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The Role of the Epidermal Growth Factor Receptor in the Mechanism and Treatment of Colorectal Cancer

Second and Third Line Treatment in Advanced Non-small Cell Lung Cancer

Abstract: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. About 50% of the patients present locally advanced or metastatic disease at the time of diagnosis. First line therapy usually consists of a combination of cisplatin or carboplatin with a third-generation agent (paclitaxel, docetaxel, gemcitabine, or vinorelbine) that results in less than 5% 5-year survival (Goldstraw et al., 2007). Recently a different approach based on histological subtype has been introduced in the first line treatment of NSCLC: in the non-squamous histotypes, cisplatin plus pemetrexed, compared to the cisplatin plus gemcitabine combination, showed a better outcome, leading to its introduction in the first line treatment setting. In recent years advances in the second and third line treatments have led to a prognostic improvement. Two cytotoxic agents, docetaxel and pemetrexed, are approved as NSCLC second line treatment, and a new class of drugs against specific molecular targets -- tyrosine Kinase inhibitors (TKI) -- has emerged as an alternative to conventional treatment. Many trials are ongoing to assess the activity of new drugs, alone or in combination with other agents, or new combinations of third-generation chemotherapeutic agents. ... Read more

The Nuclear Epidermal Growth Factor Receptor Signaling Network and Its Role in Cancer

Abstract: The epidermal growth factor receptor (EGFR) is a member of the EGFR family of receptor tyrosine kinases (RTKs). EGFR activation via ligand binding results in signaling through various pathways ultimately resulting in cellular proliferation, survival, angiogenesis, invasion, and metastasis. Aberrant expression or activity of EGFR has been strongly linked to the etiology of several human epithelial cancers including but not limited to head and neck squamous cell carcinoma (HNSCC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), breast cancer, pancreatic cancer, and brain cancer. Thus intense efforts have been made to inhibit the activity of EGFR by designing antibodies against the ligand binding domains (cetuximab and panitumumab) or small molecules against the tyrosine kinase domain (erlotinib, gefitinib, and lapatinib). Although targeting membrane-bound EGFR has shown benefit, a new and emerging role for EGFR is now being elucidated. In this review we will summarize the current knowledge of the nuclear EGFR signaling network, including how it is trafficked to the nucleus, the functions it serves in the nucleus, and how these functions impact cancer progression, survival, and response to chemotherapeutics. ... Read more

Recent Advances in Non-small Cell Lung Cancer Biology and Clinical Management

Abstract: Despite advances in surgery, chemotherapy, and radiotherapy over the last decades, the death rate from lung cancer has remained largely unchanged, which is mainly due to metastatic disease. Because of the overall poor prognosis, new treatment strategies for lung cancer patients are urgently needed. In this review, we summarize recent advances in non-small cell lung cancer (NSCLC) screening and diagnostic workup. We discuss current clinical management, highlighting stage-specific therapy approaches, chemotherapy options for advanced-stage patients, along with new agents such as vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) monoclonal antibodies, and the EGFR-targeting tyrosine kinase inhibitors erlotinib and gefitinib, and the anaplastic lymphoma kinase (ALK) inhibitor crizotinib. Finally, we give an outlook into NSCLC disease biology, focusing on the importance of EGFR activating mutations and the role of the tumor-microenvironment. CXCR4 chemokine receptors expressed on NSCLC cells are a central pathway of NSCLC cross talk with the tumor microenvironment, as they induce activation, migration, and tumor cell adhesion to stromal cells, which in turn provides growth- and drug resistance-signals. Because of the growing evidence that the microenvironment in NSCLC promotes disease progression, we expect that selected molecular pathways of cross talk between NSCLC cells and their microenvironment will become alternative therapeutic targets in the near future. ... Read more

Nuclear Mode of the EGFR Signaling Network: Biology, Prognostic Value, and Therapeutic Implications

Abstract: Epidermal growth factor receptor (EGFR) belongs to a large family of receptor tyrosine kinases that mediates many important physiological processes in both normal and cancerous cells. EGFR is best known for its classical role as a plasma membrane-bound receptor that, upon binding to its ligands, recruits and phosphorylates downstream molecules which subsequently regulate protein functions, protein-protein interactions, and gene expression. Built upon this traditional view of the EGFR pathway, a number of therapeutic agents have been developed aiming to target EGFR by blocking ligand-mediated receptor activation or by inhibiting its kinase activity. Unfortunately, most of these interventions have yielded disappointing clinical results in the majority of cancer types evaluated, with the exception of non-small cell lung cancer that carries specific EGFR mutants. Given the notion that these EGFR mutations are absent or very rare in other cancer types, extensive investigations have been directed at other potential mechanisms. Some of these efforts have led to rationales for EGFR-based combination regimens; however, they also demonstrated limited clinical benefits. In this review, we will focus on an emerging line of research that examines a novel mode of EGFR signaling that takes place in the cell nucleus. Specifically, we will outline the findings from a number of reports that have together established nuclear EGFR to be a functionally diversified molecule that regulates the biology of normal and malignantly transformed cells. In light of the fact that the impact of nuclear EGFR on anti-cancer therapy has recently developed into an area of intensive investigations, this review will also summarize the results of these investigations that suggest a potential role the nuclear EGFR may play in tumor response to radiation, chemotherapy, and EGFR-targeted therapy. ... Read more

What Is the Role and Impact of Molecular Markers on Treatment Decisions for Colorectal Cancer in the Adjuvant Setting?

Abstract: The new mantra for delivering optimal cancer treatment is "personalized care." This extends beyond the holistic to using germline and somatic tumoral mutations to link a specific therapy to some prognostic or predictive factor which defines a particularly responsive patient subgroup who might benefit most from treatment. Furthermore, inherited polymorphisms have the potential to greatly modulate the side effects of treatment, especially for chemotherapy which has a notoriously narrow therapeutic window (Walther et al., 2009). ... Read more

Implementation of Biomarker-Driven Cancer Therapy: Existing Tools and Remaining Gaps

Abstract: There has been growing interest in biomarker-driven personalized cancer therapy, also known as precision medicine. Recently, dozens of molecular tests, including next generation sequencing, have been developed to detect biomarkers that have the potential to predict response of cancers to particular targeted therapies. However, detection of cancer-related biomarkers is only the first step in the battle. Deciding what therapy options to pursue can also be daunting, especially when tumors harbor more than one potentially actionable aberration. Further, different mutations/variants in a single gene may have different functional consequences, and response to targeted agents may be context dependent. However, early clinical trials with new molecular entities are increasingly conducted in a biomarker-selected fashion, and even when trials are not biomarker-selected, much effort is placed on enrolling patients onto clinical trials where they have the highest probability of response. We review available molecular tests and therapy discerning tools, including tools available for assessing functional consequences of molecular alterations and tools for finding applicable clinical trials, which exist to help bridge the gap between detection of cancer-related biomarker to the initiation of biomarker-matched targeted therapies. ... Read more

Current Issues in the Targeted Therapy of Advanced Colorectal Cancer

Abstract: Currently used cytotoxic drugs in the treatment of advanced colorectal cancer (ACC) are primarily the fluoropyrimidines, irinotecan, and oxaliplatin. The introduction of targeted therapy has increased the therapeutic arsenal. Two classes of monoclonal antibodies have been approved for clinical use in ACC: bevacizumab, an antibody against the vascular endothelial growth factor (VEGF), and cetuximab and panitumumab, antibodies against the epidermal growth factor receptor (EGFR). We review the current status of targeted therapy and the mechanism of action of monoclonal antibodies in ACC. ... Read more

A Small Step Towards Personalized Medicine for Non-small Cell Lung Cancer

Abstract: Treatment outcome for advanced-stage non-small cell lung cancer (NSCLC) is limited by empiric administration of cytotoxic chemotherapy. Recent advances in molecular genomics have revolutionized cancer management and, specifically, epidermal growth factor receptor (EGFR) mutation has become a potent biomarker for lung cancer, which predicts tumor response to and prolonged duration of disease control by EGFR tyrosine kinase inhibitors (TKI). The Iressa Pan-Asia Study (IPASS) is a randomized phase III study comparing gefitinib (EGFR TKI) with paclitaxel/carboplatin (standard chemotherapy) in Asian non-/light smokers with adenocarcinoma. Progression-free survival (PFS) in EGFR mutation-positive patients was longer with gefitinib than with chemotherapy (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.36-0.64; p<0.0001); in EGFR mutation-negative patients, PFS was longer with chemotherapy than with gefitinib (HR 2.85; 95% CI 2.05-3.98; p<0.0001). The findings are confirmed by one single-arm study and three other randomized studies. It has become clear that personalized medicine for NSCLC is feasible. This small step towards personalized medicine represents a paradigm shift in the management of NSCLC. ... Read more

Toward Personalized Treatment of Advanced Biliary Tract Cancers

Abstract: Biliary tract cancers (BTC) are a relatively rare heterogeneous group of four to five anatomically distinct cancers whose prognosis is poor, even in the setting of attempted curative resection. Curative resection, in itself, is much less common than locally advanced unresectable and/or overt metastatic disease at presentation. Standard chemotherapy options are generally palliative for advanced BTC (aBTC), and recently the combination of gemcitabine with cisplatin has emerged as the standard-of-care providing a median overall survival of approximately one year. A movement toward molecularly based personalized cancer therapy has occurred in recent years, including for aBTC, with a number of pathways emerging as putative therapeutic targets. This review will briefly summarize the epidemiology, etiology, and general prognosis of BTC, then discuss the data supporting current standard cytotoxic treatments of aBTC, and proceed to focus on the molecular features of this heterogeneous set of diseases. Finally, we review strategies which will potentially improve our ability to individualize therapy and, ultimately, clinical outcomes in the future. ... Read more

Screening for EGFR Mutations in Lung Cancer

Abstract: Certain mutations in the epidermal growth factor receptor (EGFR) gene confer hypersensitivity to the tyrosine kinase inhibitors gefitinib and erlotinib in patients with advanced non-small cell lung cancer. Large-scale screening for EGFR mutations in such patients is feasible for predicting response to TKIs and thus guiding treatment. ... Read more

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