Combined Inhibition of the VEGFR and EGFR Signaling Pathways in the Treatment of NSCLC

Multitargeted agents represent the next generation of targeted therapies in solid tumors. The benefits of individually targeting the vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) signaling pathways have been clinically validated in recent years in a number of solid tumor types including non‐small cell lung cancer (NSCLC). Given the heterogeneity of this tumor type and potential crosstalk between these key signaling pathways (which are known to play a critical role in tumor growth, metastasis, and angiogenesis), dual inhibition of the VEGFR and EGFR signaling pathways has the potential to offer additional clinical benefits in NSCLC. A number of approaches to inhibiting both VEGFR and EGFR signaling are currently under investigation, including monotherapy with a multitargeted tyrosine kinase inhibitor (e.g., vandetanib, AEE788, XL647, BMS‐690514) or a combination of single‐targeted therapies (e.g., bevacizumab, cetuximab, erlotinib, gefitinib). Preclinical and early clinical data (phase I and II trials) support combined inhibition of the VEGFR and EGFR pathways in NSCLC. Overall, combined inhibition strategies are well tolerated and have shown promise in early clinical studies. Ongoing phase II and phase III trials will determine the clinical potential of a number of dual inhibition strategies in the treatment of advanced NSCLC.     

Rationale for targeted therapies in hepatocellular carcinoma

Recent results showing survival improvement with sorafenib, a multitargeted kinase inhibitor, in patients with advanced hepatocellular carcinoma (HCC) suggest the important role of vascular endothelial growth factor receptor (VEGFR)/platelet-derived growth factor receptor (PDGFR)/Ras signaling in this disease. In preclinical studies, hypoxia, along with vascular endothelial growth factor (VEGF) and VEGFR strongly promote angiogenesis in multiple models including HCC. VEGF and VEGFR, other tyrosine kinase receptors such as the insulin growth factor receptor type 1 (IGF-1R), and the epidermal growth factor receptor (EGFR)-1, along with intracytoplasmic kinases such as the mammalian target of rapamycin (mTOR) have been tested in preclinical studies and/or clinical trials and validated as potential targets for therapeutic interventions in HCC. In this review, we will update preclinical data supporting the rationale for clinical development and potential combinations using novel targeted therapies in patients with HCC.     

Simultaneous inhibition of EGFR, VEGFR, and platelet-derived growth factor receptor signaling combined with gemcitabine produces therapy of human pancreatic carcinoma and prolongs survival in an orthotopic nude mouse model

Although gemcitabine has been approved as the first-line chemotherapeutic reagent for pancreatic cancer, its response rate is low and average survival duration is still only marginal. Because epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR) modulate tumor progression, we hypothesized that inhibition of phosphorylation of all three on tumor cells, tumor-associated endothelial cells, and stroma cells would improve the treatment efficacy of gemcitabine in an orthotopic pancreatic tumor model in nude mice and prolong survival. We implanted L3.6pl, a human pancreatic cancer cell, in the pancreas of nude mice. We found that tumor-associated endothelial cells in this model highly expressed phosphorylated EGFR, VEGFR, and PDGFR. Oral administration of AEE788, a dual tyrosine kinase inhibitor against EGFR and VEGFR, decreased phosphorylation of EGFR and VEGFR. PDGFR phosphorylation was inhibited by STI571. Although i.p. injection of gemcitabine did not inhibit tumor growth, its combination with AEE788 and STI571 produced >80% inhibition of tumor growth and prolonged survival in parallel with increases in number of tumor cells and tumor-associated endothelial cell apoptosis, decreased microvascular density, decreased proliferation rate, and prolonged survival. STI571 treatment also decreased pericyte coverage on tumor-associated endothelial cells. Thus, inhibiting phosphorylation of EGFR, VEGFR, and PDGFR in combination with gemcitabine enhanced the efficacy of gemcitabine, resulting in inhibition of experimental human pancreatic cancer growth and significant prolongation of survival.     

Sorafenib and sunitinib in the treatment of advanced non-small cell lung cancer

Despite the optimization of chemotherapy regimens, treatment outcomes for advanced non-small cell lung cancer (NSCLC) are still considered to be disappointing. Thus, clinical research of new treatment strategies is warranted. Several targeted agents have been introduced into clinical trials in NSCLC, but to date, only a few of these new agents can offer hope of a substantial impact on the natural history of the disease. One of the main reasons for the failure of several clinical trials of targeted therapy in lung cancer is that there is multilevel cross-stimulation among the targets of the new biological agents along several pathways of signal transduction that lead to neoplastic events; blocking only one of these pathways, as most first-generation targeted agents do, allows others to act as salvage or escape mechanisms for cancer cells. Sorafenib and sunitinib are two oral multitargeted receptor tyrosine kinase inhibitors. Sorafenib is a multikinase inhibitor that inhibits the kinase activity of both C-RAF and B-RAF and targets the vascular endothelial growth factor receptor family (VEGFR-2 and VEGFR-3) and platelet-derived growth factor receptor family (PDGFR-beta and stem cell factor receptor [KIT]). Sunitinib is a multitargeted inhibitor of PDGFR, KIT, fms-like tyrosine kinase 3, and VEGFR. The kinases targeted and inhibited by sorafenib and sunitinib directly and indirectly regulate tumor growth, survival, and angiogenesis, and this might be expected to result in broad antitumor efficacy. Sorafenib and sunitinib have been approved by the U.S. Food and Drug Administration for the treatment of metastatic renal cell carcinoma; sunitinib has also been approved for the treatment of gastrointestinal stromal tumors. Their mechanism of action, preclinical data, and phase II studies suggest efficacy in the treatment of advanced NSCLC.     

The Role of Anti–Epidermal Growth Factor Receptor and Anti–Vascular Endothelial Growth Factor Therapies in the Treatment of Non–Small-Cell Lung Cancer

Standard first-line therapy for non–small-cell lung cancer (NSCLC) with platinum-based agents, given in combination with cytotoxic compounds, has reached a relative plateau in its therapeutic efficacy. Novel molecular targeted agents acting on specific pathways have emerged as effective agents for treating NSCLC; some have already produced positive results in phase III trials. Notably, inhibition of the vascular endothelial growth factor (VEGF) pathway with an anti-VEGF antibody, bevacizumab, and targeting the epidermal growth factor receptor (EGFR) pathway with a small-molecule EGFR tyrosine kinase inhibitor erlotinib or a monoclonal antibody (cetuximab) have demonstrated prolonged survival in patients with advanced disease in both the first- and second-line settings. The heterogeneity of signaling processes leading to tumor cell survival and proliferation supports the targeting of multiple signaling pathways as an effective anticancer treatment strategy. Consequently, rational combinations of molecular targeted agents might offer superior clinical efficacy and an alternative treatment option to patients refractory to, or unable to tolerate, standard chemotherapy. The challenge lies in determining which molecular entities should be pursued and the best approach to combine them. This review discusses the potential clinical utility of combining bevacizumab and erlotinib to inhibit both angiogenesis and EGFR signaling as a valid nonchemotherapeutic approach for the treatment of NSCLC. Other combinations of novel therapies that block EGFR and angiogenic pathways, as well as complementary signaling pathways, with unique modes of action and low toxicity profiles could offer an increased repertoire of individualized treatment options for patients with advanced NSCLC.     

Novel Targeted Agents for Lung Cancer

It has been quite challenging to demonstrate significant improvements in survival for patients with Non—Small-cell lung cancer (NSCLC) over the past decade, but targeted therapies such as epidermal growth factor receptor (EGFR) inhibitors and angiogenesis inhibitors have been associated with benefits sufficient to alter our treatment standards. In addition to variations within these classes and combinations of such agents, several novel targeted therapy strategies have been introduced and are now emerging with encouraging results in early clinical trials for patients with advanced NSCLC. Immunotherapies targeting the MUC1 protein, MAGE-A3, and EGFR have shown early evidence of clinical benefits. Belagenpumatucel-L is a nonspecific allogeneic vaccine derived from multiple lung cancer cell lines, and the agent talactoferrin alfa might improve clinical outcomes based on broad immune system activation and stimulation. Other approaches that inhibit insulin-like growth factor receptor or heat-shock protein, both involved with multiple pathways involved with cell growth and survival, have shown activity in early trials and are moving forward in trials that specifically focus on patients with advanced NSCLC. This article reviews current data and future directions for each of these approaches.     

肾细胞癌分子靶向治疗进展

针对血管内皮生长因子受体和表皮生长因子受体信号传导通路发展的低分子量多靶点酪氨酸激酶抑制剂、抗血管生成单克隆抗体、哺乳动物雷帕霉素靶蛋白抑制剂等分子靶向药物二线治疗肾细胞癌有延长无进展生存优势;一线治疗在无进展生存期及总生存期方面优于传统细胞因子治疗。分子靶向药物联合应用及与细胞因子或传统化疗药物的联合应用正在研究中。     

Perspective on the development of new agents in thoracic cancers

The development of several targeted agents that play a critical role in the growth and survival of carcinomas has paved the way for a new era in the treatment of patients with thoracic malignancies. The novel antimetabolite pemetrexed has emerged as a key agent in the treatment of advanced malignant pleural mesothelioma (MPM). Inhibitors of the epidermal growth factor receptor (EGFR) are one of many promising targeted therapies for non-small-cell lung cancer (NSCLC). By utilizing agents that specifically target the biochemical and molecular changes underlying cancer, it is possible to envision a future in which combinations of therapies treat cancer on multiple fronts, significantly enhancing tumor responses and improving survival beyond current expectations.     

Investigational agents in the management of non-small cell lung cancer

Novel therapeutic agents are playing an increasingly prominent role in the treatment of non-small cell lung cancer (NSCLC). Drugs that target important oncogenic proteins or pathways, whether used as monotherapy or in combination with established regimens, have largely supplanted traditional cytotoxic agents in modern clinical trials. In particular, inhibitors of the epidermal growth factor receptor (EGFR) and/or vascular endothelial growth factor (VEGF) pathways have shown significant clinical activity and in some cases have changed the standard of care for advanced NSCLC. In the past year, an unprecedented number of trials have been reported using agents targeting the EGFR (erlotinib, gefitinib, cetuximab), VEGF (bevacizumab) or the VEGF receptor (sorafenib, sunitinib, cediranib), and inhibitors of both pathways (vandetanib, erlotinib, or cetuximab plus bevacizumab). This review focuses on recently reported trials of targeted agents that have the potential to affect the treatment of patients with NSCLC.     

The emerging role of epidermal growth factor receptor (EGFR) inhibitors in first-line treatment for patients with advanced non-small cell lung cancer positive for EGFR mutations

Gefitinib and erlotinib, small-molecule tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), were the first molecularly targeted agents to become clinically available for the treatment of non-small cell lung cancer (NSCLC). During the course of their clinical development, it has become clear that the substantial clinical benefit associated with EGFR-TKIs is limited to patients harboring activating mutations of EGFR. Accumulating clinical outcomes in patients with EGFR mutation-positive NSCLC treated with EGFR-TKIs support the notion that this group of individuals constitutes a clinically distinct population. These findings have prompted investigations of the potential role of first-line treatment with EGFR-TKIs in molecularly selected patients, with platinum-based doublet chemotherapy currently being the standard of care for most individuals with advanced NSCLC. This review summarizes the results of recent clinical trials of EGFR-TKIs in selected patients and highlights the efficacy of these drugs in first-line treatment as a form of personalized medicine aimed at improving therapy for advanced NSCLC.     

ZD1839 (Iressa) in non-small cell lung cancer

Despite the advent of cisplatin-based combination chemotherapy for advanced non-small cell lung cancer (NSCLC), the prognosis for this patient population remains poor. Novel biologically targeted agents currently in development have the potential for greater efficacy against NSCLC, and possibly less toxicity than is associated with conventional cytotoxic chemotherapy. The epidermal growth factor receptor (EGFR) is recognized as a potentially useful target, and the small molecule, orally active EGFR-tyrosine kinase inhibitor ZD1839 (Iressa) is currently the furthest along in clinical development of the anti-EGFR agents. This review summarizes the currently available clinical data on the use of ZD1839 in the treatment of NSCLC.     

Targeted agents for the treatment of advanced renal cell carcinoma

Metastatic renal cell carcinoma (RCC) is currently one of the most treatment-resistant malignancies. However, the elucidation of the molecular mechanisms underlying RCC development has led to the identification of promising targets for novel therapeutic agents. The involvement of the Von Hippel-Lindau protein pathway in clear cell RCC suggests that downstream targets of this pathway, namely, signaling through vascular endothelial growth factor (VEGF) in endothelial cells, platelet-derived growth factor (PDGF) in endothelial cells and pericytes, and the epidermal growth factor receptor (EGFR) pathway in tumor cells are all reasonable and rational therapeutic targets. A number of agents are in development that target VEGF (bevacizumab, a recombinant, humanized monoclonal antibody) or its receptor, VEGFR (PTK787, SU011248, and BAY 43-9006, all of which are small molecule inhibitors). Agents targeting EGFR also are being investigated clinically (gefitinib, cetuximab, erlotinib, and ABX-EGF). The Raf/MEK/ERK pathway is an important downstream convergence point for signaling through VEGFR, platelet-derived growth factor receptor (PDGFR), and EGFR (all have receptor tyrosine kinase activity) and also has important antiapoptotic effects, thereby providing an attractive target for intervention. In addition to inhibiting VEGFR and PDGFR-mediated angiogenic pathways, BAY 43-9006 has been shown to inhibit the Raf/MEK/ERK pathway at the level of Raf kinase. MEK-directed therapeutic approaches are also in development. Given that multiple molecular pathways are implicated in tumor cell growth, antitumor activity may be increased by using individual agents that target multiple pathways, or by combining different agents to allow vertical or horizontal inhibition of relevant pathways.     

VEGFR2 blockade augments the effects of tyrosine kinase inhibitors by inhibiting angiogenesis and oncogenic signaling in oncogene-driven non-small-cell lung cancers

Molecular agents targeting the epidermal growth factor receptor (EGFR)-, anaplastic lymphoma kinase (ALK)- or c-ros oncogene 1 (ROS1) alterations have revolutionized the treatment of oncogene-driven non-small-cell lung cancer (NSCLC). However, the emergence of acquired resistance remains a significant challenge, limiting the wider clinical success of these molecular targeted therapies. In this study, we investigated the efficacy of various molecular targeted agents, including erlotinib, alectinib, and crizotinib, combined with anti-vascular endothelial growth factor receptor (VEGFR) 2 therapy. The combination of VEGFR2 blockade with molecular targeted agents enhanced the anti-tumor effects of these agents in xenograft mouse models of EGFR-, ALK-, or ROS1-altered NSCLC. The numbers of CD31-positive blood vessels were significantly lower in the tumors of mice treated with an anti-VEGFR2 antibody combined with molecular targeted agents compared with in those of mice treated with molecular targeted agents alone, implying the antiangiogenic effects of VEGFR2 blockade. Additionally, the combination therapies exerted more potent antiproliferative effects in vitro in EGFR-, ALK-, or ROS1-altered NSCLC cells, implying that VEGFR2 inhibition also has direct anti-tumor effects on cancer cells. Furthermore, VEGFR2 expression was induced following exposure to molecular targeted agents, implying the importance of VEGFR2 signaling in NSCLC patients undergoing molecular targeted therapy. In conclusion, VEGFR2 inhibition enhanced the anti-tumor effects of molecular targeted agents in various oncogene-driven NSCLC models, not only by inhibiting tumor angiogenesis but also by exerting direct antiproliferative effects on cancer cells. Hence, combination therapy with anti-VEGFR2 antibodies and molecular targeted agents could serve as a promising treatment strategy for oncogene-driven NSCLC.     

Critical update and emerging trends in epidermal growth factor receptor targeting in cancer.

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB receptor family that is abnormally activated in many epithelial tumors. The aberrant activation of the EGFR leads to enhanced proliferation and other tumor-promoting activities, which provide a strong rationale to target this receptor family. There are two classes of anti-EGFR agents: monoclonal antibodies (MAbs) directed at the extracellular domain of the receptor and small molecule, adenosine triphosphate-competitive inhibitors of the receptor's tyrosine kinase. Anti-EGFR MAbs have shown antitumor activity in advanced colorectal carcinoma, squamous cell carcinomas of the head and neck, non-small-cell lung cancer (NSCLC) and renal cell carcinomas. The tyrosine kinase inhibitors (TKIs) have a partially different activity profile. They are active against NSCLC, and a specific EGFR inhibitor has shown improvement in survival. Recently, mutations and amplifications of the EGFR gene have been identified in NSCLC and predict for enhanced sensitivity to anti-EGFR TKIs. In addition to specific anti-EGFR TKIs, there are broader acting inhibitors such as dual EGFR HER-2 inhibitors and combined anti-pan-ErbB and antivascular endothelial growth factor receptor inhibitors. Current research efforts are directed at selecting the optimal dose and schedule and identifying predictive factors of response and resistance beyond EGFR gene mutations and/or amplifications. Finally, there is a need for improved strategies to integrate anti-EGFR agents with conventional therapies and to explore combinations with other molecular targeted approaches including other antireceptor therapies, receptor-downstream signaling transduction inhibitors, and targeted approaches interfering with other essential drivers of cancer, such as angiogenesis.     

Co-expression of receptor tyrosine kinases in esophageal adenocarcinoma and squamous cell cancer

This study aimed to define the co-expression pattern of target receptor tyrosine kinases (RTKs) in human esophageal adenocarcinoma and squamous cell cancer. The co-expression pattern of vascular endothelial growth factor receptor (VEGFR)1-3, platelet-derived growth factor receptor (PDGFR)alpha/beta and epidermal growth factor receptor 1 (EGFR1) was analyzed by RT-PCR in 50 human esophageal cancers (35 adenocarcinomas and 15 squamous cell cancers). In addition, IHC staining was applied for the confirmation of the expression and analysis of RTK localisation. The adenocarcinoma samples revealed VEGFR1 (97%), VEGFR2 (94%), VEGFR3 (77%), PDGFRalpha (91%), PDGFRbeta (85%) and EGFR1 (97%) expression at different intensities. Ninety-four percent of the esophageal adenocarcinomas expressed at least four out of six RTKs. Similarly, squamous cell cancers revealed VEGFR1 (100%), VEGFR2 (100%), VEGFR3 (53%), PDGFRalpha (100%), PDGFRbeta (87%) and EGFR1 (100%) expression at different intensities. All esophageal squamous cell carcinomas expressed at least four out of six RTKs. While VEGFR1-3 and PDGFRalpha and EGFR1 was expressed by tumor cells, PDGFRbeta was restricted to stromal cells, which also depicted a PDGFRalpha expression. Our results revealed a high rate of RTK co-expression in esophageal adenocarcinoma and squamous cell cancer and may encourage application of multi-target RTK inhibitors within a multimodal concept as a promising novel approach for innovative treatment strategies.     

Targeting epidermal growth factor receptor in lung cancer: Perspective from the Asia–Pacific region

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB family that is frequently overexpressed in non‐small cell lung cancer (NSCLC), and has been identified as a novel therapeutic target for lung cancer. The development of small molecule EGFR‐tyrosine kinase inhibitors (TKI) such as gefitinib and erlotinib has resulted in paradigm shift in the treatment of advanced NSCLC. The impact of EGFR‐TKI in the treatment of NSCLC is even greater in Asia–Pacific region because one of the greatest clinical benefits of EGFR‐TKI has been seen in patients of East Asian ethnicity. The discovery of somatic mutations in EGFR‐tyrosine kinase domain has so far answered some, but not all, of the questions regarding the clinical response to EGFR‐TKI in NSCLC. In addition, other molecular profiles such as KRAS mutations have also been found to play an important role in EGFR targeted therapy. In this article, we review EGFR targeted therapy in NSCLC with the focus on perspective from the Asia–Pacific region.     

Epidermal growth factor receptor tyrosine kinase inhibitors in elderly or poor performance status patients with advanced non-small cell lung cancer

Elderly and poor performance status advanced non-small cell lung cancer (NSCLC) patients often tolerate chemotherapy poorly. Special approaches are needed for these patient populations. Tyrosine kinase inhibitors (TKIs) of the epidermal growth factor receptor (EGFR), erlotinib and gefitinib, are active agents in the treatment of advanced NSCLC. Several phase II trials have been conducted utilizing EGFR TKIs in elderly or poor performance status patients with advanced NSCLC. This review will summarize the results of erlotinib or gefitinib in these subsets of patients with advanced NSCLC.     

Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer

First-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer (NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Second-generation EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs.     

'Targeting' the epidermal growth factor receptor tyrosine kinase with gefitinib (Iressa) in non-small cell lung cancer (NSCLC)

Gefitinib (ZD1839, Iressa), a selective drug inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase (TK), was recently approved for the treatment of patients with advanced non-small cell lung cancer (NSCLC). This article reviews the identification of EGFR as a therapeutic target and the steps in the development of gefitinib as "targeted" monotherapy for patients with NSCLC. Whether EGFR is required for the maintenance of lung tumor survival is also discussed. Finally, strategies to identify predictors of response to gefitinib are explored.     

First-line therapy of mutated non-small cell lung cancer: an update

Currently, many treatment options and new targets for cancer therapies for patients with advanced non-small cell lung cancer (NSCLC) are being evaluated. This article discusses in detail the significance of first-line and second-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and inhibitors of the vascular endothelial growth factor receptor (VEGFR) and EML4-ALK. Furthermore, the article summarizes the implications and future prospects of using molecular testing in the field of NSCLC with focus on EGFR mutations, KRAS mutation, EML4-ALK fusion gene detection, and EGFR expression.