A Concise Review on Targeted Therapy for Oral Cancer

Thariny E1, Ezhilarasan D*2, Brundha M.P.3 1Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai-77, Tamilnadu, India 2Department of Pharmacology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai-77, Tamil Nadu, India 3Department of General Pathology, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai-77, Tamilnadu, India


INTRODUCTION
Oral cancer is a life-threatening disease which forms tumours in the head and neck area. According to the International Agency Research Cancer-World Health Organisation evaluates that the oral cancer rate has been increased from 10 million to 15 million cases in 2020. The etiological factors which cause oral cancer include tobacco use, change of lifestyle and diet, alcohol intake, viral infections, occupational risk, and genetic factors. Educational and inancial services concentrate on high-cost, highmorbidity, and unnecessary high-mortality procedures in the global population. Oral cancer can strike mental and physical health, social and personal life. This disease can severely affect the normal functioning of the body, which decreases the quality of life of an individual. The traditional method of treatment, which includes surgical procedures and chemotherapy rely on the tumor location, and on the feasibility of organ preservation. However, their function in treating oral cancer is non-selective and can harm normal tissue Chemoradiotherapy, in particular, is associated with systemic toxicity that also decreases patient commitment and prevents treatment from being completed on time. Developing targeted therapies to target chosen pathways. The targeted cancer therapies are medications which inhibit cancer development by obstructing the speci ic molecules that intricates the progression of tumors (Williams, 2010).
The targeted therapy drugs mainly aim at selective inhibition of the molecules and the cells which cause the changes in oral cancer. Target therapy can be successful than the conventional treatments and fewer noxious to normal cells in the body. These targeted molecules are normally present in the cell but in case of cancer, they get mutated or overexpressed. Newer studies are going for better understanding of the mechanism in inhibiting the tumor proliferation by particularly targeting the proteins or signalling pathway that aids in the progression of cancer without affecting the normal cells (Du et al., 2014).
Targeted therapy with small and monoclonal antibodies can serve as an alternative for chemotherapy, radiotherapy, etc., in treating oral cancer. This therapy also has a few side effects on normal body cells. While these targeted therapies are selective, they can have signi icant unwanted changes which includes skin rashes, abnormal organ function. The drug delivery system also plays a major role in exhibiting the result of targeted therapy. This therapy speci ically induces cell death by induction of apoptosis or by evoking the immune system indirectly for the deduction and elimination of abnormal cells and their harmful products. Targeted therapy through small molecule drugs by oral administration can spread into cells and function on targets within the cell. Another type of targeted cancer therapy is mAbs.
Such medications are given in a parenteral fashion, however, because they are protein in nature and vulnerable to degradation by the intestinal mucosa. Some monoclonal antibodies are guided to target the outside surface of the cell since they are not able to perforate the membrane of the cell. There are multiple modalities of treatment used to treat cancer, including chemotherapy, immunotherapy, radiation therapy, cryosurgery, and hormone therapy. Owing to its limited side effects, targeted therapy has gained popularity over all other cancer therapies (Nagao, 2020).
Chemotherapy is a method of anti-cancer treatment in which cancer proliferating cells are destroyed by using powerful chemicals. But this treatment can cause adverse effects like hair loss, dry skin, anaemia, weight loss, sores and neurological disorders in which it causes dysfunction of the brain leading to mood swing, impair attention and concentration (Oun et al., 2018).
Immunotherapy is another treatment in which it boosts the immune system to ight against the cancerous cells. This may also cause side effects like edema of a leg due to luid retention, dyspnea, congestion of sinus, etc., Hormone therapy is a type of hormonal therapy that aims to add, block or remove hormones from the body to terminate the cancer growth. Side effects include gaining of weight, memory problems, thinning of hair and abnormal changes in bones and muscles (Patil, 2020).
Cryosurgery is a kind of surgery requiring the use of intense cold to kill abnormal tissues, such as tumors. Side effects Swelling, Scarring, Lack of feeling for 12 to 18 months in the treatment area, lack of pigmentation, loss of hair in the treatment area. Cancer radiation therapy involves skin problems because of powerful radiation beams to kill the side effects of cancer cells. At the same time, it causes a high cytotoxic effect on the cells. It may also cause burning dry skin with peeling experience. Fatigue describes a feeling almost invariably tired or drained. Targeted therapy also plays a pivotal role in dentistry, as it reduces oral cancer proliferation and metastasis, thereby reducing mortality and morbidity rates. To date, nearly 30 drugs in targeted therapy have been accepted for treating a wide range of forms of human cancer in clinical use, separately or in combination with any other treatment like chemotherapy. Targeted therapy can be more effective when combined with chemotherapy or immunotherapy that has a supra-additive effect (Dinardo, 2018).
The purpose of this review is to give a clear explanation of its method of targeted therapy and its impact on oral cancer in order to provide advanced cancer cure care.

MATERIALS AND METHODS
Oral cancer develops in the head and neck area, which includes the mucous membrane of the mouth and throat. There are many types of cancer among which oral cancer stands at 6 th position worldwide. Alcohol consumption and smoking have a vital role in the cause of oral cancer. However, there is growing evidence in some patients, human papillomavirus is also considered as one of the etiological factors in causing oral cancer which is associated about 20% with oral cancer (Stefani, 2002).
Currently, the treatment for oral carcinoma includes postoperative radiotherapy surgery, surgical removal of tumor, radiation therapy along with surgery, radiation therapy alone and chemotherapy together with additional treatments. Such traditional treatment approaches are nevertheless correlated with serious side effects of this type of Mucositis caused by radiation, and loss of organ function as systemic toxicity. Thus, the oncology branch focuses on understanding OSCC's molecular basis for targeting selective pathways involved in carcinogenesis. Oral cancer occurs as a change in 2 factors, in alteration of DNA or RNA (Marcazzan et al., 2018).

Molecular Alterations in Oral Cancer
In OSCC molecular alterations were divided into changes to DNA pro iling and changes in RNA proiling. Changes to DNA pro iling includes Oncogenic changes and Tumor Suppressor Gene Alterations(TSG). Oncogenes are genes associated with tumors present in all types of those cancers. For carcinogenesis to occur, it is necessary to alter or mutate either one or more of the oncogenes in a cell to activate the pathways. These proto-oncogenes include primarily cell proliferation and growth. Epidermal growth factor (EGFR) is a glycoprotein present in the transmembrane with tyrosine kinase activity which contributes a major role in controlling the growth and survival of cancerous cells. Cyclin D1 Which is encoded by gene CCND1 controls the growth of the tumor. RAS mutations are signi icant in which they show resistance to inhibitor therapy of EGFR. Melanomas, some gliomas, thyroid carcinoma expresses BRAF gene (Pracht and Berthold, 2014). Tumor suppressor gene gets altered or mutated to make the carcinogenesis pathway get activated. The p53 gene located on chromosome 17p13 was one of the familiar tumor proteins related to head and neck cancer. Some of the genetic changes in oral cancer includes deletion, ampli ication and point mutation; Tumor suppressor gene CDKN2A most commonly gets inactivated by deletion or methylation. Alterations in RNA pro iling include tumor cells that are advanced with capability in analysing the messenger RNA which are abnormally expressed (over or under-expressed), are identi ied by microarray RNA pro iling (Suda and Mitsudomi, 2014).

About targeted therapy
Drugs used in targeted therapy tend to obstruct the proliferation of cancer cells and the spread of cancer via particular molecules. It was irst performed to illustrate the capacity of the drug that speci ically aims at microorganism. However, now it serves as a treatment for oral cancer. The success of targeted therapy treatment lies in identifying the correct goal for the eradication of cancer.
The genetic modi ication leading to mutation and receptors facilitating cell survival and proliferation is one of the bases of cancer incidence. Genome sequencing can be used to identify the cancer markers which aids the researchers to differenti-ate between normal and neoplastic cells to recognize improvements in the sequencing of signals technology can sequence a wide range of cancerous genomes to expose genetic heterogeneity between a normal and abnormal cell in a person. This is important in determining the effective drug production against the aim targets. Targeted therapy has targets to control the disease which includes growth factors like VEGF, EGFR etc., molecules in signalling, protein in the cell cycle, apoptosis controller and molecule that promotes angiogenesis (Gotwals et al., 2017).

Mechanism of action
The therapeutic drugs used in targeted therapy can show various biological properties. These drugs operate upon the targets that are selected to control the progression of new cell formation leading to abnormal proliferation of cells. Drugs in targeted therapy can congest the signals which promote the growth of neoplastic cells, interfere with the regulation of cell cycle, instigate apoptosis to destroy neoplastic cells. The immune mechanism is stimulated by attacking the cancerous cell, along with the constitutions of the microenvironment of the tumor (Sawyers, 2004).

Small molecules
The small molecules characterized by comparatively low molecular weight capable of penetrating through cells; Targeting speci ic protein inside the cell. Most of the small molecule inhibitors inhibit the kinase and interrupt the signals that enable carcinogenesis. Enzymes like cyclin-dependent kinase, poly ADP ribose polymerase (PARP) inhibitor are targeted by the small molecules in order to activate apoptosis, checkpoints in the cycle (Ke and Shen, 2017).

Monoclonal antibodies
Monoclonal antibodies (mAbs) are usually targeted toward the cell surface from outside because they cannot go into the cell as they are large in size. mAbs directly target the protein outside the cell and terminate the human proliferation by communicating with the receptor and ligand. After binding to the cancer cell, the small molecule acts either by direct or indirect mechanism. The direct mechanism usually involves the binding of small molecules through receptors of cells, proteins on the membrane and antigens leading to cell death.

Cancer vaccines
Cancer vaccines react by immune responses that are mediated to produce anti tumor effects that are differentiated into the patient-speci ic type and non-patient speci ic type. In patient-speci ic type, the vaccines are obtained from the tumor cells of the patient itself, while nonspeci ic are generated by generalizing and immunological effects which exhibit an anti-tumor activity in a small group of patients (Ezhilarasan et al., 2018).

Gene therapy
Gene therapy works by inculcating the genetic material like DNA or RNA into neoplastic cells to suppress or prevent the development. The bene its of selective molecular therapy are its capacity to deliver drugs effectively-highly speci ic, but less harmful than traditional chemotherapy. Common adverse effects of this treatment are rashes, low blood pres-sure, proteinuria, pigmentation defect and hepatotoxicity. The side effects occur in normal cells due to abnormal regulation of inhibited molecules (Curran, 2007).

Intervention of targeted therapy in oral cancer
Targeted therapies using small-molecule inhibitors are as follows. Molecules that underwent clinical trials for oral cancer by targeted therapy is mentioned in (Table 1).

EGFR inhibition (Ge itinib and Erlotinib)
EGFR upregulation is not only seen in cancerous tissue but also in normal tissue adjacent to it. This concept is called ield cancerization, which is de ined as a multifocal growth of precancerous or cancerous lesion during the carcinogenic epithelial exposure.

EGFR directed mAbs (Cetuximab, Panitumub, and Zalutumumab)
Putative mechanisms of anticancer behaviour dependent on the EGFR mAb are divided into groups. In the irst group, the extracellular domain of EGFR is prevented from binding with ligands which may sequentially lead to degradation of the respective receptor. The second group attach to the EGFR indirectly by evoking the immune system, which induces cytotoxicity mediated by antibody, complimentary system and complimentary cell-dependent mechanism. mTOR (Rapamycin Everolimus and Temsirolimus), and PARP (Poly (ADP-ribose)-Iniparib and olaparib. Cetuximab is the only targeted molecule that is approved for HNSCC treatment by the Food and Drug Administration (FDA). According to the FDA guidelines, this medicinal product is approved for use under the following conditions locally or regionally advanced HNSCC in combination with radiation therapy, recurrent locoregional disease or metastatic HNSCC in combination with 5-FU platinum-based therapy and recurrent or metastatic progression of HNSCC after Platinum Therapy.

Tyrosine kinase inhibitors
Sorafenib, Sunitinib, Lapatinib EGFR tyrosine kinase inhibitors show the conceptual bene its of stopping signal activation of cytoplasm as well when compared with agents that block extracellular activation.

BCR-ABL inhibitors
Imatinib was the irst discovered target in targeted therapy to treat chronic myeloid leukemia. It prevents the chromosomal translocation of the BCR-ABL protein kinase (Lee et al., 2018).

Inhibition of growth inhibitory signals
In the normal state, the cell growth and death are maintained by tumor suppressor gene but incase of cancer the tumor suppressor gene gets mutated, leading to uncontrolled proliferation of cells, ultimately leading to the neoplastic condition.

Initiators of apoptosis
Apoptosis may be initiated by triggering an intracellular and extracellular pathway. After the activation of caspase and cascade, destruction of cells occurred by enzymes released from these processes. Alteration in apoptosis good leads to avoidance of programmed cell death and can serve as a possible target for targeted therapy.

PD-1 inhibitors
The monoclonal antibody Nivolumab (Opdivo) prevents apoptotic protein 1 and affects the PD-1 interaction with ligands. PD-L1 and PD-L2 are the two types of ligands (Gupta and Others, 2017).

Angiogenesis inhibitors (Bevacizumab and Vandetanib)
The growth factor of the endothelial vascular cells has a strong capacity to induce neovascularization and proliferation of neoplastic cells. About 40 percent of cancer exhibited vascular endothelial growth factor. The kinase inhibitors HNSCC, sunitinib, sorafenib, and pazopanib affect several pathways involved in the development of malignant tumours. It blocks the vascular spread of neoplasm, besides blocking tyrosine kinase pathways.

Inhibitors of tissue invasion and metastasis
Doxycycline has various inhibitory effects for the production and activity of MMP. Cyclooxygenase-2 is one of the factors which are abnormally expressed in the malignant condition in head and neck cancer. Celecoxib selective COX-2 inhibitors do away with tumor development in experimental models.

Carcinoembryonic antigen
CEA de inition is not commonly accepted in head and neck cancer. CEA is a potential target for speci ic HNSCC immunotherapy through vaccines (Hamakawa, 2008).

Mechanism of targeted therapy drugs on oral cancer
The occurrence of head and neck cancer is a multistage disease that results in carcinogenesis. Clonal cell spread causes genomic instability identi ied by biomarkers, oral premalignant lesion measurement, and intraepithelial neoplasia.
ABT-263 (Navitoclax) substantially increased rates of expression of the C / EBP-homologous protein and its messenger RNA, leading to programmed cell death in four different cell lines originating from human oral cancer (Yang, 2019).
A small-molecule Ge itinib and inhibitor of tyrosine kinase was effective in cancer treatment. A clinical trial (Phase II) documented a good activity and showed an improvement in the health of patients with recurrent cancer in head and neck.
Erlotinib is orally administered small-molecule against EGFR. Erlotinib mainly inhibits the tyrosinekinase. A clinical phase trial (I / II) revealed the erlotinib with cisplatin and radiotherapy was effective in locally advanced HNSCC.
Treatment with PI-828 and PI-103 exhibited growth inhibition and growth of OSCC cells with associated changes in the regulation of cell cycle, apoptosis induction, and reduced invasiveness of the epithelium (Aggarwal, 2019).
Patients suffering from oral cancer caused by human papillomavirus can be treated with pemetrexed/etoposide separately, or in conjugation with cisplatin, a chemotherapeutic drug, can serve as an effective drug in oral cancer and an alternate may be used as novel alternatives in a for concurrent chemoradiotherapy. However, further investigations are still needed.
Recent studies revealed numerous targeted therapy drugs such as bortezomib, vorinostat, resveratrol, and colchicine can be used as a potential chemotherapeutic drug in treating oral cancer.
In vitro and in vivo study showed that the photo thermal therapy, photo dynamic therapy along with chemotherapy produced a synergistic outcome, thereby signi icantly improving therapeutic effectiveness compared to cancer monotherapy. Previous research also reported an elevated level of SPARC cystine which causes head and neck cancer and CAF (chemotherapeutic combination cyclophosphamide, doxorubicin hydrochloride (adriamycin) and luorouracil).
Powerful antioxidant astaxanthin (AXT) causes inhibition of PI3K / Akt and downregulation of NF-ÿB and STAT-3 signaling pathways in an oral neoplastic cell which is demonstrated in the cell line of hamster buccal carcinogenesis model (Kowshik, 2019).
Drugs preventing neovascularization in oral cancer include nimotuzumab and cetuximab, and EGFR inhibitor aids in the prevention of invasion and migration in epithelial cells during carcinogenesis. Chlorine e6-Photo dynamic therapy along with these drugs, can decrease the growth of tumor cells in various endothelial cancers.
Celastrol induced apoptosis of cells by the downregulation of Bcl-2 expression, not Bcl-xL. Celastrol mainly aime at hindering JNK I/II signalling, which is the main pathway for apoptosis (Lin, 2019).
An animal study with nude mice demonstrated knockdown xenografting cancer with reduced cell growth and a high level of apoptosis with AKT dephosphorylation after chemotherapy with S-1.
8αTGH extracted from V. cinerea induces the inhibition of STAT2 and STAT3 phosphorylation, the arrest of M phase of the cycle, thereby reducing the growth of neoplastic cells (Pouyfung et al., 2019).
BRCA2 knockdown using low inhibiting RNA suppression elevated the human oral cells more sensitive (SAS and HSC3) to 5-FU (Nakagawa, 2014).

outcomes of targeted therapy in oral cancer
A monoclonal antibody drug bevacizumab acts against vascular endothelial growth factors which give rise to poor wound healing and stomatitis. Some of the common adverse effects caused by VEGF inhibitors are aphthous-like ulcers. Platelet-Derived Growth Factor can cause dysgeusia. Mucositis and peripheral neuritis is caused by HERS, trastuzumab. Sorafenib can alter the taste sensation, causing dysgeusia.
The targeted therapy provides better treatment with minimal side effects compared to other treatments for cancer. It is noted for 3 main outcomes, namely, locoregional tumor control without affecting other organs, disease-free survival by cancer cell eradication, to its core, and quality of life by providing a cure in such a way that the disease does not occur in an individual (Mehta, 2019).

CONCLUSIONS
Targeted therapy in the medicinal ield could serve as an effective platform in treating cancer. By inculcating this method of treatment in oral cancer may produce predictable effects without harming the normal function of the body. Targeted therapy can also be combined with other anticancer therapies which could bring a synergistic effect. The main advantage of this targeted therapy is that it concentrates only on the affected cells by identifying their receptors; thereby, it does not produce any severe side effects as seen in chemotherapy or radiotherapy. Thus, the result greatly suggests that the effectiveness of targeted therapy has been taken into account and extended to improve oral disease care strategies in dentistry in order to provide effective care.