Keywords
oral squamous cell carcinoma - therapeutic drugs - targeted therapy
Introduction
Oral cancer is cited as tumors particularly arising in the hard palate, anterior two-thirds
of the tongue, lips, upper and lower alveolar ridges, posterior deltoid muscles of
molars, buccal mucosa, and oral cavity.[1] Approximately 90% of oral cancer have squamous differentiation in the mucosal epithelium;
therefore, it is known as oral squamous cell carcinoma (OSCC). It is the sixth most
prevalent cancer worldwide. OSCC has a survival rate of 5 years in approximately 50
to 60% of cases in the early stage. In advanced stages of OSCC, it drops to 30 to
40% of cases. Unluckily, 60 to 80% of cases of OSCC are recognized at the advanced
stage. With regular development in diagnosis and treatment knowledge, the survival
rate has been increased.[2] In the present scenario, proteomics, genomics, metabolomics, and different biomedical
sciences have been established expeditiously. Subsequently, targeted therapies that
target cancer-specific genetic targets, for example, genes responsible for invasion,
division, proliferation, and metastasis of carcinogenic cells, have deliberately become
the hot topic in the field of research.[3]
[4] Targeted therapies choose comparable therapeutic drugs as per the specific carcinogenesis
location. It has the advantages of low toxicity, high selectivity, and high therapeutic
indexes. In modern day, individual targeted therapeutic drugs have accomplished promising
results in cancer treatment.
This review scrutinized the existing documentation in the literature related to the
targeted therapies for OSCC. English language articles were searched in various databases
such as PubMed, Scopus, Science Direct, and Google Scholar. The keywords used for
searching are “oral squamous cell carcinoma,” “targeted therapy,” an “therapeutic
drugs.”
In this review, characterization of presently most encouraging and well-known molecular
targeting strategies, which is directly used in the treatment of advanced head and
neck cancer, is discussed.
Drugs Targeting the Programmed Cell Death Receptor 1
Drugs Targeting the Programmed Cell Death Receptor 1
Programmed cell death receptor-1 (PD-1) is associated with the CD28 family. PD1 is
expressed on natural killer cells, T-cells, B-cells, dendritic cells, and macrophages.
When PD1 binds with PD-L1 (programmed cell death ligand 1), it results in apoptosis
of effector T-cells, which leads to immune escape of tumor.[5]
[6] Also, it increases the synthesis of interleukin-10 cytokines, which suppress inflammatory
responses.[7] In various studies, it is observed that overexpression of PD-L1 is seen in 50 to
90% of OSCC patients. This increased expression is positively correlated with cervical
lymph node metastasis. Their coexpression was analogous to the prognosis of different
malignant tumors such as melanoma and OSCC.[8]
[9] Presently, two drugs are used to target PD-1. They are nivolumab and pembrolizumab.
These drugs are permitted for use by the U.S. Food and Drug Administration in the
treatment of advanced melanoma. Pembrolizumab is used for head and neck squamous cell
carcinoma patients.[10]
[11]
Drugs Targeting the Cyclin-Dependent Kinase (CDK) Inhibitors
Drugs Targeting the Cyclin-Dependent Kinase (CDK) Inhibitors
The altered expression of cyclin-dependent kinases (CDK) is associated with the disproportionate
proliferation of malignant cells. The cell cycle is normally regulated by cyclin and
its regulatory partner, that is, CDKs. These CDKs are divided into two subgroups:
cell cycle CDKs and transcriptional CDKs. The altered expression of CDKs is associated
with the disproportionate proliferation of malignant cells. The cell cycle is normally
regulated by cyclin and its regulatory partner, that is, CDKs. These CDKs are divided
into two subgroups: cell cycle CDKs and transcriptional CDK.[12]
[13] The CDKs are the principal components of cell-cycle initiation and progression.
In various malignancies, increased expression of cyclin and CDKs is seen. Also, decreased
expression of endogenous CDK inhibitors and regulators such as CIP/KIP and INK4 is
recognized in various malignancies. According to Chang et al, the CDK1 gene expression
in OSCC was 17.2 times that of normal tissue. This overexpression is linked with malignant
behaviors. Chen et al observed that in patients having recurrent OSCC or lymph node
metastasis, CDK1 protein is overexpressed. The expression of CDK1 is considered a
prognostic indicator of OSCC survival.[14]
[15]
CDKs turn into natural targets for anticancer therapy as CDKs play a considerable
role in cellular transcription and cell-cycle regulation. Various studies enlighten
that CDKs inhibitors have therapeutic potential for various diseases like kidney diseases,
cancer, infectious diseases, and diabetes.[16]
Flavopiridol is the first CDK inhibitor that is used in human clinical trials. Flavopiridol
is a semisynthetic flavonoid-based CDKs inhibitor. It is observed that flavopiridol
inhibits cell proliferation by blocking G2/M and G1/S phases. Also, flavopiridol inhibits
the growth of OSCC cells in a dose-dependent and time-dependent manner. Mihara et
al observed that after exposure to flavopiridol, decreased expression of cyclin A,
cyclin B, CDK4, CDK1, and cyclin D was seen.[17]
[18]
Drugs Targeting the Vascular Endothelial Growth Factor and Its Receptor Inhibitors
Drugs Targeting the Vascular Endothelial Growth Factor and Its Receptor Inhibitors
Tumor angiogenesis plays a pivotal role in the growth and metastasis of tumors. Hence,
suppressing angiogenesis is advised to be efficient in the treatment of OSCC. The
vascular endothelial growth factor (VEGF) is known as a diffusible endothelial cell-specific
mitogen as well as an angiogenic factor. It is directly associated with increased
vascular permeability.[19] The VEGF is an important molecule in tumor angiogenesis and is highly expressed
in OSCC. Various agents that are counter to VEGF and its receptors consist of multikinase
inhibitors like vandetanib and sorafenib, or monoclonal antibodies like bevacizumab.[20]
[21]
Bevacizumab, a humanized monoclonal antibody, targets VEGF-A. It inhibits angiogenesis
and increases the distribution of chemotherapeutic agents to tumor cells by reducing
pressure within the tumor and by reducing microvascular permeability.
Bevacizumab inhibits biological activity that is mediated by VEGF by binding to VEGF
receptors, which in turn reduces tumor angiogenesis and thereupon suppresses tumor
growth. In a phase II study, it was observed that a combination of bevacizumab, cetuximab
plus cisplatin was well acceptable in phase III/IVB head and neck squamous cell carcinoma,
including OSCC.[22]
Sorafenib, a multitargeted and multikinase inhibitor, inhibits different targets like
Raf serine/threonine kinase, c-Kit, platelet-derived growth factor receptor β (PDGFR-β),
and VEGFR (vascular endothelial growth factor receptor) 1–3, by inhibiting the growth
and proliferation of tumor cells and also suppressing tumor angiogenesis.[23] By downregulating Mcl-1, it induces tumor cell apoptosis. Combination of sorafenib
along with radiation results in synergistic effects on OSCC cells by suppressing the
nuclear factor kappa B activity.[24]
[25]
The results of preclinical trials suggested that sorafenib in consolidation with chemotherapy
increases the antitumor effect by prohibiting cell growth, cell migration, and cell
invasion.[26]
[27] Sorafenib breaks the radio-resistance of head and neck squamous cell carcinoma by
prohibiting the repair of double-stranded DNA breakages.[28]
[29]
Vandetanib, a tyrosine kinase receptor, adequately inhibits the VEGFR-2 and EGFR tyrosine
kinase activities. The result of preclinical studies indicates that vandetanib inhibits
the proliferation of xenograft tumor cells that includes OSCC. Vandetanib along with
cisplatin and radiotherapy has the potential to conquer resistance to EGFR inhibitors
during pre-clinical trials.[30]
Sunitinib, a kinase inhibitor, targets the PDGFR, VEGFR, and c-Kit tyrosine kinase.
It is used for the treatment of imatinib-resistant gastrointestinal stromal tumors
and renal cancer. Monotherapy with sunitinib confirms unsatisfactory activity in the
palliative treatment of head and neck squamous cell carcinoma.[31]
[32] The combination of sunitinib with cetuximab results in reduced tumor cell proliferation
and increases in their differentiation.[33]
Drugs Targeting the Mammalian Target of Rapamycin Inhibitors
Drugs Targeting the Mammalian Target of Rapamycin Inhibitors
Mammalian Target of Rapamycin (mTOR) is a serine/threonine–protein kinase. Its function
is to control cell survival, the cell cycle, and proliferation. The PI3K/AKT signal
pathway shows a significant impact on the regulation of cell growth and cell proliferation.[34] As a subsequent molecule of the PI3K/AKT signal pathway, mTOR plays the principal
role in the development of tumor, metastasis, invasion, and angiogenesis. In a study
done by Liao et al, they observed that 85 patients out of 160 patients suffering from
tongue squamous cell carcinoma showed overexpression of phosphorylates mTOR.[35]
[36]
There are two types of mTOR inhibitors: first-generation inhibitors and second-generation
inhibitors. The first-generation inhibitors were developed from rapamycin. The rapamycin
forms a complex with cytoplasmic protein, that is, peptidyl-prolyl cis-trans isomerase
tacrolimus binding protein. The rapamycin analogs are temsirolimus and everolimus.
The second-generation mTOR inhibitors are PP242, Torin 1, and PP30.[37]
Temsirolimus is an intravenous drug used for the treatment of kidney cancer. Various
research studies or trials show that temsirolimus suppresses the proliferation of
head and neck squamous cell carcinoma.[38]
Everolimus, the derivative of rapamycin, is used as an immunosuppressant for the treatment
of kidney cancer. Various studies and trials show that everolimus has antiangiogenesis
and antitumor effects in the treatment of head and neck squamous cell carcinoma.[39]
[40]
Drugs Targeting the Epidermal Growth Factor Receptor
Drugs Targeting the Epidermal Growth Factor Receptor
Epidermal growth factor receptor (EGFR), a cytoplasmic transmembrane protein, belongs
to the human epidermal growth factor receptor tyrosine kinase family. It is generally
made up of transmembrane domains, extracellular ligand-binding domains, and intracellular
domains having tyrosinase kinase activity.[41] Various endogenous ligands are transforming growth factor-α (TGF-α), , neuregulin,
and epiregulin. When these endogenous ligands are attached to the extracellular domain
of EGFR, they form heterogeneous or homologous dimmers.[42] These dimmers triggered tyrosine kinases, which result in autophosphorylation of
tyrosine residue and afterward triggered various downstream signaling pathways like
phosphatidylinositol 3-kinase/ protein kinase B(PI3K/Akt) pathway and Ras-Raf-mitogen-activated
protein kinase pathway, which give rise to antiapoptosis, proliferation, metastasis,
and angiogenesis of tumor cells.[43]
It is observed that higher expression of EGFR receptor is seen in well-differentiated
and moderately differentiated tumors when correlated with high-grade tumors
At present, two types of drugs are used contrary to this target. These drugs are monoclonal
antibodies like cetuximab and nimotuzumab, and tyrosine kinase inhibitors (TKIs) like
erlotinib, gefitinib, and afatinib.[44]
[45]
The monoclonal antibodies act by binding to the extracellular domain of the EGFR that
inhibits the link between ligands and results in the inhibition of signal transmission
into the cell. Cetuximab is an immunoglobulin G1 (IgG1) monoclonal antibody that is
used as first-line treatment, in association with radiotherapy, for advanced head
and neck squamous cell carcinoma.[46]
Cetuximab can efficiently prohibit endogenous ligand-activated receptors by binding
to the extracellular ligand-binding domain of EGFR, which results in increased cell
apoptosis and lessened cell proliferation, metastasis, invasion, and angiogenesis.
Vermorken et al 2008 conducted a randomized phase III clinical trial in different
European countries. In their study, they observed that cetuximab when combined with
cisplatin extends progression-free survival (PFS) from 3.3 to 5.6 months (p < 0.001), the overall survival (OS) from 7.4 to 10.1 months, and increases tumor
response rate from 20 to 36% (p < 0.001).[47]
[48]
Cetuximab monotherapy for platinum-resistant recurrent or metastatic head and neck
squamous cell carcinoma shows a PFS of 2.2 to 2.8 months and a response rate of 10
to 13%.[49]
Nimotuzumab, a humanized IgG1 monoclonal antibody, is used in the treatment of head
and neck squamous cell carcinoma, nasopharyngeal cancer, and glioblastoma. In comparison
with cetuximab, it has a long half-life and moderate affinity, which substantially
lowers the side effects such as skin toxicity and immunogenicity. Nimotuzumab has
been directly involved in mediating antitumor effects by suppressing the survival,
proliferation, and angiogenesis of cancer cells. In a study done by Xu, he observed
that docetaxel–cisplatin and fluorouracil were added to nimotuzumab in the treatment
of patients with advanced oral cancer, and the efficacy of the combined treatment
group was 95%. In the case of the conventional chemotherapy group, the efficacy was
65%. No adverse reactions were seen in both groups.[50] These results proved that nimotuzumab in consolidation with chemoradiotherapy has
extensive high value in the treatment of OSCC.
Panitumumab is a human EGFR monoclonal antibody that is used as a first-line treatment
in patients with metastatic colon cancer. In a randomized phase III trial, a combination
of panitumumab with chemotherapy did not show any signs of OS of patients with metastatic
head and neck squamous cell carcinoma.[51] Gefitinib is the first oral EGFR-TKI. In vitro and in vivo research has concluded
that it could prohibit the proliferation of oral squamous cells in a time-dependent
and dose-dependent manner, which results in cell accumulation in the G1 phase, cell
cycle arrest, and cell decrease in the S phase.[52]
[53]
Erlotinib is one of the TKIs that is used in the treatment of oral cavity cancer.
In vitro studies prove the effectiveness of erlotinib, in a dose-dependent manner,
in the prohibition of the growth of tongue squamous cell carcinoma.[54] Erlotinib inhibits the G2/M transition and the intra-S phase of the cell cycle.
Erlotinib with cisplatin and radiation shows a synergistic effect in growth inhibition
of SCC-15 cells.[55]
Lapatinib, a TKI, shows specificity for EGFR. In various studies, it is seen that
lapatinib has an affinity for treating head and neck squamous cell carcinoma. Lapatinib
with capecitabine shows effectiveness in the metastatic form of head and neck squamous
cell carcinoma.[56]
[57]
Other Targeted Therapies
The activin receptor-like kinase 1 (ALK1) belongs to TGF-β and plays an important
role in angiogenesis. Dalantercept prohibits ALK1 signaling and is an antiangiogenic
agent.[58] The phase I study shows that dalantercept shows considerable ability as an anticancer
therapy in head and neck squamous cell carcinoma.[59]
Bortezomib, a proteasome inhibitor, is used for the treatment of mantle cell lymphoma
and multiple myeloma. Primary results show a 50% control rate in patients having metastatic
and recurrent head and neck squamous cell carcinoma while taking low-dose bortezomib.[60]
Endostatin, a definitive endogenous angiogenesis inhibitor, inhibits the binding of
VEGF to endothelial cells by adhering to integrin, heparin sulfate, and nucleolin
receptor on endothelial cells, which results in suppression of tumor cell proliferation
and angiogenesis.[61] Endostatin along with chemotherapy was efficient in the treatment of head and neck
squamous cell carcinoma.[62]
Conclusion
Targeted therapy highlights the treatment modalities of cancer at molecular level.
These therapies are extremely targeted and specific. As a likely new method, it is
universally used in treatment of OSCC. It is proclaimed that in future these targeted
therapies succeed the traditional methods and become choice of treatment for tumor
cases.
