Key words: cancer stem cells, cancer
treatment, head and neck cancer, tar-
Acknowledgments: The oncologic
project of the ENT Clinic and of the
Molecular Biology Section at the Uni-
versity of Ferrara is supported by a
grant for scientific research from the
University of Ferrara.
Correspondence to: Chiara Bianchini,
MD, ENT Department, University Hos-
pital of Ferrara, C.so Giovecca 203,
44100 Ferrara, Italy.
Received May 3, 2010;
accepted December 6, 2010.
Targeted therapy in head and neck cancer
Chiara Bianchini1, Andrea Ciorba1, Stefano Pelucchi1, Roberta Piva2,
and Antonio Pastore1
1ENT Department, University Hospital of Ferrara, Ferrara;2Molecular Biology Section, Department
of Biochemistry and Molecular Biology, University of Ferrara, Ferrara, Italy
Aims and background.This review focuses on recent advances in understanding the
molecular mechanisms at the basis of cancer initiation and progression in the head
and neck and also discusses the possible development of targeted cellular strategies.
Intrinsic and acquired resistance of cancer cells to current conventional treatments,
as well as recurrence, represent a major challenge in treating and curing the most ag-
gressive and metastatic tumors also in the head and neck. Even though in some
hematologic malignancies (i.e., non-Hodgkin’s lymphomas) antibodies specifically
designed to target tumor-specific cells have already been introduced, in solid tumors
molecular targeted therapy is now entering clinical practice.
Methods. A PubMed database systematic review.
Results and conclusions. Molecular targeting could achieve specific damage to can-
cer cells, at the same time preserving functionally important tissues. This could offer
new prospectives in primary and adjuvant treatment also of head and neck tumors.
Head and neck cancer is still the sixth most common cancer type worldwide. Sur-
gery, radiotherapy and chemotherapy, alone or in combination, are considered the
main therapeutic approaches. Disappointingly, despite significant advances in head
and neck treatments, survival rates and prognosis have only improved moderately
through the years1. Recently, studies have suggested that several factors may be in-
volved in the head and neck carcinogenetic process. The highly tumorigenic“expres-
sion” of some cancer types, cancer progression to locally invasive and metastatic
states, and recurrences are often associated with resistance to treatments. This could
be explained by accumulating genetic and/or epigenic alterations in cancer cells that
may contribute to their uncontrolled growth, survival and invasion, as well as to their
intrinsic or acquired resistance to clinical treatments2.
In particular, the concept of cancer stem cells or cancer-initiating cells has been
proposed to explain cancer initiation and progression to metastatic disease states
and resistance to conventional therapies3-5.
A major problem in the treatment of cancer is still the specific molecular targeting of
age to healthy cells and target tumor compartments that have the highest sensitivity.
In the present review, the importance of considering these new concepts in the role
of cancer progenitor cells and cancer development in order to overcome resistance to
conventional cancer therapies is discussed.
Cancer stem cells in head and neck tumors
There already are several reports that focus on the possible role of stem cells in can-
cer occurrence and progression in head and neck tumors3,6,7. It is likely that carcino-
genesis should be considered as a multistep process, in
which an accumulation of genetic and epigenetic alter-
ations forms the basis for development from a normal
cell to a cancer cell6. Particularly, the alteration of two
key genes, p53 and p16, seems to be involved in this
Cancer stem cells could represent a minor population
of tumor cells that possess the stem cell property of self
renewal. De-regulation of stem cell self renewal is a like-
ly requirement for the development of cancer3. The
presence of these cancer progenitors may partially ex-
plain the rapid recurrence as well as the high metastat-
ic rate of the most aggressive tumors after current clini-
Moreover, the reactivation of several developmental
stem cell factor/KIT, platelet-derived growth factor
(PDGF)/PDGFR, sonic hedgehog (SHH/PTCH/GLI tran-
scription factor, and/orWnt/catenin)] combined with al-
tered DNA repair and mechanisms of multi-drug resist-
ance in cancer progenitor cells may take part and may be
considered responsible, at least in part, for their resist-
ance to current clinical therapies2,9.
Possible specific targets in head and neck
Recent advances in basic research, particularly ge-
nomics and proteomics, have already improved but will
probably develop more in the near future our under-
standing of the molecular processes governing head
and neck cancer origin and progression.
It has been reported that the simultaneous blockade
of several oncogenic cascades activated in cancer pro-
genitor cells during cancer development has been
judged essential for improving the current clinical treat-
ing head and neck cancers2,10-18. Particularly, the molec-
ular targeting of developmental cascades including
hedgehog, Wnt/catenin, Notch, EGFR, PDGFR and KIT
pathways and/or oncogenic signaling elements (telom-
erase, Src, ABL, PI3K/Akt, MYC, NF-KB and survivin),
which assume a critical function in regulating the self-
renewal, survival and invasion of cancer progenitor
cells as well as in drug resistance and disease relapse,
has been defined of therapeutic interest2,10-19(see also
So far, the two most promising and advanced strate-
gies are the blockage of growth factor-based cellular sig-
naling and interference with angiogenesis-related path-
ways. One of the most comprehensive investigated can-
didate is the EGFR family. EGFR is the most prominent
candidate for therapeutic targeting due to its more than
90% expression rate in head & neck squamous cell car-
cinoma and its influence on regulation of proliferation,
apoptosis, metastasis, angiogenesis and cell differentia-
tion9. It has been reported that down-stream signaling
or inhibition of EGFR may result in arrest of the G1
phase of the cell cycle, due to induced upregulation/ac-
cumulation of the cyclin-dependent kinase inhibitors
p27kip1 and/or p21cip1/waf1, and this may stop cancer
cell proliferation9. The extracellular part of the EGFR
can be inhibited by monoclonal antibodies and the in-
tracellular part by more or less specific tyrosine kinase
A clinically tested EGFR inhibitor is cetuximab, a
monoclonal antibody with a high affinity to EGFR, and
there are already several encouraging reports about the
use of the drug in treating head & neck squamous cell
Instead, there only are very few data available about
the use of tyrosine kinase inhibitors in head and neck
cancer treatment. In particular, it has been shown that
tyrosine kinase inhibitors block EGFR downstream sig-
nal transduction pathways, inducing an immediate cell
ducing a decrease in angiogenic growth factors9.
Gefinitib and erlotinib are the two most advanced drugs
available, but their use is still experimental9,20,21.
Currently, EGFR inhibitors have been tested as a sin-
gle agent or in combination with other therapies. As a
single agent, there are several reports showing that
these molecules are moderately active in patients af-
fected by head and neck squamous cell carcinoma. In
some cases, they have provided disease control with a
reasonable therapeutic index in patients who are
chemotherapy refractory or are deemed unfit for cyto-
toxic therapy. However, the activity of single-agent anti-
EGFR therapy in the head and neck squamous cell car-
cinoma setting is largely based on uncontrolled, single-
arm, phase II trials (see also Table 2).
Few phase II and III trials have tested the addition of
ry to platinum-based therapy. Nonetheless, so far the
combination appears to confer no further benefit over
anti-EGFR agents alone (see also Table 2)22,23-30.
138C BIANCHINI, A CIORBA, S PELUCCHI ET AL
Table 1 - Possible sites of intervention for arresting head and
neck cancer cells progression
EGFR in head & neck
squamous cell carcinoma stopping cellular
Arrest G1 phase cell cycle,3,11,38,39,40
Insulin-like growth factor Inhibition of intracellular
1 receptor, telomerase,
Inducing apoptosis in specific
Reduction of cellular
growth & angiogenesis
AN UPDATE IN TARGETED THERAPY IN HEAD AND NECK CANCER139
It is known that angiogenesis plays a key role in the
pathogenesis of solid tumors, including those of the
head and neck. Experimentally, it has already been
shown in mice that inhibition of vascular endothelial
growth factors and their receptors decreases angiogen-
esis and tumor growth. Therefore, several strategies to
target vascular endothelial growth factors have been de-
veloped and are currently being explored. Clinical trials
on the use of these types of molecules alone or in com-
bination with conventional chemotherapies are already
The development of new biological agents should fo-
cus on inhibitors that are likely to hit multiple targets.
The complexity of aberrant signaling in head and neck
tumors explains why interfering with only single steps
in this pathway have not yet shown marked clinical re-
distinct specific pathways is likely to inhibit the escape
of tumor cells by alternate mechanisms leading to more
ical factors and risk habits can result in distinct genetic
and epigenetic alterations, which may trigger different
signaling pathways, thus impacting differently the de-
velopment and progression of head and neck tumors.
To evaluate the efficacy of these biological agents, there
is urgent need to identify novel biomarkers that can be
used to accurately assess and individualize therapy31.
The concept of “field cancerization”
A genetic progression model of head and neck tumors
has to be associated also to the concept of“field cancer-
ization” of the aerodigestive tract. Slaughter et al.32used
the term “field cancerization”, firstly studying 783 pa-
tients with oral cancer33. After performing histological
examinations, they proposed the concept of field can-
cerization to describe a situation in which: 1) oral can-
cer develops in multifocal areas of precancerous
change; 2) histologically abnormal tissue surrounds the
tumor; 3) oral cancer often consists of multiple inde-
pendent lesions that sometimes coalesce; and 4) the
persistence of abnormal tissue after surgery may ex-
plain second primary tumors and local recurrences4-6.
At the time of the study32, there was no molecular basis
for these observations, and the term “field canceriza-
tion” has subsequently taken on a slightly different
meaning in the literature.
In fact, the concept has been re-proposed to explain
the development of locally recurrent cancer and/or sec-
ond primary tumors in head and neck cancer patients
by Leemans et al.33, who suggested that head and neck
carcinomas recur at the primary site in about 10-30% of
the cases with advanced tumors, even when a complete
resection of the primary carcinoma has been per-
Ha and Califano35considered the term of field cancer-
ization from a “molecular” point of view. It could be
considered the result of either independent molecular
events affecting multiple cells separately, or as a molec-
ular event in a single clonal progenitor that gives rise to
the phenomenon. These two mechanisms may not be
mutually exclusive and may be simultaneous and/or
Further knowledge, and thus possibly further new
therapeutic targets, could arise from the comprehen-
sion of head and neck cancer stem cell biology, since
methods to isolate and characterize the ex vitro and in
vivo properties of cancer stem/progenitor cells have
been recently provided and improved. Therefore, a re-
analysis of the oncogenic gene products specifically ac-
tivated in cancer progenitor cells will be necessary. Par-
ticularly, further investigations by using cancer stem
cells isolated from primary cancer patients’ malignant
metastatic disease should help toidentifynew biomark-
ers for the development of more effective diagnostic
and prognostic methods and targeted therapies against
aggressive and metastatic cancers.
Table 2 - Clinical trials of molecular targeted therapies in recurrent and/or metastatic head & neck squamous cell carcinoma: an-
ti-EGFR molecular-targeted therapies as single agent and in combination (modified from Le Tourneau and Siu22)
PhaseReferenceTreatmentOverall survival (mo)
Cetuximab 400 mg/day
Gefitinib 500 mg/day
Gefitinib 250 mg/day
Platinum + cetuximab
Platinum + cetuximab
Platinum + cetuximab
Cisplatin + erlotinib
Erlotinib & bevacizumab
Platinum + cetuximab
Platinum + cetuximab
Platinum + cetuximab
Cisplatin + erlotinib
Erlotinib & bevacizumab
7 I, II
140C BIANCHINI, A CIORBA, S PELUCCHI ET AL
However, evaluation of the functional and molecular
properties of these cells ex vivo must be considered with
caution, since multiple extrinsic factors may influence
the in vitro behavior of this subset of cells. More specif-
ically, experimental culture conditions do not necessar-
ily reflect the local tumor microenvironment and the in-
tercellular signaling environment. Further investiga-
tions of cancer progenitor cells in more vigorous exper-
imental conditions are required to help to elucidate the
molecular mechanisms that provide a critical role for
their uncontrolled self-renewal and/or aberrant differ-
entiation capacity. The specific biomarkers and func-
tional properties of cancer progenitor or stem cells
clearly should be explored in order to assess selected
possible targets. This particularly considering that can-
cer progenitor/stem cells may also exhibit a differential
genomic and proteomic pattern, compared to the bulk
mass of further cancer cells11,36-47. It is also necessary to
consider that these molecular markers might allow a
very sensitive detection of minimal residual cancer cells
or micrometastasis in the various body compartments
and/or in lymph nodes, thus facilitating the prognosis
The development of new effective and safe targeted
therapies by eradicating the total population of cancer
progenitor cells and their further differentiated proge-
nies at the primary and secondary neoplasms should al-
disease relapse, and thereby induce a complete cytoge-
netic remission and cure of cancer patients in the clinic.
gical technique progresses. A newer pathway of nan-
otechnology and molecular medicine will also lead to
technical advancements in areas such as free tissue
transfer, robotics, minimal-access surgery, as well as ap-
plication of new lasers and optical technologies. Ad-
vances in these fields could expand our capabilities to
repair, restore and preserve organ/tissue function, thus
personalizing and tailoring the treatment to the “indi-
A cancer“targeted therapy” actually represents one of
the most promising resources in the development of
new strategies including in head and neck oncology. A
targeted therapy with biological markers in head and
neck cancer is a new and fast-growing field with inter-
esting aspects concerning decreasing early and late tox-
icity with better functional outcome and survival. Since
it is likely that carcinogenesis may be considered as a
process that arises from the malignant transformation
of embryonic or adult stem/progenitor cells into cancer
progenitor cells3,6,7, cancer progenitor cells can provide
critical functions in cancer initiation and progression
into metastatic and recurrent disease states. Based on
these observations, the molecular targeting of cancer
progenitor cells must be considered for improving the
efficacy of current cancer therapies.
Traditional diagnostic methods such as clinical as-
sessment, histopathological examination and imaging
techniques are not considered sufficient to provide all
the information related to prognosis and treatment of
choice in head and neck cancer36,37. Additional investi-
gations to identify the specific molecular biological
characteristics of head and neck tumors should be per-
formed. Only comprehension of the origin and molecu-
lar behavior of head and neck cancer will lead us to pro-
gram and perform a more specific, safe, effective, per-
sonalized and targeted therapeutic plan.
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