Molecular targeted therapy of head and neck cancer: review and clinical development challenges

Recently, new targets have been identified in head and neck squamous cell carcinomas (HNSCC) as playing key roles in tumour proliferation and metastases. The first target that has led to the approval of a molecularly based therapy in HNSCC has been the epidermal growth factor receptor (EGFR). Indeed, cetuximab, a monoclonal antibody directed against EGFR, has recently been approved in combination with radiation therapy in patients with locally advanced HNSCC, and in patients with platinum-refractory recurrent or metastatic (R/M) HNSCC. This review discusses novel targeted anticancer agents that do not exclusively target EGFR. The initial assessments of novel agents have typically been in patients with heavily pre-treated R/M HNSCC, with response rates and times to progression that are often disappointing. Evaluation of novel agents in the pre-operative 'window' setting, or as first-line therapy for R/M disease, may offer a more optimal understanding of their molecular and clinical effects.     

Autophagic action of new targeting agents in head and neck oncology

The survival rates of patients with squamous cell carcinoma of the head and neck (HNSCC) have not improved significantly despite multi-modality therapy, including surgery, radiation therapy, and chemotherapy. Recently, molecular targeted agents have shown significant improvement in clinical outcomes; for example, in chronic myelogeneous leukemia with imatinib, breast cancer with trastuzumab, colon cancer with bevacizumab and cetuximab, and renal cell cancer with sorafenib and sunitinib. In HNSCC, the epidermal growth factor receptor antibody cetuximab has shown promising results in combination with radiation. Targeted agents including cetuximab induce stresses to activate prosurvival autophagy. Combining autophagy inhibitors with agents that induce autophagy as a prosurvival response may therefore increase their therapeutic efficacy. Whether autophagy contributes to the prosurvival response or to the antitumor effect of chemotherapeutic drugs is largely unknown. This review will discuss the possible role of autophagy as a novel target for anticancer therapy agents in HNSCC.     

Therapeutic targets in head and neck squamous cell carcinoma: identification, evaluation, and clinical translation

Head and neck squamous cell carcinoma (HNSCC) encompasses a diverse group of malignancies originating in the oral cavity, oropharynx, larynx and hypopharynx. Although treatment modalities have improved, carefully designed biomarker-driven clinical trials will yield the best opportunities to enhance HNSCC therapy options in the future. Due to the heterogeneous nature of HNSCC, discovering a "silver bullet" for the treatment of HNSCC is unlikely. Consequently, impactful HNSCC clinical trials will require multiple assay platforms and expanded technical expertise. In this review, we will outline pathways critical to HNSCC oncogenesis and highlight signaling nodes within these pathways that represent biomarkers for prognosis and potential targeted therapies. All treatment modalities are subject to mechanisms of resistance; thus, lessons learned from HNSCC investigations and studies of similar targeted agents in other pertinent malignancies will be discussed.     

Targeted therapy in head and neck cancer

Head and neck squamous cell carcinoma (HNSCC) of multi-factorial etiopathogenesis is rising worldwide. Treatment-associated toxicity problems and treatment failure in advanced disease stages with conventional therapies have necessitated a focus on alternative strategies. Molecular targeted therapy, with the potential for increased selectivity and fewer adverse effects, hold promise in the treatment of HNSCC. In an attempt to improve outcomes in HNSCC, targeted therapeutic strategies have been developed. These strategies are focusing on the molecular biology of HNSCC in an attempt to target selected pathways involved in carcinogenesis. Inhibiting tumor growth and metastasis by focusing on specific protein or signal transduction pathways or by targeting the tumor microenvironment or vasculature are some of the new approaches. Targeted agents for HNSCC expected to improve the effectiveness of current therapy include EGFR inhibitors (Cetuximab, Panitumumab, Zalutumumab), EGFR tyrosine kinase inhibitors (Gefitinib, Erloitinib), VEGFR inhibitors (Bevacizumab, Vandetanib), and various inhibitors of, e.g., Src-family kinase, PARP, proteasome, mTOR, COX, and heat shock protein. Moreover, targeted molecular therapy can also act as a complement to other existing cancer therapies. Several studies have demonstrated that the combination of targeting techniques with conventional current treatment protocols may improve the treatment outcome and disease control, without exacerbating the treatment related toxicities. Some of the targeted approaches have been proved as promising therapeutic potentials and are already in use, whereas remainder exhibits mixed result and necessitates further studies. Identification of predictive biomarkers of resistance or sensitivity to these therapies remains a fundamental challenge in the optimal selection of patients most likely to benefit from targeted treatment.     

Non-rash skin toxicities associated with novel targeted therapies

Many novel targeted agents have emerged against a variety of malignancies. Although papulopustular rash is the most commonly observed side effect associated with many of these agents, several non-rash skin toxicities have been identified that frequently result in the delay or discontinuation of anticancer therapy. These toxicities include skin hyperpigmentation, xerosis, pruritus, hair growth and color abnormalities, periungual and nail alterations, and hand-foot skin reaction. It is important to recognize these toxicities, so that they can be diagnosed early and treatment or dose modification can be initiated, if necessary. This review discusses several non-rash dermatologic toxicities observed with targeted therapeutic agents and guidelines for their diagnosis and treatment.     

抗EGFR单抗在转移性结直肠癌中耐药机制的研究进展

抗表皮生长因子受体（EGFR）单克隆单抗分子靶向药物在转移性结直肠癌中的应用,显著改善了患者无进展生存期及总生存期,由于迅速产生继发性耐药限制了其临床运用效果。因此,寻找生物标志物初步筛选敏感人群及预测耐药,以及研究分子靶向药物耐药机制的产生以逆转耐药,都是进一步提高转移性结直肠癌治疗效果的关键,目前靶向药物联合应用有望进一步提高治疗有效率并逆转耐药。     

Poly(ADP-ribose) polymerase inhibitors in cancer treatment: A clinical perspective

Inbuilt mechanisms of DNA surveillance and repair are integral to the maintenance of genomic stability. Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that plays a critical role in DNA damage response processes. PARP inhibition has been successfully employed as a novel therapeutic strategy to enhance the cytotoxic effects of DNA-damaging agents. We have shown that PARP inhibition has substantial single agent antitumour activity with a wide therapeutic index in homologous DNA repair-defective tumours such as those arising in BRCA1 and BRCA2 mutation carriers. This is the first successful clinical application of a synthetic lethal approach to targeting cancer. Exploitation of defects in DNA repair pathways through targeted inhibition of salvage repair pathways is an exciting anticancer approach, with potentially broad clinical applicability. Several PARP inhibitors are now in clinical development. This review outlines the biological function and rationale of targeting PARP, details pre-clinical and clinical data and discusses the promises and challenges involved in developing these antitumour agents.     

Nanotechnology assisted photo- and sonodynamic therapy for overcoming drug resistance

Drug resistance is considered the most important reason for the clinical failure of cancer chemotherapy. Circumventing drug resistance and improving the efficacy of anticancer agents remains a major challenge. Over the past several decades, photodynamic therapy (PDT) and sonodynamic therapy (SDT) have attracted substantial attention for their efficacy in cancer treatment, and have been combined with chemotherapy to overcome drug resistance. However, simultaneously delivering sensitizers and chemotherapy drugs to same tumor cell remains challenging, thus greatly limiting this combinational therapy. The rapid development of nanotechnology provides a new approach to solve this problem. Nano-based drug delivery systems can not only improve the targeted delivery of agents but also co-deliver multiple drug components in single nanoparticles to achieve optimal synergistic effects. In this review, we briefly summarize the mechanisms of drug resistance, discuss the advantages and disadvantages of PDT and SDT in reversing drug resistance, and describe state-of-the-art research using nano-mediated PDT and SDT to solve these refractory problems. This review also highlights the clinical translational potential for this combinational therapy.     

Current role of EGF receptor monoclonal antibodies and tyrosine kinase inhibitors in the management of head and neck squamous cell carcinoma

New agents and treatment strategies that can be safely and effectively integrated into current treatment paradigms for head and neck squamous cell carcinoma (HNSCC) are urgently needed. To date, the anti-EGF receptor (EGFR) monoclonal antibody, cetuximab, is the first and only molecularly targeted therapy to demonstrate a survival benefit for patients with recurrent or metastatic disease. Other anti-EGFR-targeted therapies, including monoclonal antibodies (e.g., panitumumab and zalutumumab) and reversible and irreversible ErbB family tyrosine kinase inhibitors (e.g., lapatinib, afatinib and dacomitinib) are being actively investigated in Phase II and Phase III clinical trials. In addition, validated biomarkers are needed to predict clinical benefit and resistance to anti-EGFR therapy in HNSCC. This review will compare and contrast the mechanisms of action of anti-EGFR monoclonal antibodies and tyrosine kinase inhibitors and also discuss their role in the management of HNSCC and the potential impact of human papillomavirus status in the development of these targeted agents.     

The levels of telomere-binding proteins in human tumours and therapeutic implications

Tumours require telomeric integrity to maintain viability, conferred by adequate length of telomeric DNA replenished by telomerase, and binding of telomere-binding proteins (TBPs), thus telomeres have received attention as an anticancer target. Levels of TBPs in tumour tissue may have implications for drug development if they render some cancers relatively more sensitive or resistant to telomere targeted agents. This review gives an overview of the studies examining the levels of TBPs in tumours and discusses possible reasons for differences in the findings, given the interplay between various factors determining telomere stability. Whether cancers with lower levels of TBPs will be more susceptible to therapies targeting telomere maintenance will require clinical trials of these novel therapies.     

Novel cytotoxic drugs: old challenges, new solutions

The discovery of cytotoxic agents was revolutionary for anticancer therapy in the last century, improving survival rates and the quality of life of patients with different types of tumours. However, the development of agents that combine efficacy, safety and convenience remains a great challenge, due to the narrow therapeutic index of some drugs, the fact that they may damage not only cancer cells, but also normal and healthy tissue and the occurrence of resistance, limiting anticancer efficacy. Novel cytotoxic agents have brought certain advantages over the conventional ones, such as shorter administration time, mechanisms to overcome drug resistance and lower incidence of adverse events. In this review we highlight the development of promising novel cytotoxic drugs that will hopefully offer not only gains in efficacy, but also in safety, tolerability and convenience in the treatment of patients with cancer.     

Recent advances of molecular targeted agents: opportunities for imaging

A number of agents targeting components of pathways and processes critical to neoplastic transformation and progression are ongoing clinical development. Notable successes include imatinib mesylate (STI571, Gleevec) in Chronic Myelogenous Leukemia (CML), and Gastrointestinal Stromal Tumors (GIST) and trastuzumab (Herceptin) in HER2 amplified breast carcinoma. More recently, gefitinib (ZD1839, Iressa) and bortezomib (PS-341, Velcade) have been approved for refractory nonsmall cell lung carcinoma (NSCLC) and multiple myeloma (MM), respectively. In addition, promising results from randomized studies of bevacizumab (Avastin) and cetuximab (IMC-225, Erbitux) have been reported and shortly may lead to their approval for the treatment of colorectal carcinoma (CRC). To what degree the success or failure of these agents has been due to target, the agent, the dose or the selection of patients is uncertain. Certainly, further evaluation of these factors is required to optimize the therapeutic impact of targeted agents and imaging modalities may play a vital role in this process. The purpose of this review is to summarize recent results from trials of selected targeted agents and to suggest roles imaging may play in the further development of these and other targeted agents.     

Therapeutic potential of thymoquinone in combination therapy against cancer and cancer stem cells

The long-term success of standard anticancer monotherapeutic strategies has been hampered by intolerable side effects, resistance to treatment and cancer relapse. These monotherapeutic strategies shrink the tumor bulk but do not effectively eliminate the population of self-renewing cancer stem cells (CSCs) that are normally present within the tumor. These surviving CSCs develop mechanisms of resistance to treatment and refuel the tumor, thus causing cancer relapse. To ensure durable tumor control, research has moved away from adopting the monotreatment paradigm towards developing and using combination therapy. Combining different therapeutic modalities has demonstrated significant therapeutic outcomes by strengthening the anti-tumor potential of monotreatment against cancer and cancer stem cells, mitigating their toxic adverse effects, and ultimately overcoming resistance. Recently, there has been growing interest in combining natural products from different sources or with clinically used chemotherapeutics to further improve treatment efficacy and tolerability. Thymoquinone (TQ), the main bioactive constituent of Nigella sativa, has gained great attention in combination therapy research after demonstrating its low toxicity to normal cells and remarkable anticancer efficacy in extensive preclinical studies in addition to its ability to target chemoresistant CSCs. Here, we provide an overview of the therapeutic responses resulting from combining TQ with conventional therapeutic agents such as alkylating agents, antimetabolites and antimicrotubules as well as with topoisomerase inhibitors and non-coding RNA. We also review data on anticancer effects of TQ when combined with ionizing radiation and several natural products such as vitamin D3, melatonin and other compounds derived from Chinese medicinal plants. The focus of this review is on two outcomes of TQ combination therapy, namely eradicating CSCs and treating various types of cancers. In conclusion, the ability of TQ to potentiate the anticancer activity of many chemotherapeutic agents and sensitize cancer cells to radiotherapy makes it a promising molecule that could be used in combination therapy to overcome resistance to standard chemotherapeutic agents and reduce their associated toxicities.     

Dynamic survivin in head and neck cancer: molecular mechanism and therapeutic potential

Although disease management of head and neck squamous cell carcinomas (HNSCC) has improved significantly, therapy resistance leading to tumor recurrence still counteracts improvement of long-term survival. Consequently, identification of molecular markers that signal increased risk of treatment failure or, which can be exploited by targeted therapy, is urgently needed. Survivin is strongly expressed in HNSCC, and its proposed dual role as an apoptosis inhibitor and a mitotic effector positioned survivin in the front line of cancer research. Notably, survivin is detected as a cytoplasmic and as a nuclear protein in HNSCC patients, which stimulated numerous studies to investigate and to speculate on the functional and prognostic significance of its dynamic localization. This review focuses on our current understanding of the molecular mechanisms regulating survivin's intracellular localization and discusses its potential prognostic and therapeutic relevance for head and neck cancer.     

TGF-β信号通路与肿瘤耐药相关性研究进展

肿瘤对化疗药耐药是目前影响患者预后的重要因素,近年文献报道TGF-β信号通路与化疗耐药有关,并可通过调控TGF-β信号通路抑制耐药。本文就TGF-β信号通路与肿瘤耐药相关机制作一综述。     

Targeted therapies for advanced non-small-cell lung cancer: current status and future implications

Lung cancer remains the leading cause of malignancy-related mortality worldwide, with over one million cases diagnosed yearly. Non-small-cell lung cancer (NSCLC) accounts for >80% of all lung cancers. Because lung cancer is typically diagnosed at an advanced stage, chemotherapy (CT) is the mainstay of management. Conventional treatment of NSCLC has apparently reached a plateau of effectiveness in improving survival of patients, and treatment outcomes must still be considered disappointing. Hence, considerable efforts have been made in order to identify novel targeted agents that interfere with other dysregulated pathways in advanced NSCLC patients. In order to further improve the results of targeted therapy, we should not forget that lung cancer is a heterogeneous disease with multiple mutations, and it is unlikely that any single signaling pathway drives the oncogenic behaviour of all tumours. The relative failure of some targeted therapies may be a result of multilevel cross-stimulation among the targets of the new biological agents along several pathways of signal transduction that lead to neoplastic events. Thus, blocking only one of these pathways allows others to act as salvage or escape mechanisms for cancer cells. We summarize the most promising research approaches to the treatment of NSCLC, with particular attention to drugs with multiple targets or combining targeted therapies.     

Multimodal approach using oncolytic adenovirus,cetuximab, chemotherapy and radiotherapy in HNSCC low passage tumour cell cultures

Head and neck squamous cell carcinoma (HNSCC) is a common and often devastating disease without curative treatment when advanced or recurrent. The aim of this study was to assess whether capsid-modified oncolytic adenoviruses have therapeutic efficacy in HNSCC low passage tumour cell cultures and if it could be further improved by combination with cetuximab, radiotherapy and chemotherapy. We investigated which adenoviral capsid modifications allow best gene transfer and cell killing of HNSCC substrates. Gene transfer was assessed using replication-deficient adenoviruses expressing luciferase. Cell killing was studied in vitro and in vivo using oncolytic adenoviruses, which kill tumour cell by viral replication. The most effective capsid-modified oncolytic adenoviruses were combined with HNSCC standard therapies and their efficacy was assessed in vitro as well as in vivo. Cell killing was assessed in vitro by MTS assay and in vivo by HNSCC subcutaneous tumour growth follow-up in nude mice. Cetuximab treatment was found to enrich CD133+ and CD44+ tumour-initiating type cells in tumours grown in mice. Capsid-modified viruses showed increased transduction and oncolysis of HNSCC substrates in comparison to Ad5-based agents. Polylysine (pK7)-modified oncolytic virus resulted in significant tumour growth reduction in vivo. Combination of chemotherapy (cisplatin and 5-fluorouracil), radiotherapy and cetuximab with oncolytic adenovirus therapy resulted in further increases in cell killing effect in vitro and complete eradication of tumours in vivo. Our pre-clinical data suggest that it is feasible and efficacious to combine oncolytic adenoviruses with HNSCC standard therapies into a multimodality treatment regimen for clinical testing in HNSCC patients.     

Statins are logical candidates for overcoming limitations of targeting therapies on malignancy: their potential application to gastrointestinal cancers

Purpose

Molecular targeting approaches have been an intensive focus of treatment strategies against advanced gastric and colorectal cancers. Recent clinical trials have demonstrated promising survival prolongation of targeted human epidermal growth factor receptors; however, patients harboring mutations in the K-Ras gene (human homolog of the Kirsten rat sarcoma-2 virus oncogene) do not derive benefit from the anti-epidermal growth factor receptor antibodies. K-Ras mutations cause a stimuli-independent activation of a large cohort of downstream effectors that permit cells to acquire a sustained growth. The perpetuated growth activation manifests resistance to molecular targeting therapies.

Methods

Literature review has been made to explore the possibilities that, given that K-Ras or downstream effector proteins require farnesyl or geranylgeranyl moiety for their activity (e.g., prenylation), statins are logical candidates to overcome the limitations of or to potentiate the effect of molecular targeting therapies as statins suppress the mevalonate pathway leading to depletion of an end product of mevalonate such as farnesylpyrophosphate and geranylgeranylpyrophosphate, which are used as substrates by their respective transferase enzyme for protein prenylation, and ultimately impair functions of K-Ras and downstream effector proteins.

Results

In the last few years, statins have gained interest in therapeutic value for anticancer treatments extending beyond their lipid-lowering effects as single agents or in combined use with other chemotherapeutic agents. This review provides insights into possible anticancer mechanisms of statins and introduces current achievements or ongoing studies of statins in the field of cancer treatment in single or combined uses. This review also offers information to help establish optimal treatment schedules of statins that overcome current limitations of molecular targeting therapies.

Conclusions

It is expected that therapeutic scope of statins will expand considerably in the future as anticancer agents in addition to their proven benefits of hyperlipidemia.     

Cancer Stem Cells and Stemness Markers in Oral Squamous Cell Carcinomas

Head and neck squamous cell carcinoma (HNSCC) is one of the world top ten most common cancers withits highest occurrence in the Indian subcontinent and different aggressive and etiological behavioural patterns.The scenario is only getting worst with the 5 year survival rates dropping to 50%, persistent treatment failuresand frequent cases of relapse/recurrence. One of the major reasons for these failures is the presence of cancerstem cells (CSCs), a small population of cancer cells that are highly tumourigenic, capable of self-renewal andhave the ability to differentiate into cells that constitute the bulk of tumours. Notably, recent evidence suggeststhat cancer stem cells are especially resistant to conventional therapy and are the “drivers” of local recurrenceand metastatic spread. Specific markers for this population have been investigated in HNSCC in the hope ofdeveloping a deeper understanding of their role in oral cancer pathogenesis, elucidating novel biomarkers forearly diagnosis and newer therapeutic strategies. This review covers the fundamental relevance of almost all theCSC biomarkers established to date with a special emphasis on their impact in the process of oral tumourigenesisand their potential role in improving the diagnosis, prognosis and treatment of OSCC patients.