Targeting EGFR in pancreatic cancer treatment

The prognosis of patients with pancreatic cancer is extremely poor, and current systemic therapies provide marginal survival benefits for treated patients. The era of targeted therapies has offered a new avenue to search for potentially more effective strategies. Epidermal growth factor receptor (EGFR) is a member of the erbB/human epidermal growth factor receptor family of tyrosine kinases, which includes erbB2/HER2, erbB3/HER3 and erbB4/HER4. Epidermal growth factor receptor overexpression may be detected in up to 90% of pancreatic tumors. Two pharmacologic approaches have been successfully used to inhibit epidermal growth factor receptor function in cancer treatment: neutralizing monoclonal antibodies and small molecule tyrosine inhibitors. The randomized trials studying the addition of EGFR targeted agents to gemcitabine compared with gemcitabine alone have been disappointing, although results with the EGFR tyrosine kinase inhibitor erlotinib were statistically significant but clinically of marginal benefit. In this article, we review the epidermal growth factor receptor signaling network in pancreatic cancer, the strategies to increase the effectiveness of epidermal growth factor receptor inhibitors, and the clinical trials of these inhibitors in pancreatic cancer.     

Molecular design and clinical development of VEGFR kinase inhibitors

Vascular angiogenesis has been shown to play a key role in many solid tumors. The vascular endothelial growth factor (VEGF) isoforms and their tyrosine kinase receptors (VEGFRs) have been under intense research for effective anticancer drug candidates. Epidermal growth factor (EGF) and its receptor (EGFR) provide another pathway critical in monitoring angiogenesis. VEGF exerts its effect through binding to tyrosine kinase receptors, mainly VEGFR-1 (Flt-1, the fms-like tyrosine kinase-1) and VEGFR-2 (Flk-1/KDR, fetal liver kinase-1). This paper reviews the progress, mechanism, and binding modes of recently approved kinase inhibitors, such as sunitinib (Sutent), sorafenib (Nexavar) and dasatinib (Sprycel), as well as other inhibitors that are still under clinical development. Recent clinical treatments suggest that most inhibitors of VEGFR (and/or EGFR) exert their therapeutic effect through not only targeting the VEGFR (and/or EGFR) pathway, but also inhibiting other pathways, such as RAF/MEK/ERK pathway. A new pharmacophore model for second generation of type II tyrosine kinase inhibitors and recent advances in the combination of VEGFR tyrosine kinase inhibitors and other chemotherapeutics are also covered.     

HER family inhibitors in pancreatic cancer: current status and future directions

Pancreatic cancer is characterized by multiple genetic abnormalities that can be used as targets for specific therapeutics. The HER family consists of four transmembrane growth factor receptors. Targeting HER1 with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib demonstrated a survival advantage for patients with advanced pancreatic cancer. Multiple other agents that target members of the HER family are under investigation. These include reversible and irreversible, single and pan HER tyrosine kinase inhibitors. Chimeric, humanized and fully human monoclonal antibodies that target specific HER receptors are also being studied. These agents are also radiation sensitizers. This article reviews clinical trials of HER family inhibitors in pancreatic cancer, discusses the role of these agents in the management of patients and outlines future directions for pancreatic cancer management.     

Tyrosine kinase inhibitors and gemcitabine: new treatment options in pancreatic cancer?

Pancreatic cancer (PCa) is one of the most lethal malignancies in humans. Gemcitabine is the current standard chemotherapy of advanced PCa but it is still far from optimal and novel therapeutic strategies are urgently needed. For the near future, tyrosine kinase inhibitors (TKIs) hold great promise as a therapeutic strategy. Tyrosine kinases (TKs) play a pivotal role in intercellular signal transduction and regulate crucial processes of tumor cells such as proliferation, migration, survival and angiogenesis. Several TKs--such as EGFR, VEGFR, PDGFR and Src--are known to be overexpressed or constitutively activated in PCa. Hence, blocking receptor tyrosine kinases (RTKs) and non-receptor, cytoplasmic tyrosine kinases (CTKs) represents a rational approach to treat PCa. In particular, cetuximab and erlotinib, the monoclonal antibodies against EGFR-1 (ErbB-1) showed promising activity in Phase II and Phase III trials and their combination with gemcitabine resulted in synergistic antitumor activity. In addition, small antiangiogenic molecules such as VEGFR-2 inhibitors, PDGFR inhibitors and multiple receptor targeting agents are under active investigation. Association of chemoresistance with the activity of certain tyrosine kinases (e.g. ErbB-1 and Src) has been described for pancreatic cancer and makes a strong case for combining gemcitabine with TKIs. Combinations of different TKIs might also be used to target the cancer cell micro-environment. Detailed molecular characterization of tumor cells and combinations of appropriate TKIs with cytotoxic agents such as gemcitabine are expected to lead to improved therapy of pancreatic cancer.     

HER family inhibitors in pancreatic cancer: current status and future directions

Pancreatic cancer is characterized by multiple genetic abnormalities that can be used as targets for specific therapeutics. The HER family consists of four transmembrane growth factor receptors. Targeting HER1 with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib demonstrated a survival advantage for patients with advanced pancreatic cancer. Multiple other agents that target members of the HER family are under investigation. These include reversible and irreversible, single and pan HER tyrosine kinase inhibitors. Chimeric, humanized and fully human monoclonal antibodies that target specific HER receptors are also being studied. These agents are also radiation sensitizers. This article reviews clinical trials of HER family inhibitors in pancreatic cancer, discusses the role of these agents in the management of patients and outlines future directions for pancreatic cancer management.     

EGFR, HER2 and VEGF pathways: validated targets for cancer treatment

Targeted therapies are rationally designed to interfere with specific molecular events that are important in tumour growth, progression or survival. Several targeted therapies with anti-tumour activity in human cancer cell lines and xenograft models have now been shown to produce objective responses, delay disease progression and, in some cases, improve survival of patients with advanced malignancies. These targeted therapies include cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody; gefitinib and erlotinib, EGFR-specific tyrosine kinase inhibitors; trastuzumab, an anti-human EGFR type 2 (HER2)-related monoclonal antibody; lapatinib, a dual inhibitor of both EGFR- and HER2-associated tyrosine kinases; and bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody.On the basis of preclinical and clinical evidence, EGFR, HER2 and VEGF represent validated targets for cancer therapy and remain the subject of intensive investigation. Both EGFR and HER2 are targets found on cancer cells, whereas VEGF is a target that acts in the tumour microenvironment. Clinical studies are focusing on how to best incorporate targeted therapy into current treatment regimens and other studies are exploring whether different strategies for inhibiting these targets will offer greater benefit. It is clear that optimal use of targeted therapy will depend on understanding how these drugs work mechanistically, and recognising that their activities may differ across patient populations, tumour types and disease stages, as well as when and how they are used in cancer treatment. The results achieved with targeted therapies to date are promising, although they illustrate the need for additional preclinical and clinical study.     

Antiangiogenic agents: an update on small molecule VEGFR inhibitors

Angiogenesis is a tightly regulated process that leads to the formation of new blood vessels sprouting from pre-existing microvasculature and occurs in limited physiological conditions or under pathological situations such as retinopathies, arthritis, endometriosis and cancer. Blockade of angiogenesis is an attractive approach for the treatment of such diseases. Particularly in malignancies, antiangiogenic therapy should be less toxic in comparison with conventional treatments such as chemotherapy, as angiogenesis is a process relatively restricted to the growing tumor. Vascular endothelial growth factor (VEGF) is one of the most important inducers of angiogenesis and exerts its cellular effects mainly by interacting with two high-affinity transmembrane tyrosine kinase receptors: VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1). It has been proven that inhibition of VEGF receptor activity reduces angiogenesis. For these reasons, the inhibition of VEGF or its receptor signalling system is an attractive target for therapeutic intervention. The most studied and developed inhibitors are monoclonal antibodies that neutralize VEGF, ribozymes, and small molecule VEGFR kinase inhibitors. Many important reviews dealing with VEGF-induced angiogenesis and its inhibition through the block of VEGF receptors have been reported, especially from a biological point of view. Here, we will review small synthetic VEGFR inhibitors that have appeared in literature in the last few years, focusing our attention on their medicinal chemistry in terms of chemical structure, mechanisms of action and structure-activity relationships. In fact, there have been an increased number of tyrosine kinase inhibitors in the most recent literature reports; their biological profile is extremely interesting and could be of great importance to medicinal chemists working in this area in improving their efficacy.     

Clinical experience with erlotinib in non-small-cell lung cancer

Lung cancer is the leading cause of cancer death worldwide. Despite the introduction of more- effective chemotherapeutic agents, it appears that a survival plateau has been reached, so new treatment strategies are clearly needed. One innovative therapeutic cancer strategy is the introduction of biological agents that target specific intracellular pathways related to the distinctive properties of cancer cells. Among these agents, epidermal growth factor receptor (EGFR)-targeting agents have received particular attention in lung cancer. Numerous EGFR blockers have been evaluated, including monoclonal antibodies to the receptor and small-molecule tyrosine kinase inhibitors. The present review focuses on the tyrosine kinase inhibitor erlotinib. Preclinical studies have shown that erlotinib blocks the growth of human non-small-cell lung cancer (NSCLC) cell lines in vitro by inhibiting the receptor and the downstream protein phosphorylation. In a randomized study conducted by the National Cancer Institute of Canada (BR.21) in second- and third-line NSCLC treatment, erlotinib significantly prolonged overall survival and decreased symptoms compared with placebo. A crucial aspect of the clinical development of molecular-targeted therapies is to understand which patients will obtain clinical benefit from their use. Sensitivity to erlotinib has been associated with EGFR mutations, most commonly deletions of four to six amino acids in exon 19 or a point mutation (L858R) in exon 21. Increased EGFR gene copy number has also been pointed out as a good predictive marker for erlotinib response. Intense research activity is ongoing to validate known predictive markers and to discover new tools which maximize clinical benefit using erlotinib. However, there is no conclusive evidence, as yet, linking response to survival.     

Recent advances in targeted therapy for non-small cell lung cancer

Non-small-cell lung cancer (NSCLC) is characterized by wide molecular heterogeneity. In recent years, novel agents that target specific, aberrant molecular pathways in NSCLC have been under rigorous evaluation. Erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, improves survival for advanced NSCLC patients who progressed following one or two prior chemotherapy regimens. Novel molecular predictive markers, such as EGFR mutations and gene amplification, are at present under evaluation to select patients for therapy with erlotinib. Another area of progress is the recent demonstration that bevacizumab, a monoclonal antibody against the vascular endothelial growth factor (VEGF), extended survival when administered in combination with chemotherapy for patients with non-squamous NSCLC. Promising anticancer activity has also been noted with agents that inhibit the VEGF receptor tyrosine kinase in patients with advanced NSCLC. Inhibitors of the proteosomal complex, histone deacetylase, mammalian target of rapamycin pathway, and other growth factor receptor-mediated signaling are under investigation for treatment of NSCLC. These developments have paved the way for a new era of tailor-made therapies based on clinical or molecular/genetic profiles in the treatment of NSCLC. This article reviews the recent advances in targeted therapy of advanced NSCLC.     

Recent advances in targeted therapy for non-small cell lung cancer

Non-small-cell lung cancer (NSCLC) is characterized by wide molecular heterogeneity. In recent years, novel agents that target specific, aberrant molecular pathways in NSCLC have been under rigorous evaluation. Erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase, improves survival for advanced NSCLC patients who progressed following one or two prior chemotherapy regimens. Novel molecular predictive markers, such as EGFR mutations and gene amplification, are at present under evaluation to select patients for therapy with erlotinib. Another area of progress is the recent demonstration that bevacizumab, a monoclonal antibody against the vascular endothelial growth factor (VEGF), extended survival when administered in combination with chemotherapy for patients with non-squamous NSCLC. Promising anticancer activity has also been noted with agents that inhibit the VEGF receptor tyrosine kinase in patients with advanced NSCLC. Inhibitors of the proteosomal complex, histone deacetylase, mammalian target of rapamycin pathway, and other growth factor receptor-mediated signaling are under investigation for treatment of NSCLC. These developments have paved the way for a new era of tailor-made therapies based on clinical or molecular/genetic profiles in the treatment of NSCLC. This article reviews the recent advances in targeted therapy of advanced NSCLC.     

Novel substituted quinazolines for potent EGFR tyrosine kinase inhibitors

The type I receptor tyrosine kinases (RTKs) are involved in various aspects of cell growth, survival, and differentiation. Among the known RTKs, the epidermal growth factor receptor (EGFR) and ErbB-2 (HER-2) are two widely studied proteins that are prototypic members of the ErbB family which also includes ErbB-3 (Her-3) and ErbB-4 (Her-4). Overexpression of ErbB-2 and EGFR has been associated with aggressive disease and poor patient prognosis in a range of human tumour types (e.g. breast, lung, ovarian, prostate, and squamous carcinoma of head and neck). Disruption of signal transduction of these kinases has been shown to have an antiproliferative effect. Various approaches have been developed to target the ErbB signalling pathways including monoclonal antibodies (trastuzumab/Herceptin? and cetuximab/Erbitux?) directed against the receptor, and synthetic tyrosine kinase inhibitors (gefitinib/Iressa? and erlotinib/Tarceva?). Since many tumours overexpress ErbB receptors, simultaneous targeting of multiple ErbB receptors therefore becomes a promising approach to cancer treatment. Lapatinib (Tykerb?), a potent dual EGFR/ErbB-2 inhibitor, was approved for the treatment of ErbB-2-positive breast cancer. Despite years of intensive research on EGFR inhibitors, there is a surprising dearth of chemically distinct small inhibitors with a high degree of selectivity. There is also a need for new scaffolds due to the recent finding of EGFR mutations which render the kinase resistant to gefinitib and erlotinib. The structures under study will be quinazolines with different substituents. The structure-activity relationships and biological evaluation of compounds published during the last four years will be reviewed herein.     

表皮生长因子受体抑制剂相关性皮肤毒性的研究进展

表皮生长因子受体抑制剂包括小分子酪氨酸激酶抑制剂及单抗类,在肺癌、结直肠癌等肿瘤的分子靶向治疗中起着重要作用。其中小分子酪氨酸激酶抑制剂包括吉非替尼、厄洛替尼、埃克替尼等,单抗类包括西妥昔单抗、帕尼单抗等。以痤疮样皮疹为代表的皮肤毒性是表皮生长因子受体抑制剂使用后最常见的不良反应,严重的皮肤毒性导致药物剂量减少与治疗的中断,影响药物的抗肿瘤疗效。但目前临床对于这一类皮肤毒性仍没有十分有效的处理方法。已有临床试验涉及的处理方法包括口服四环素类药物、局部应用维生素K乳剂、局部应用他克莫司、防晒霜以及表皮生长因子凝胶等。本文综述了此类皮疹的发生机制、治疗皮疹药物的临床试验结果及已有的专家共识或指南,以期为这一类不良反应的处理提供临床思路。     

Recent advances in antiangiogenic agents with VEGFR as target

Angiogenesis is required for invasive tumor growth and metastasis and constitutes an important point in the control of cancer progression. Its inhibition may be a valuable approach to cancer therapy. Antiangiogenic agents are designed to attack the tumor vasculature and cut off the tumor's supply of nutrients. Systemic blockade of angiogenesis has been recently approved for the treatment of several types of human cancers. Antiangiogenic therapy presents various advantages as compared to conventional treatment. Vascular endothelial growth factor (VEGF) is considered to be one of the most important regulators of angiogenesis and a key target in anticancer treatment. VEGF binding to its receptor (VEGFR) leads to cell proliferation and new vascular formation by tyrosine kinase (TK) pathway. VEGF/VEGFR pathway is becoming attractive target for anticancer drug design. It is believed to be important in the control of angiogenesis. Antiangiogenic therapy based on inhibition of VEGFR was reported to be powerful clinical strategies. In this review, the authors describe the existing literature regarding VEGFR inhibitors in the last few years. We attempt to cover all essential publications on the medicinal chemistry in terms of chemical structure, pharmacological profile and structure-activity relationships.     

Epidermal growth factor receptor targeting

Dr. Jose Baselga (Hospital Vall d'Hebron, Barcelona, Spain) chaired and led a discussion of several posters on the marking and detection of the epidermal growth factor receptor (EGFR), and compounds that target this receptor. The posters consisted of biological studies and phase I trials with EGFR tyrosine kinase (TK) inhibitors. The basis of EGFR targeting in cancer therapy depends on the overexpression in malignancy and potential inhibition with antibodies and TK inhibitors. Correlations have been made between receptor function and inhibition of growth.     

Epidermal growth factor receptor inhibitors in non-small-cell lung cancer

The epidermal growth factor receptor (EGFR) is a cell membrane receptor that plays a key role in cancer development and in the progression of many human malignancies, including non-small-cell lung cancer (NSCLC). EGFR-dependent signaling is involved in cancer cell proliferation, apoptosis, angiogenesis, invasion and metastasis. Targeting the EGFR is a valuable molecular approach in cancer therapy. This receptor is overexpressed in up to 80% of NSCLC cases. Thus, several molecules inhibiting this critical biologic pathway have been synthesized and tested as a single agent or in combination with other anticancer modalities in a wide of clinical trials, including reversible and irreversible small tyrosine kinase inhibitors, such as gefitinib and erlotinib, dual vascular endothelial growth factor receptor EGFR tyrosine kinase inhibitors, such as vandetanib (ZD-6474), and monoclonal antibodies, such as cetuximab, which have shown promising activity in patients with NSCLC. This review focuses on the preclinical and clinical results available with EGFR inhibitors in the treatment of NSCLC patients.     

Second-generation epidermal growth factor tyrosine kinase inhibitors in non-small cell lung cancer

Inhibiting the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) has an established role in the treatment of advanced non-small cell lung cancer. The first-generation EGFR inhibitors erlotinib and gefitinib have been approved for treatment in the second- and third-line setting. Second-generation EGFR tyrosine kinase inhibitors are now in development aiming to improve efficacy and overcome primary and secondary resistance to the first-generation drugs. The two most common strategies being used to achieve these aims are irreversible binding of drug to target and kinase multi-targeting. This is an overview of the early clinical development of selected second-generation tyrosine kinase inhibitors focusing on the treatment of non-small cell lung cancer.     

The clinical application of fruquintinib on colorectal cancer

ABSTRACT

Introduction: Anti-angiogenetic agents are currently the most commonly used drugs for the treatment of colorectal cancer (CRC) patients, including various inhibitors targeting the epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and VEGF receptors (VEGFRs). Fruquintinib (HMPL-013), a highly selective and long-term small-molecule inhibitor of VEGFR (VEGFR1, 2, and 3) was recently approved in China for CRC treatment. Clinical studies have shown it has many advantages, such as low off-target toxicity, good drug tolerance, and strong effect.

Areas covered: In the review, the molecular structure, mechanism of action, pharmacokinetics, clinical efficacy, and safety of fruquintinib are introduced in detail. The potential clinic application on non-small cell lung cancer (NSCLC) and gastric cancer is also discussed.

Expert commentary: Fruquintinib was approved for patients with metastatic colorectal cancer (RAS wild type) who have previously received fluorouracil, oxaliplatin, and irinotecan-based chemotherapy and who have received or are not suitable for anti- VEGF therapy and anti- EGFR therapy. As a novel, therapeutic approach to CRC, Fruquintinib could be used as a third-line drug for the treatment of CRC patients. Due to drug resistance during the long-term therapy, the combination of fruquintinib with other targeted therapy drugs may be an effective option for CRC treatment.     

Recent advances in small molecule inhibitors of VEGFR and EGFR signaling pathways

Aberrant angiogenesis has been observed in many solid tumors. The formation and metastases of tumors such as non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) are very complex, often regulated by proangiogenic factors such as the vascular endothelial growth factor (VEGF) and other tyrosine kinases. The VEGFR, EGFR and mTOR pathways have played critical roles in controlling cell proliferation and angiogenesis. This paper reviews the mechanism and binding modes of recently approved tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib, nilotinib, dasatinib, sunitinib, sorafenib, pazopanib, lapatinib, afinitor, and temsirolimus. We also cover the progresses of the recent development of tyrosine kinase inhibitors that are currently in the clinical trials at the phases I, II, and III, targeting the VEGFR, EGFR and/or mTOR pathways. Combination therapy intended to overcome drug resistance is also discussed. Recent TKI design based on the activation loop and the "DFG" conformation, is also discussed.     

Erlotinib-induced trichomegaly in a male patient with pancreatic cancer

In this report we present a case of erlotinib-induced trichomegaly in a male patient who received erlotinib for his pancreatic cancer. Trichomegaly as a side effect of epidermal growth factor receptor (EGFR) inhibitor therapy is uncommon in male patients. Also, it has not been reported previously in a patient with pancreatic cancer. Previous reported cases all involved female lung cancer patients. We emphasize the importance of recognizing the side effects of EGFR inhibitor therapy and its implications on the prognosis of the cancer treated.     

Acute left ventricular dysfunction induced by a panHER and VEGFR tyrosine kinase inhibitor in a phase I trial

Tyrosine kinase inhibitors (TKI) or monoclonal antibodies targeting EGFR, HER2 or VEGFR receptors have demonstrated substantial clinical benefit in patients with advanced breast cancer, colon cancer, head and neck cancer, non-small cell lung cancer, and renal cell carcinoma. Nevertheless, these drugs have some target related adverse effects, particularly cardiovascular toxicities. We report here the case of a patient included in a phase I trial of a new compound, a tyrosine kinase inhibitor targeting HER1, HER2, HER4 and VEGFR2. The patient developed during this treatment an acute and transient left ventricular systolic dysfunction. Careful management of this adverse effect allowed the patient to continue therapy and to achieve a major partial response.