Current Cancer Drug Targets

ISSN: 1568-0096

Current Cancer Drug Targets
Volume 7, Number 7, November 2007

Contents

Recent Advances in Molecular Targeting of Head and Neck Cancer
Guest Editor: Dong Moon Shin, M.D.


Editorial Pp. 605


Pathobiology of Head and Neck Squamous Tumorigenesis Pp. 606-612
Adel K. El-Naggar
[Abstract]


Exploration of Metastasis-related Proteins as Biomarkers and Therapeutic Targets in the Treatment of Head and Neck Cancer Pp. 613-622
Zhuo (Georgia) Chen
[Abstract]


Current Status and Future Perspectives of Chemoprevention in Head and Neck Cancer Pp. 623-632
Carmen M. Klass and Dong M. Shin
[Abstract]


Anti-Tumor Vaccines in Head and Neck Cancer: Targeting Immune Responses to the Tumor Pp. 633-642
Theresa L. Whiteside
[Abstract]


Targeting Angiogenesis in Head and Neck Cancer Pp. 643-649
Nabil F. Saba, Dong M. Shin and Fadlo R. Khuri
[Abstract]


EGFR-Targeting Monoclonal Antibodies in Head and Neck Cancer Pp. 650-665
Igor Astsaturov, Roger B. Cohen and Paul Harari
[Abstract]


Treatment of Squamous Cell Carcinoma of the Head and Neck in the Metastatic and Refractory Settings: Advances in Chemotherapy and the Emergence of Small Molecule Epidermal Growth Factor Receptor Kinase Inhibitors Pp. 666-673
Syed M. Ahmed and Ezra E.W. Cohen
[Abstract]


Recent Advances in Combined Modality Therapy for Locally Advanced Head and Neck Cancer Pp. 674-680
Lori J. Wirth and Marshall R. Posner
[Abstract]


General Articles


Recent Approaches in Chemoprevention of Prostate Cancer Pp. 681-688
Charles Y.F. Young
[Abstract]


Targeting MDM2 and MDMX in Retinoblastoma Pp. 689-695
Nikia A. Laurie, Chie Schin-Shih and Michael A. Dyer
[Abstract]




Abstracts


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Editorial

The incidence of squamous cell carcinoma of the head and neck (SCCHN) is expected to reach approximately 45,000 new cases and nearly 12,000 deaths in the United States, and more than 600,000 cases worldwide in the year 2007. The majority of patients who develop this disease are middle-aged males who have a history of tobacco and/or alcohol use. However, there has been an alarming increase in the number of patients with this disease who are under 40 years of age and do not have significant tobacco or alcohol related history. This younger population may have other associated etiologies including human papillomavirus (HPV).

More than two-thirds of SCCHN patients will present with locally and regionally advanced disease, and their prognoses are dismal. For these advanced SCCHN cases, aggressive surgical procedures are technically feasible and frequently required, but they result in significant long-term anatomic, functional, physiologic and/or cosmetic sequallae in the surviving patients. This has led to the development of organ preserving treatment strategies.

In contrast to the poor prognosis of patients with advanced disease (stage III or IV), SCCHN is a potentially curable malignancy when diagnosed at an early stage (stages I/II). Therefore, early detection of this disease is a very important strategy to increase survival. Furthermore, the prevention of invasive cancer is even more critical in decreasing the incidence of the disease. Multidisciplinary approaches using surgery, radiation therapy, chemotherapy, or combined modalities have proven to be effective treatments for advanced disease, albeit with significant toxic effects. Recently developed molecularly-targeted agents alone or in combination with conventional treatment modalities are very important strategies to minimize toxicity and maximize treatment effects.

Included in this issue of Current Cancer Drug Targets are articles that address important issues regarding cancer prevention, molecularly-targeted therapy, induction chemotherapy and concurrent chemo-radiation therapy to reduce the incidence of this disease and provide effective treatments. These articles discuss epidermal growth factor receptor (EGFR) antibodies while focusing on their biology, their use with radiation therapy, and the use of cetuximab or erbitux in particular, with or without chemotherapy. Also, EGFR tyrosine kinase inhibitors alone or in combination with chemotherapy are important strategies to improve the outcome of therapy, and are considered within. Another area touched upon in this issue is angiogenesis in SCCHN with an approach to treatment with anti-angiogenesis agents. We also focus on reviewing the recent advances in chemotherapy, particularly for locally advanced disease as induction chemotherapy with concurrent chemo-radiation in previously untreated patients and post-operative settings. Other areas covered include immunology and vaccine development for head and neck cancer and also an understanding of invasion and metastasis as well as biomarkers, pathology, and biology in head and neck cancer. Finally, to decrease the incidence of SCCHN, prevention approaches are critical, which we address by reviewing chemoprevention strategies with novel compounds.

In conclusion, this series of review articles is intended to provide readers with a timely review of the recently developed multimodality therapies and molecularly-targeted agents in head and neck cancer and perhaps stimulate new thinking and shape future investigation in this important area of research.


Dong Moon Shin, M.D.
Emory University School of Medicine,
Winship Cancer Institute,
1365-C Clifton Road,
Atlanta, GA 30322, USA
E-mail: dong.shin@emoryhealthcare.org


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Pathobiology of Head and Neck Squamous Tumorigenesis
Adel K. El-Naggar

Head and neck squamous epithelial carcinogenesis is a complex multistep process that entails a progressive acquisition of alterations in diverse vital cellular pathways. The nature of these alterations and the order of their occurrence have remained unresolved. In the past 15 years, the thrust of research in this field has centered on the epithelial genetic and/or epigenetic changes attendant to their development and progression. Little efforts, however, have been expended on changes in structural or host microenvironment and their role in these tumors. Only recently has the latter topic become the focus of attention. This review will address recent advances in both cellular and structural findings in head and neck squamous carcinoma development and progression. Targeting these events for biological and therapeutic approaches is a desirable goal for future effective treatment of patients with this cancer.


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Exploration of Metastasis-related Proteins as Biomarkers and Therapeutic Targets in the Treatment of Head and Neck Cancer
Zhuo (Georgia) Chen

Head and neck (HN) cancer is a significant health-care problem worldwide. One of the major prognostic factors for squamous cell carcinomas of the head and neck (HNSCC) is metastasis. Early detection of lymph node metastasis and the identification of key protein targets for the treatment of metastatic HNSCC remain a challenge in current cancer research. Recent developments in molecular analysis technologies, such as DNA microarray and proteomic analyses, have provided powerful tools for the detection of metastatic signatures in primary tumors, opening new avenues toward the molecular diagnosis and prognosis of HN cancers. Evaluation of gene expression profiling identified in metastatic signatures has further facilitated the understanding of HNSCC metastasis at the molecular level. This review will focus on current exploration of metastatic proteins in HNSCC with an emphasis on molecular signatures of metastatic HNSCC in order to understand the functions of metastasis-related proteins involved in adhesion, invasion, dissemination, and survival, and to define appropriate biomarkers and targets for the treatment of this disease.


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Current Status and Future Perspectives of Chemoprevention in Head and Neck Cancer
Carmen M. Klass and Dong M. Shin

The incidence of SCCHN is expected to be approximately 42,800 new cases in the United States with more than 12,000 deaths from this disease for the year 2006. The five-year survival rate for patients with SCCHN in the United States and other developed countries is still poor, approximately 40%, and even those patients who do not experience recurrence of the original cancer, have a high risk of developing a second primary malignancy. Thus, a preventative approach before the development of invasive cancer is highly desirable and novel strategies to reduce cancer incidence in SCCHN and other tobacco-carcinogen related malignancies are being pursued. Ever since the last two decades have seen the rise and fall of the results of clinical trials using carotinoids and retinoids as chemopreventive agents, new treatment strategies are needed. Selective and nonselective COX-1/2 inhibitors and EGFR tyrosine kinase inhibitors have shown promising results in cancer therapy and are currently evaluated in chemoprevention trials. However, associated high costs and side effects make these less attractive to patients with premalignant lesions. Phytochemical containing foods like green tea, pomegranate juice and other natural compounds are attractive since they are less costly, nontoxic and widely available. While small trials have shown promising results using these agents, larger trials have yet to be conducted to establish chemopreventive effects. Since premalignant lesions of the oral cavity are easily accessible for topical treatments, it remains to be seen if there is a role for topical treatments. Current clinical trials using these novel agents for prevention of second primary tumors or treatment of premalignant lesions will further elucidate which agents should be used but also will help to establish the role of chemoprevention in head and neck cancer.


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Anti-Tumor Vaccines in Head and Neck Cancer: Targeting Immune Responses to the Tumor
Theresa L. Whiteside

Immune therapies aiming at the destruction of a residual tumor and inducing tumor-specific memory responses are gaining acceptance among clinicians treating head and neck squamous cell carcinoma (HNSCC). This solid tumor lends itself remarkably well to currently popular vaccination strategies. Immune suppression is a hallmark of HNSCC, and its reversal accompanied by the vaccine-mediated restoration of antitumor immunity might be a promising approach to achieving improved survival of HNSCC patients. To date, few antitumor vaccines for HNSCC have been clinically evaluated. The reasons for this slow start are discussed, and the ongoing phase I clinical vaccination trials for HNSCC patients are briefly described. The emphasis is on dendritic cell (DC)-based vaccines, largely because of enhanced immunogenicity of epitopes presented by adoptively-transferred DC to responder T cells in vivo. Delivery of such antitumor vaccines in combination with conventional therapies and in the setting of a minimal residual disease to HNSCC patients takes advantage of exquisite specificity of the immune system at the time when tumor-induced suppression is reduced. Vaccine-driven generation, long-term survival and maintenance of tumor-specific immune cells are the objectives that antitumor vaccines have to realize to be clinically beneficial in HNSCC.


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Targeting Angiogenesis in Head and Neck Cancer
Nabil F. Saba, Dong M. Shin and Fadlo R. Khuri

In the early 1970s, the hypothesis that tumor growth is dependent on angiogenesis was first established [1]. Since then, the role played by blood vessels in tumor growth and progression has been extensively studied and debated. Preclinical evidence strongly suggests that VEGF plays a role in promoting the growth and progression of disease in various tumor types including squamous cell carcinoma of the head and neck (SCCHN), of which close to 38,500 new cases are diagnosed each year. In SCCHN, the role of anti-angiogenic therapy has yet to be defined. Traditional therapy of SCCHN has involved a multimodality approach with radiotherapy, surgery as well as chemotherapy. More recently, novel therapeutic agents have been subject to preclinical and clinical development, among which anti-angiogenic therapy has gained much recent interest. In this critical review, we give an overview of angiogenesis and its potential therapeutic targets, and we focus on its preclinical and clinical applications in SCCHN.


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EGFR-Targeting Monoclonal Antibodies in Head and Neck Cancer
Igor Astsaturov, Roger B. Cohen and Paul Harari

The epidermal growth factor (EGFR) and its receptor were discovered nearly 40 years ago. Over the past decade interruption of this pathway has been exploited in the treatment of various solid tumors. Antibodies that interfere with ligand binding to and dimerization of the EGFR (and small molecules that inhibit the EGFR tyrosine kinase) are anti-proliferative, profoundly radiosensitizing, and synergistic with DNA-damaging cytotoxic agents. Proposed mechanisms of radio- and chemosensitization include enhanced apoptosis, interference with DNA repair and angiogenesis, receptor depletion from the cell surface and antibody-dependent cell-mediated cytotoxicity.

This article provides a reader with a comprehensive review of EGFR-targeting antibodies under development for the treatment of head and neck squamous cell cancer (HNSCC) and also summarizes relevant clinical data in this disease with small molecule EGFR inhibitors. One of the monoclonal antibodies, cetuximab, recently received full FDA approval for the treatment of patients with locally advanced (with radiation) or metastatic HNSCC (as a single agent). Regulatory approval followed reporting of a large international study in which the addition of cetuximab to definitive radiation therapy in HNSCC resulted in statistically significant improvements in locoregional control and overall survival. Results of the pivotal trial, other clinical data supporting the regulatory approval, and a preview of the next generation of clinical trials are presented. Considerable work remains to be done, particularly to enhance our understanding of factors that may predict for favorable response to EGFR inhibitor therapy and to evaluate the impact of integrating anti-EGFR therapies into complex chemoradiation programs delivered with curative intent.


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Treatment of Squamous Cell Carcinoma of the Head and Neck in the Metastatic and Refractory Settings: Advances in Chemotherapy and the Emergence of Small Molecule Epidermal Growth Factor Receptor Kinase Inhibitors
Syed M. Ahmed and Ezra E.W. Cohen

Approximately 475,000 cases of squamous cell carcinoma (SCCHN) of the head and neck occur worldwide. Whereas significant advances have been made in the treatment of early and locally advanced disease, the prognosis for recurrent and metastatic (R/M) disease remains poor. Compounds with demonstrated activity include cisplatin and carboplatin, antimicrotubular compounds such as taxanes and vinorelbine, and fluoropyrimidines. In refractory and metastatic disease, regimens combining platinum agents with taxanes or fluorouracil based agents produce a 30% response rate and a median overall survival of six to eight months. Newer three agent chemotherapy regimens have produced response rates in the range of 40-50%, without significant improvements in overall survival noted. Recently, a new class of medications targeting signal transduction pathways has come into focus in the treatment of various malignancies. In SCCHN, given the high prevalence of expression of the epidermal growth factor receptor (EGFR) and its role in promoting cellular growth and proliferation, molecules targeting the receptor’s intracellular kinase domain are a logical strategy. The agents gefitinib and erlotinib have yielded response rates in the 5-15% range when used as single agents. In addition, newer agents with broad activity against the EGFR and other related erbB receptor family members are being developed in clinical trials. Strategies to enhance the activity of EGFR tyrosine kinase inhibitors (TKIs) in treating SCCHN are being investigated, as well as strategies to select individuals with tumors more likely to respond to these drugs. This article reviews the advances that have made in treating refractory and metastatic disease, with particular focus on the challenges that are faced in successfully translating EGFR inhibition as a paradigm of tumor treatment in SCCHN.


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Recent Advances in Combined Modality Therapy for Locally Advanced Head and Neck Cancer
Lori J. Wirth and Marshall R. Posner

Half of all patients with squamous cell carcinoma of the head and neck (SCCHN) present with locally advanced disease. Despite the development of new treatment strategies, mortality rates have only improved over the last decade by 2.6% per year, and prognosis remains poor. Combined modality therapy offers the potential for organ preservation, particularly for tumors arising in the larynx, hypopharynx and oropharynx. Organ preservation with concurrent chemoradiotherapy (CRT) was first established in laryngeal carcinoma. Recent results of the laryngeal study, RTOG 9111, indicate that even though larynx preservation is improved with CRT compared to induction chemotherapy followed by radiotherapy alone, laryngectomy-free survival is the same. Future attentions should be focused not only on improving treatment efficacy, but also on efforts to minimize the long term toxicities of therapy for SCCHN, particularly because long term toxicities not only diminish quality of life, but seem to impact on survival. In the future, targeted therapies may be incorporated into combined modality therapy for SCCHN, offering the chance to enhance the anticancer effects of treatment without increasing toxicity. Improvements in radiotherapy techniques may also move the field forward. Finally, there is renewed interest in the role of induction chemotherapy as part of a sequential treatment approach for advanced SCCHN. If the current generation of studies evaluating sequential therapy is favorable, future studies incorporating targeted therapies into this platform will offer further potential for advancing the treatment of SCCHN.


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Recent Approaches in Chemoprevention of Prostate Cancer
Charles Y.F. Young

In highly developed countries like USA, approximately one out of 6 in the male population will expect to have prostate cancer in their life time. Chemoprevention is presumably one of most effective means to combat many types of cancer including prostate cancer (PCa). Because clinically significant PCa usually requires more than a decade to develop, therefore, it would be an ideal target for chemoprevention. This review will focus on recent findings of the most studied, naturally occurring, synthetic or semi-synthetic chemicals for potential use in preventing PCa. Newly discovered chemicals which show potential in preventative or therapeutic effects will be included. Molecular mechanisms and gene/pathway targets by which the above agents act on target cells will be briefly discussed. The recent findings on the chemicals possessing anti-androgen receptor, anti-DNA methyltransferase, or anti-histone deacetyltransferase activity will also be presented. It will further present some important issues regarding how the interactions of chemopreventing agents with genetic polymorphisms or epigenetic factors might affect anti-cancer effects of the agents. Related large trials, if appropriate, will also be discussed.


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Targeting MDM2 and MDMX in Retinoblastoma
Nikia A. Laurie, Chie Schin-Shih and Michael A. Dyer

Retinoblastoma is the third most common form of cancer in infants, and metastatic retinoblastoma is lethal in approximately 90% of cases. Early detection and aggressive therapy has resulted in a 95% probability of survival for retinoblastoma patients in the United States. However, the United States only represents 3-4% of the retinoblastoma cases worldwide. The majority of children diagnosed with retinoblastoma each year live in developing countries where the probability of survival is closer to 50%. This difference in survival rates reflects poor early detection rates and limited resources for the aggressive therapy necessary to treat retinoblastoma and manage the side effects associated with broad-spectrum systemic chemotherapy in young children. In order to have the most significant impact on retinoblastoma treatment in the United States and worldwide, current efforts have focused on local delivery of targeted chemotherapy. In this review, we summarize recent data showing that the p53 pathway is inactivated in 75% of retinoblastoma patients due to extra copies of the MDM2 and MDMX genes. A small molecule inhibitor of MDM2 called nutlin-3 can induce p53-mediated cell death in retinoblastoma cells. Subconjunctival delivery of nutlin-3 in preclinical models of retinoblastoma confirmed the efficacy of this approach in vivo. The advantage of local application of targeted chemotherapeutic agents such as nutlin-3 is that greater intraocular drug concentrations can be achieved without the side effects associated with systemic broad-spectrum chemotherapy. We propose that subconjunctival administration of targeted chemotherapy may be the best treatment option for children with retinoblastoma in the United States and throughout the developing world because it provides greater tumor response without the costs and complications associated with current treatment protocols.