine kinase inhibitors, as they are insensitive to EGFR
tyrosine kinase inhibitors [7]. Patients with ALK-positive tumors
were enrolled on an expansion arm of a phase I clinical trial of an
oral ALK tyrosine kinase inhibitor, crizotinib (PF-02341066). The
maximum tolerated dose was determined to be 250 mg twice daily,
and major toxicities included nausea, vomiting, diarrhea, fatigue,
and transaminitis, as well as a characteristic visual disturbance when
transitioning from dark to light. In a preliminary report, among 82
patients with ALK-positive NSCLC treated in the expansion phase of
the phase 1 study, the response rate was 63% and the disease control
rate was 87% [13]. To date, the median progression-free survival
(PFS) and overall survival (OS) have not yet been reached, as the

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Lung Cancer
majority of patients are still receiving treatment after a median
follow-up of 6.4 months.
Based on these promising results, a phase III registrational trial is
currently enrolling patients with metastatic NSCLC containing ALK
translocations. This trial randomizes 318 patients with ALK FISHpositive, advanced-stage NSCLC to second-line crizotinib vs pemetrexed or docetaxel, with the aim of demonstrating superior PFS in this
selected group of patients. In addition, a companion phase II singlearm study is enrolling patients who are ALK-positive but either (1)
ineligible for the phase III study or (2) developed progressive disease
on the chemotherapy arm of the phase III trial. In addition, a first-line
trial is under development for patients with previously untreated ALKpositive lung cancer. If this drug is established to be superior to
standard chemotherapy, it should become a new standard of care in
the fraction of patients with ALK-positive NSCLC. In addition, other
highly potent ALK tyrosine kinase inhibitors are in the early stages of
clinical development, and other targeted agents such as HSP-90
inhibitors may inhibit this pathway as well [14].

Insulin-like growth factor type 1 receptor

The IGF pathway is an ancient signaling system which is used for the
regulation of carbohydrate energy balance at the level of the organism,
as well as control of individual cell growth [15]. Signaling through the
IGF pathway occurs when the IGF ligands, IGF-1 or IGF-2, bind to the
extracellular domain of the IGF-1R receptor, which is modulated by
the presence of extracellular IGF binding proteins (IGFBPs) (for review
see Ref. [16]). Signals downstream of the IGF-1R tyrosine kinase
include the MAP kinase pathway, which activates cellular proliferation,
as well as the PI3K pathway, which inhibits apoptosis. Many normal
tissues and tumor cells express IGF receptors as well as the closely
related insulin receptor, which can form heterotetramers with IGF-1R,
leading to alterations in its signaling ability. Normally, circulating
IGF-1 and IGF-2 are produced by the liver in response to growth hormone (GH) stimulation, as well as in tissues in an autocrine and paracrine manner. There is mounting evidence from population-based
studies that higher circulating levels of IGF-1 can increase the risk of
breast and prostate cancer, and perhaps even lung cancer [1720].
Preclinical models have suggested that inhibition of this pathway may
potentiate chemotherapy, EGFR inhibitors, and even radiation effects in
NSCLC cell lines [2123]. Two classes of inhibitors are being developed
to target the IGF pathway in various tumor types: monoclonal antibodies to the IGF-1R extracellular domain and small molecule inhibitors of the IGF-1R tyrosine kinase domain.
A handful of IGF-1R antibodies are in various stages of clinical
development, including figitumumab (CP-751, 871), robatumumab
(R1507), cixutumumab (IMC-A12), dalotuzumab (MK0646), and
AMG479. A unique toxicity of this class of agents is hyperglycemia,
which results from inhibition of negative feedback to the pituitary
from IGF-1R signaling, with resultant hyperglycemia and insulin
resistance from growth hormone oversecretion, increased IGF-1 levels,
and increased IGFBP levels [18]. In lung cancer, figitumumab has
been tested most extensively. In a phase I dose-escalation trial in
combination with carboplatin and paclitaxel, 40% of patients with
NSCLC had a response, including one complete response [24]. In
a subsequent phase II trial, 156 patients were randomized to

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39

chemotherapy alone or chemotherapy plus figitumumab. While the

addition of figitumumab appeared to increase the response rate in
both adenocarcinoma and squamous cell histology, the response rate
among patients with squamous cell histolology was an astonishing
78%, which was subsequently duplicated in an expansion cohort [25].
Based on these results, a large study randomized 681 patients with
non-adenocarcinoma histology to carboplatin and paclitaxel with and
without figitumumab. However, in December 2009, this phase III
study was prematurely terminated, due to a trend toward worse OS in
the group receiving figitumumab and chemotherapy (10.3 months vs.
8.5 months, hazard ratio (HR) 1.23, P = 0.051), perhaps due to an
increase in infection and cardiovascular events [26]. In a subgroup
analysis, patients with high levels of IGF-1 (>1 ng/ml) had a trend
toward improved survival and less toxicity from the combined treatment; however, IGF-1 levels did not appear to be predictive of
response in the phase II study [27].
Clinical development may continue for other indications such as refractory Ewings sarcoma, in which figitumumab appears to have single agent
activity [28], but the phase III trial with figitumumab in combination
with erlotinib in the second-line treatment of non-adenocarcinoma
NSCLC was closed in March 2010 due to futility. Clinical trials testing
other monoclonal IGF-1R antibodies both along and in combination are
ongoing in both NSCLC and SCLC.
The second class of IGF-1R inhibitors, the small molecule TKIs, are
less clinically developed. Unlike the monoclonal antibodies, which
specifically inhibit IGF-1R, these drugs generally inhibit both IGF-1R
and insulin receptor signals by binding to the ATP binding site in the
kinase domain. In theory, this may result in more severe hyperglycemic disturbances. In a preliminary report of toxicity from a phase I
trial with the small molecule IGF-1R inhibitor OSI-906, adverse events
included hyperglycemia, nausea, vomiting, fatigue, lethargy, and
diarrhea, but these were generally less than grade 3 [29]. Future
development of this drug and other molecules with a similar spectrum
of activity, such as BMS-754807, will hopefully include diseasespecific trials in lung cancer.

Histone deacetylases
Acetylation of histones is one of the many post-translational modifications, which occurs on these DNA-packaging proteins, which generally leads to increased accessibility of promoter regions and
increased transcription of genes in localized areas of chromosomes
[30]. This process is opposed by the histone deacetylase classes of
enzymes, which promote condensation of chromatin and repression
of gene expression. Small molecule HDAC inhibitors bind to the zinccontaining catalytic domain and have varying specificity against the
distinct classes of HDAC enzymes. Many cancers express high levels of
HDAC and appear to have an increased sensitivity to HDAC inhibitors
relative to normal cells [31]. Interestingly, the activity of many other
proteins involved in cancer is also modulated through acetylation,
such as p53 [32] c-MYC [33], and the molecular chaperone HSP90
[34]. Therefore, the pleiotropic mechanisms by which HDAC inhibitors exhibit antitumor effects likely include altering gene expression
and cell differentiation via histone acetylation, as well as modifying
the cell cycle and lowering the apoptotic threshold by changing the
acetylation state of other cellular proteins [31].

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Lung Cancer
Multiple HDAC inhibitors are in clinical development to target a wide
variety of solid and hematologic malignancies, including vorinostat
(MK-0683/SAHA), romidepsin (FK-228/depsipeptide), entinostat
(SNDX-275/MS-275), and panobinostat (LBH589). Of these, the
development of vorinostat is most matured in lung cancer. Vorinostat
is FDA approved as oral monotherapy for the third-line treatment of
cutaneous T-cell lymphoma based on a response rate of 30% in
otherwise refractory patients [35]. The most common side effects were
diarrhea, fatigue, nausea, dysguesia, and thrombocytopenia, but were
generally mild. In lung cancer, a phase II trial of single agent vorinostat in 14 refractory patients with NSCLC demonstrated no objective responses, but disease was transiently stabilized in 8 patients [36].
Based on this, carboplatin and paclitaxel were combined with escalating doses of vorinostat was tested in patients with solid tumors, and
partial responses were observed in 10 of 19 patients with advancedstage NSCLC, which is higher than expected with chemotherapy alone
[37]. Similarly encouraging results were observed in a randomized
phase II study of 94 patients, in which 34% of patients receiving
chemotherapy plus vorinostat responded to treatment, as compared
with 12% of patients receiving chemotherapy and placebo, with a
trend toward improved survival in the vorinostat arm [38]. However,
the subsequent phase III randomized trial of 253 patients was terminated prematurely due to failure to demonstrate an improvement
in response rate, PFS, or OS in the vorinostat arm [39]. While this
represents a setback for this combination, other clinical trials are
ongoing in small cell lung cancer, and in NSCLC with vorinostat in
combination with other targeted agents. One particularly intriguing
combination is vorinostat plus erlotinib, an epidermal growth factor
receptor tyrosine kinase inhibitor (EGFR-TKI). The rationale for
combining HDAC inhibitors with EGFR-TKIs is based on preclinical
data that HDAC inhibition restores sensitivity to EGFR-TKIs after the
development of resistance, and also dramatically reduces the concentration of erlotinib necessary for cell death in a variety of NSCLC
cell lines [40, 41]. Entinostat and romidepsin are similarly being
tested in combination with erlotinib, and results of these trials may
yield different results as all of these agents have different activity
against individual HDAC proteins.

Hedgehog
The Hh signaling pathway was named for its role in development in
fruit flies, but it also remains highly evolutionarily conserved in
mammals. Hh signaling, represented in Fig. 1, is initiated by binding
of ligand to the transmembrane patched (Ptch) proteins, which normally repress the transmembrane smoothened (Smo) protein. Without the negative repression by Ptch, Smo can activate the Gli
transcription factor, resulting in activation of target genes important in
development and cancer, including IGFBP3, BCL2, N-MYC, and likely
many others [4244]. The connection between the Hh pathway and
cancer was first identified in patients with nevoid basal cell carcinoma
syndrome (Gorlin syndrome). These patients have a strong genetic
predisposition for basal cell cancer (BCC) and medulloblastoma,
caused by a loss-of-function mutation in the PTCH1 gene, resulting in
constitutive activation of Hh signaling after a second genetic hit to the
remaining functional allele [45]. Interestingly, most sporadic BCCs
also contain mutations which activate the Hh signaling [4648], and

Exciting New Targets in Lung Cancer Therapy

Hh

Ptch

Smo

Neal and Sequist

41

Cyc

Gli activation
Gene transcription

Figure 1. Schematic of Hedgehog signaling pathway. Activation of Hedgehog signaling is initiated by binding of

hedgehog ligand (Hh) to the transmembrane patched (Ptch) proteins. Ptch normally represses the transmembrane
smoothened (Smo) protein. Without the negative repression by Ptch, Smo can activate the Gli transcription
factor, resulting in activation of the transcription factor target genes important in development and cancer.
Cyclopamine (Cyc) and its derivatives bind to Smo and inhibit Hedgehog signaling
multiple solid and hematologic malignancies have dysregulation of
this pathway. In lung cancer, Ptch mutations have not been observed,
but ligand-dependent activation of the Hh pathway appears to be
important for the growth of many SCLC cell lines [49]. Transduction
of Hh signaling, as measured by Gli1 expression, is even more frequent in ex vivo NSCLC and SCLC tumor samples than in lung cancer
cell lines [50, 51], suggesting a potential role for a stromal paracrine
effect in these tumors [52]. There is also growing evidence that Hh
signaling is critical for survival of cancer stem cells, such that inhibitors of this pathway might kill the relatively small population of
chemotherapy-resistant self-renewing cells within a tumor [53].
There are a number of druggable targets within the Hh pathway.
Cyclopamine, a natural steroidal alkaloid product of the corn lily
plant, binds to Smo and inhibits downstream signaling [54]. A
number of cyclopamine derivatives with improved pharmacokinetic
properties have entered clinical development in lung cancer, including
GDC-0449, IPI-926, and BMS-833923/XL-139. Molecules which target multiple other steps in the Hh pathway have also been recently
identified [55, 56]. Of the cyclopamine derivatives, the most extensively studied is GDC-0449. This agent has elicited remarkable
responses in metastatic BCC and medulloblastoma [57, 58]. In lung
cancer, the Eastern Cooperative Oncology Group (ECOG) 1508 phase
II trial is enrolling patients with SCLC for treatment with cisplatin and
etoposide, in combination with either GDC0449 or the IGF-1R antibody cixutumumab. BMS-833923 is also being evaluated for safety in
a phase Ib trial in combination with carboplatin and etoposide in
SCLC. If the Hh inhibitors are indeed active against putative SCLC
stem cells, these agents might confer durable responses in a disease
that often rapidly becomes chemoresistant.

Conclusions
Research into the molecular mechanisms of tumorigenesis has yielded
the development of novel therapeutic agents which hopefully will
augment the standard regimens of chemotherapy in lung cancer. The
ALK inhibitors appear to be effective in a subset of NSCLC driven by
characteristic EML4-ALK translocations, which underscores the
importance of early testing of new drugs in molecularly selected

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patient populations. Recent large trials of both the IGF-1R inhibitor
figitumumab and the HDAC inhibitor vorinostat failed to demonstrate a benefit in unselected patients with NSCLC, but other ongoing
trials with these and newer agents may help to identify a particular
subgroup of patients for whom this therapy is most appropriate.
Finally, the Hh inhibitors have demonstrated preclinical efficacy in the
treatment of SCLC, and trials are ongoing to determine whether these
agents might augment the efficacy of chemotherapy in this disease.
Hopefully over the next few years, novel pathway inhibitors will
become an integral part of our therapeutic arsenal in the battle against
lung cancer.

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