Hypopharynx Cancer

Insulin-Like Growth Factor 2 - The Oncogene and its Accomplices

The era of personalized medicine for cancer treatment has just begun opening up novel molecular targets improving cancer therapy. Members of the insulin-like growth factor 2 (IGF2) axis have been described to be altered and to have prognostic relevance in several different tumor identities.

IGF2 belongs to the most complexly regulated growth factors known. As an imprinted gene it is controlled by epigenetic alterations. IGF2 mRNA binding proteins (IMPs/IGF2BPs) further regulate its translation. IGF2 activity is contained through IGF binding proteins (IGFBPs) and differential expression of the target receptors. The necessity of such a complex regulation implies pathophysiological effects of a deregulated expression of IGF2. This review attempts to summarize the different levels of IGF2 regulation, especially in the context of cancer. Members of the IGF2 axis are enlightened from the perspective of novel molecular targets for cancer therapy. Preclinical as well as experimental therapeutic interventions targeting IGF2 in cancer will be surveyed.

An Updated Review of Natural Products Intended to Prevent or Treat Oral Mucositis in Patients Undergoing Radio-Chemotherapy

Oral mucositis is a major clinical challenge in oncology and is characterized by pain and inflammation of the mucous membrane surface resulting from radiotherapy for head and neck cancer or from chemotherapeutic agents. Manifestations range from a burning sensation to ulcer formation that affect the patients’ quality of life by producing pain and discomfort on swallowing, ultimately leading to malnutrition and dehydration. Due to complications arising from the use of chemical drugs, in recent decades, increasing attention has been paid to natural-based agents. The results from several studies evaluating natural products for the prevention or reduction of chemotherapy- and radiotherapy-induced oral mucositis are promising. This comprehensive review aims to provide updated information concerning the natural agents that are effective against mucositis in cancer patients receiving radiotherapy and/or chemotherapy.

VEGFA and PlGF Protein Signature of Primary Stage IV Rectal Cancer Pre and Post Neoadjuvant Radiotherapy, Bevacizumab, and Chemotherapy

Vascular endothelial growth factor-A (VEGFA) and placental growth factor (PlGF) can mediate cancer progression and anticancer treatment failure. We therefore analyzed (sub)cellular patterns of VEGFA and PlGF expression, and mean vessel density (MVD) in primary rectal tumor samples of stage IV patients, who could benefit from improved therapies. VEGFA, PlGF and MVD were measured immunohistochemically in paraffin-embedded rectal tumor tissue before and after pelvic radiotherapy and systemic neoadjuvant treatment with bevacizumab, capecitabine, and oxaliplatin. The relation between baseline expression of VEGFA and PlGF, and MVD and pathologic response to treatment was also analyzed. At diagnosis, 91% of the 46 tumors expressed VEGFA in the cytoplasm and 50% in the nucleus of tumor cells. PlGF was expressed by 74% in the tumor cell's cytoplasm. There were no differences in VEGFA expression and MVD at baseline between the nine patients with pathologic complete response (pCR) and the 30 patients with residual tumor after treatment. All patients with pCR expressed PlGF in tumor cells at baseline, as did 19 of the 30 patients with residual tumor. After treatment, nuclear VEGFA expression in tumor cells and MVD were lower in residual tumors as compared to the initial tumor [15% vs. 56%, P = 0.024, and 10.3 (±4.2) vs.16.4 (±6.0), P < 0.0001]. PlGF expression in residual cancer did not significantly differ from the paired pre-treatment values. These data indicate the relevance of VEGFA and PlGF to rectal tumor biology, and might suggest PlGF blockade as being of interest to test in metastatic rectal cancer.

The Role of HTS in Drug Discovery at the University of Michigan

High throughput screening (HTS) is an integral part of a highly collaborative approach to drug discovery at the University of Michigan. The HTS lab is one of four core centers that provide services to identify, produce, screen and follow-up on biomedical targets for faculty. Key features of this system are: protein cloning and purification, protein crystallography, small molecule and siRNA HTS, medicinal chemistry and pharmacokinetics. Therapeutic areas that have been targeted include anti-bacterial, metabolic, neurodegenerative, cardiovascular, anti-cancer and anti-viral. The centers work in a coordinated, interactive environment to affordably provide academic investigators with the technology, informatics and expertise necessary for successful drug discovery. This review provides an overview of these centers at the University of Michigan, along with case examples of successful collaborations with faculty.

Chemo-Radiation Association in Head and Neck Squamous Cell Carcinoma: Evidences and Criticisms

Recently new strategies such as the association of chemotherapy with radiotherapy have emerged for the improvement of therapeutic outcome in the curative treatment of HNSCC: for patients with locally advanced HN-SCC, where outcome with radiotherapy alone is poor. More than one-hundred Phase III trials collected in large meta-analyses have showed that loco regional control and overall survival may be improved at high level of evidence by chemo-radiotherapy especially if delivered with synchronous approach. Sequential or synchronous chemo-radiotherapy regimens can also play a crucial role in larynx-function preservation programs without the risk of overall survival reduction for patients with larynx or hypo pharynx tumors who are candidates to radical surgery. Recently, strong evidence for an improved outcome for high-risk resected patients has been shown by the use of adjuvant concomitant chemoradiotherapy. Despite hundreds of clinical trials in patients with advanced disease, there is no absolute consensus about patient selection for type of chemo-radiotherapy association, radiation or chemotherapy dose schedule. Nevertheless, awaiting for the results from ongoing trials where chemo-radiotherapy is explored in conjunction with new targeted therapies, many well-conducted clinical studies have expanded therapy options besides standard radiotherapy and have contributed to defining the evolving standard of care for patients with HNSCC.

Targeted Therapies in Head and Neck Cancer: Past, Present and Future

Head and neck cancers remain a significant health problem globally. The addition of chemotherapy to radiotherapy for locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN) has led to improvements in locoregional disease control and in survival, but is associated with substantial acute and late toxicities. In recurrent and/or metastatic SCCHN, there have been no improvements in survival, despite the manipulation of standard therapeutic regimens and the introduction of newer cytotoxic agents. Over the last decade, targeted therapies have been increasingly used in a range of solid tumor types. This article discusses the clinical evidence for the use of a number of targeted agents in the treatment of locoregionally advanced and recurrent and/or metastatic SCCHN. The article focuses on the epidermal growth factor receptor (EGFR) inhibitors, for which the majority of clinical information is available. These include the monoclonal antibody (MAb) cetuximab and the tyrosine kinase inhibitors, erlotinib and gefitinib. Clinical data for the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, are also presented.

EGFR-Targeting Monoclonal Antibodies in Head and Neck Cancer

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.

EGFR Inhibitors and Radiation in HNSCC

Epidermal growth factor receptor (EGFR) signalling has previously been identified as an important prognostic factor in patients with head and neck cancer (HNC). EGFR has been confirmed in a phase III randomized trial as a critical target in combination with radiation therapy for locally advanced HNC patients. Provocatively, the outcomes, at first glance, appear similar to patients treated with conventional chemo-radiation; but with less mucosal toxicity. Promising options for EGFR inhibition include targeting the epidermal growth factor receptor (EGFR) with tyrosine kinase inhibitors (EGFR-TKIs), and monoclonal antibodies to prevent ligand binding. There are limitations to EGFR inhibition as only 10% of patients respond to EGFR blockade with advanced disease; therefore, immunohistochemistry, fluorescence in situ hybridization (FISH), gene arrays and molecular analysis techniques have been performed in an effort to predict which patients will respond to EGFR targeted therapies. Are there new issues and discoveries regarding EGFR biology that will provide information to determine at the outset, which patients will respond to this type of therapy, and which patients will benefit from alternative “ targeted agents ” ? In development are agents that target selective parts of the EGFR pathway such as Akt, mTor or Src kinase inhibitors. Novel drugs attacking both the EGFR and angiogenic pathways may provide wider applicability and improve radiation response further. This review will update head and neck specialists as to relevant new information regarding EGFR inhibition, alternative approaches with targeted agents and challenges facing oncology investigators to better define the appropriate patient population to benefit from these new agents.

EGFR-Targeting Monoclonal Antibodies in Head and Neck Cancer

The epidermal growth factor (EGF) 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, 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 antibodydependent cell-mediated cytotoxicity. This article provides the 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 locoregionally 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.