Epidermal Growth Factor Inhibitors Research Articles

Successful Treatment of Carcinomatous Meningitis with Gefitinib in a Patient with Lung Adenocarcinoma Harboring a Mutated EGF Receptor Gene

Carcinomatous meningitis is a severe complication of lung cancer. Although treatment with gefitinib, a tyrosine kinase inhibitor of epidermal growth factor (EGF) receptor, has been reported to be highly effective against lung cancers harboring a mutated EGF gene, its effect against carcinomatous meningitis is unknown. Here, we report successful treatment of carcinomatous meningitis with gefitinib in a lung cancer patient suffered from meningeal metastasis. A 62-year-old, non-smoking, Japanese male was admitted for headache, failing vision, and temporary loss of consciousness and was subsequently diagnosed with stage IV lung adenocarcinoma and carcinomatous meningitis. A tumor sample revealed the in-frame deletion of codons 746 to 750 (E746 to A750) in exon 19 of the EGF gene, which leads to constitutive activation of the tyrosine kinase domain and high-affinity binding of gefitinib. The patient's performance status was poor owing to progression of the meningitis and elevated cerebrospinal fluid (CSF) pressure. Combined treatment with gefitinib (250 mg/day) and whole-brain irradiation (36 Gray total) proved to be effective. It is noteworthy that the level of gefitinib in the CSF was less than 1% of the serum level (serum: 117 nM before drug re-administration and 132 nM 2 hrs later; CSF: 0.9 nM both before and 2 hrs after drug re-administration). Gefitinib treatment should be considered for patients with carcinomatous meningitis and lung adenocarcinoma harboring a mutated EGF gene.

Adverse Cutaneous Reactions to Erlotinib

Introduction Erlotinib is an inhibitor of human epidermal growth factor approved for treating nonsmall cell lung cancer. The aim of this prospective observational study was to determine the prevalence of adverse cutaneous reactions caused by erlotinib and assess the management of such effects. Methods Eleven patients with lung cancer and 1 with ovarian cancer received erlotinib at a dose of 150 mg/d. The prevalence, severity, and time course of the adverse cutaneous reactions were assessed. Results The most frequent cutaneous reaction was acneiform eruption (10 cases). The patients were treated with topical erythromycin and clindamycin, or with doxycycline. Also reported were seborrheic dermatitis (5), paronychia (4), xerosis (3), mouth blisters (3), blepharitis (2), cheilitis (1), and fissures on the hands and feet (1). The first reactions to appear were seborrheic dermatitis (9.8 days until onset) and acneiform eruption (11.8 days), whereas the paronychia presented latest (65.3 days). One patient with acneiform eruption and another with paronychia suspended treatment until the lesions improved. Conclusions Erlotinib induces adverse effects in most patients treated. Acneiform eruption, seborrheic dermatitis, and paronychia are the most frequently reported reactions and can lead to temporary suspension of erlotinib administration.

Long-Term in vitro Expansion of Retinal Progenitor Cells by Culturing Intact Neurospheres in Monolayer

This study developed a modified monolayer culture technique for expansion of retinal progenitor cells in vitro. Using this method, spheres collected by low centrifugation from free floating cultures were re-seeded onto poly-D-lysine pre-coated flasks, and cultured in the retinal progenitor cells medium (including fibrous growth factor, epidermal growth factor and leukemia inhibitor factor) plus 5% FBS for the first 24 h, then FBS was removed. These cultured cells were proliferative, and in addition to expressing the neuroectodermal marker nestin they were multipotential. By immunocytochemistry and FACS analysis, we demonstrated that the percentage of nestin-expressing cells in passage 2 and passage 8 was 92.5 and 85.5%, respectively, which was greater than the percentage of their counterparts, 81.9 and 76.2%, in simple adhesive cultures (p < 0.05). Moreover, these cells preferentially differentiated into retinal neurons rather than glial cells.

Minocycline decreases severity of cetuximab rash

Prophylactic treatment with oral minocycline decreases the severity of cetuximab-related rash, but the benefi cial eff ects are short-lived (J Clin Oncol 2007; 25: 5390–96). Cetuximab is an epidermal growth factor (EGFR) inhibitor that is used to treat metastatic colorectal cancer. However, cetuximab produces an acnelike rash in over 80% of patients treated. Although unpleasant, the appearance of this rash shows a response to the anti-EGFR treatment. Evidence to support an eff ective treatment for rashes linked to EGFR inhibitors has been absent; control of severe cetuximab-related eruptions has been by interrupting treatment or reducing the dose. Alon Scope (Memorial SloanKetter ing Cancer Center, NY, USA) and colleagues randomly assigned 48 patients about to start cetuximab to receive oral minocycline (100 mg daily) or placebo for 8 weeks. Patients were also randomly assigned to receive topical tazarotene treatment to either the right or left side of the face. Total facial lesion counts were lower in patients receiving minocycline between weeks 1 and 4, and at week 4, fewer patients in the minocycline group reported moderate-to-severe itch (20% vs 50%, p=0·05). By week 8, the diff erences between the two groups had diminished. Tazarotene treatment produced no clinical benefi t. The researchers conclude that prophylactic minocycline treatment at the initiation of cetuximab is reasonable, but that beyond 8 weeks, the strategy is not benefi cial. Importantly, suppression of the rash in this manner does not seem to aff ect response to cetuximab. Siegfried Segaert (University Hospital Sint-Rafael, Leuven, Belgium) suggests that prophylactic treatment should now be compared with a reactive regimen, whereby only patients developing severe rash are given the systemic tetracycline. “Then you don’t give oral tetracyclines in an unnecessary way to patients with only mild rash, and you don’t lose rash severity as a pharmacodynamic marker.”

Venous Thromboembolism and Non-Small Cell Lung Cancer: A Pooled Analysis of National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) Trials.

Purpose: To determine the incidence of venous thromboembolism (VTE) in patients with early and advanced non-small cell lung cancer (NSCLC); to explore predictive factors for VTE occurrence during trials in these populations, and to investigate the effect of VTE on overall survival in patients with NSCLC.Patients and Methods: Data from three National Cancer Institute of Canada Clinical Trials Group trials were included in the analyses (n=1987). JBR.10 was a randomized study of post-resection adjuvant vinorelbine/cisplatin versus observation in stage IB/II NSCLC. BR.18 was a randomized study of paclitaxel/carboplatin ± the metalloproteinase inhibitor BMS-275291 in advanced NSCLC (1st line). BR.21 was a randomized study of erlotinib versus placebo in previously treated (2nd or 3rd line) NSCLC. The relationship between VTE, cancer treatment, concomitant medications, and baseline patient characteristics was explored with univariate and multivariate analysis. Cox regression analysis was performed to determine whether VTE was independently associated with survival. Each trial was analyzed separately; in addition a pooled analysis was performed with the advanced disease trials (BR.18 and BR.21).Results: The incidence of VTE was 0% in the observation arm of JBR.10 and ranged from 3% in the adjuvant chemotherapy arm of JBR.10 to 8% in BR.18. In JBR.10, VTE was independently associated with the administration of adjuvant chemotherapy (p=0.015), baseline obesity (p=.001), and low platelet count (p=.007). For patients with advanced NSCLC, VTE was significantly more common in patients receiving chemotherapy (BR.18) compared to patients receiving erlotinib or placebo (BR.21) (8% vs 2%, p< 0.0001). In BR.18, but not BR.21, VTE was associated with a prior history of VTE (p=0.001). When BR.18 and BR.21 were pooled, prior VTE remained significant. In BR.18 and BR.21, VTE was associated with shorter survival in multivariate analysis (HR=1.69, 95%CI 1.32–2.17, p<.0001); further analyses, including JBR.10, are planned to explore this finding.Conclusion: VTE is a frequent event in patients with advanced NSCLC and is associated with the administration of chemotherapy. Treatment with metalloproteinase or epidermal growth factor inhibitors does not appear to increase the risk of VTE. In early NSCLC, adjuvant chemotherapy, morbid obesity and a prior history of VTE are associated with increased risk. VTE is associated with shortened survival in patients with advanced NSCLC. Funding for this study was provided by the Canadian Cancer Society.

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.

New nitric oxide-releasing polymers for implantable devices

The application claims for a new polymer formulation derived from modified polyimines that can be used either to entirely fabricate or to simply coat medical devices. Interestingly, these new biocompatible polymers can include nitric oxide-releasing molecules, essentially diazeniumdiolates, and other different bioactive agents (immunosuppressants, antiproliferatives, anti-inflammatory, epidermal growth factor inhibitors and so on). Although this polymer could be adopted for different medical devices (urethral and biliary stents, sutures, ocular devices and so on), vascular stents should be the main application. In this indication, the invention could represent an evolution of the so-called drug eluting stents, that at their presentation were considered by the FDA as a breakthrough technology while, at present, are under critical careful review because of a debated increased risk of stent thrombosis.

Xerosis und Exsikkationsekzem unter Therapie eines metastasierten Adenokarzinoms mit monoklonalem Anti-VEGF-Antikörper Bevacizumab (Avastin®)

Recently, inhibitors of epidermal growth factor (VEGF) were approved by health authorities for treatment of metastatic carcinomas including colorectal and breast carcinoma. During therapy with inhibitors of epidermal growth factor, cutaneous side effects (e. g. acneiform eruptions, xerosis and paronychia) occur very frequently. We report on a 64 year old male patient with pulmonal, pleural, bone metastasis and suspected liver metastasis from an adenocarcinoma of unknown origin. During the therapy he developed within a few weeks generalized xerosis and palmoplantar pronounced asteatotic eczema. This observation, among others, could be a hint that, despite lacking affinity towards the EGF receptor, cutaneous side effects known from blockade of the EGF signal transduction could also occur during therapy with antibodies directed against VEGF in some cases.

Acquired Trichomegaly and Symptomatic External Ocular Changes in Patients Receiving Epidermal Growth Factor Receptor Inhibitors

To report the external ocular changes in 2 patients receiving epidermal growth factor receptor (EGFR) inhibitors. Retrospective observational case series. Two patients receiving epidermal growth factor inhibitors for metastatic non-small-cell lung carcinoma were followed clinically and with external photographs. Findings included acneiform facial changes, telangiectasia of eyelid margins, meibomitis, tear film dysfunction, and unusual, hyperpigmented, tortuous eyelashes. EGFR inhibitors used in the treatment of certain malignancies can lead to symptomatic adnexal and ocular surface changes. Ophthalmologists should be aware of these to appropriately manage them.

Lysophosphatidic Acid Decreases Epidermal Growth Factor Receptor Binding in Airway Epithelial Cells

We showed previously that treatment of human airway smooth muscle cells and lung fibroblasts with lysophosphatidic acid (LPA) increases the binding of epidermal growth factor (EGF) to EGF receptors (EGFRs). The purpose of this study was to determine whether LPA also regulates EGFR binding in airway epithelial cells. Airway epithelial cells were incubated in the absence or presence of 10 microM LPA for increasing times, and binding of 125I-EGF to intact cells on ice was measured. Exposure to LPA for only 15 min caused a 30 to 70% decrease in EGFR binding in a dose-dependent manner, depending on the cell line. This decrease in binding was sustained to at least 18 h in BEAS-2B and primary human bronchial epithelial cells. In contrast, the LPA-induced decrease in binding reversed rapidly in two lung cancer epithelial cell lines, H292 and A549, returning to control levels within 3 h. LPA increased phosphorylation of the EGFR in BEAS-2B cells, and this phosphorylation was inhibited by both 4-(3'-chloroanilino)-6,7-dimethoxy-quinazoline (AG1478; EGFR tyrosine kinase inhibitor) and N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-l-tryptophan methylamide (GM6001; matrix metalloproteinase inhibitor) but not by CRM197 (heparin-binding EGF inhibitor). AG-1478 and GM6001 also inhibited the LPA-induced decrease in EGFR binding but only by 50%, suggesting only partial involvement of EGFR transactivation in the decrease in EGFR binding. In summary, LPA stimulates a decrease in EGFR binding in airway epithelial cells that is sustained in normal cells but that rapidly reverses in cancer cells. LPA-induced transactivation of EGFRs occurs and contributes to the decrease in EGFR binding, but additional pathway(s) may also be involved.

A phase I trial of RAD001 in combination with cetuximab in patients with advanced solid tumors

14075 Background: Cetuximab is a selective epidermal growth factor (EGFR) inhibitor approved for use in EGFR expressing advanced colorectal cancers. RAD001 inhibits mTOR (mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway. Preclinical studies suggest that RAD001 may restore sensitivity to EGFR inhibitors in resistant cell lines, and that in combination it may augment anti-tumor activity. We assessed safety, pharmacokinetics (PK), and pharmacodynamic (PD) endpoints for mTOR inhibition and tumor vascular permeability in a phase I combination study. Methods: Pts with EGFR-expressing advanced solid tumors were randomized to a 3 week run-in of single agent RAD001 or cetuximab Q wk, followed by RAD001 + cetuximab Qwk. RAD001 was dosed at 30–70 mg PO. Standard dosing of cetuximab was used (400 mg/m2 IV loading, followed by 250 mg/m2 IV Qwk). DLT was defined as any grade 4 hematologic or =grade 3 non-hematologic toxicity associated with treatment during cycle 1. In addition to plasma analysis for the PK of RAD001, we performed 18FDG-PET and dynamic contrast-enhanced (DCE) MRI before and during combination therapy, to assess for early changes in tumor metabolic activity and vascular permeability. Phosphorylation of p70S6K, a biomarker for RAD001 activity, was measured in peripheral blood mononuclear cells. Results: 12 pts (median age 56, 5 M/7F, median PS 0) were treated at dose levels 1–2 (RAD001 30–50mg/cetuximab 250 mg/m2), with 3 per dose order. Observed toxicities were all grade 1–2, and included mucositis (2/12), rash (8/12), fatigue (6/12), anorexia (4/12), nausea (5/12), and vomiting (5/12). 2 pts (parotid and ovarian CA) had SD (4+ mos) as best response, with decreased serum CA-125 in the ovarian CA pt. PET findings in pts with SD confirm decreased tumor metabolic activity. Conclusions: At these doses, neither drug appears to increase the toxicity of the other. Analysis of full dose RAD001 in the combination is nearing completion. Preliminary PET findings suggest biological activity of the combination. No significant financial relationships to disclose.

Patterns of management of rash associated with epidermal growth factor receptor inhibitors (EGFRIs): A national practice survey

14081 Background: Dermatological toxicities are frequent in patients receiving epidermal growth factor inhibitors (EGFRIs), which significantly affect health and quality of life. No current consensus or guidelines exist for the management of these manifestations. In order to gain insight on actual management approaches, a retrospective survey was conducted across oncology practices in the US. Methods: A survey in person was carried out that included 51 questions to 110 practitioners administering EGFRIs in the US, during which time erlotinib, cetuximab and gefitinib were FDA-approved. Open- and closed-ended questions relating to frequency and CTC-graded (G) severity of rash observed, management patterns, and impact on continued EGFRI therapy were evaluated. Statistical testing for correlations was done using Fisher’s exact test. Results: Respondents (resp) included MDs (72%), nurses (23%), NPs (4%), and pharmacists (1%). Majority (&gt;50%) of rash events observed were mild/moderate (G1 in 39% + G2 in 34%). Interventions against rash by resp was based on severity, with G1 treated by 47%, G2 (71%), G3 (87%), G4 (80%). Treatments for G1/2 included only topical agents (TA) by 30% of providers, and combined TA + systemic agents (SA) for G3 (G4) by 48% (30%) of providers. Interestingly, 84% of resp indicated G2 rash improved with TA+SA therapy and only 44% with SA only. Although severe events were reported infrequently (4% and 3% of resp see &gt;50% of G3 and 4 events, respectively), EGFRIs were frequently dose modified (76%) or discontinued (32%) due to rash. Conclusions: Rash is frequent and its management heterogeneous across the US, which increases with rash G. These findings suggest that combined therapy (TA + SA) is more effective than single-agent. Therefore, the high frequency of dose EGFRI modification/discontinuations reported may be minimized by proactive interventions. Trials evaluating proactive and reactive combined TA + SA against rash are currently underway. No significant financial relationships to disclose.

Photosensitive rash due to the epidermal growth factor receptor inhibitor erlotinib

A papulopustular rash occurs in 45-100% of patients undergoing anti-cancer treatment with epidermal growth factor (EGFR) inhibitors. Although the majority of cases involve the face and upper trunk, ultraviolet radiation has not yet been documented to play a major role in inducing or exacerbating symptoms. We describe a 75-year-old man who was being treated with the EGFR inhibitor erlotinib and developed the characteristic rash on unprotected areas of the trunk after photoexposure, while the protected areas (face and neck) remained uninvolved. This case underscores the importance of sun protection in patients treated with EGFR inhibitors and supports in vitro data showing that EGFR blockade results in altered keratinocyte survival and proliferation in response to ultraviolet radiation.

Pharmacology of epidermal growth factor inhibitors

Research into the molecular bases of malignant diseases has yielded the development of many novel agents with potential antitumor activity. Evidence for a causative role for the epidermal growth factor receptor (EGFR), which is now regarded as an excellent target for cancer chemotherapy in human cancer, leads to the development of EGFR inhibitors. Two classes of anti-EGFR agents are currently in clinical use: monoclonal antibodies directed at the extracellular domain of the receptor, and the low-molecular-weight receptor tyrosine kinase inhibitors acting intracellularly by competing with adenosine triphosphate for binding to the tyrosine kinase portion of the EGFR. The effect on the receptor interferes with key biological functions including cell cycle arrest, potentiation of apoptosis, inhibition of angiogenesis and cell invasion and metastasis. Cetuximab, a monoclonal antibody, and the receptor tyrosine kinase inhibitors gefitinib and erlotinib are currently approved for the treatment of patients with cancer. New agents with clinical activity are entering the clinic, and new combinatorial approaches are being explored with the aim of improving the potency and pharmacokinetics of EGFR inhibition, to increase the synergistic activity in combination with chemotherapy and overcome resistance to the EGFR inhibitors.

Insulin‐induced proliferation of bladder cancer cells is mediated through activation of the epidermal growth factor system

The mechanism behind the growth-promoting effect of insulin is a subject of debate. Employing RT4 bladder cancer cells, we examined the cross-talk between insulin and the epidermal growth factor system. We found that insulin induced a time- and dose-dependent (25-1000 nmol.L(-1) insulin) increase in mRNA expression of three ligands from the epidermal growth factor system. Times for peak increase and fold increase after incubation with 250 nmol.L(-1) insulin were as follows: heparin-binding epidermal growth factor-like growth factor, 0.5 h, 1.4-fold, P < 0.05; epiregulin, 3 h, 14-fold, P < 0.0001; and amphiregulin, 3 h, 12-fold, P < 0.001. Induction of heparin-binding epidermal growth factor-like growth factor and amphiregulin was verified at the protein level. We demonstrate that incubation of RT4 bladder cancer cells for 24 h with 250 nmol.L(-1) insulin increases proliferation by 43% (P < 0.0001) as compared to untreated cells. At the same time, phosphorylation and thereby activation of the epidermal growth factor receptor (HER1) was observed. Both phosphorylation and insulin-induced proliferation were almost completely inhibited by the HER1 inhibitor Iressa (P < 0.0001). This shows that insulin leads to activation of HER1, and that HER1 plays an essential role in mediating the growth-promoting effect of insulin. Iressa inhibited not only the activation of HER1 caused by insulin but also the insulin-induced increase in the three ligands (heparin-binding epidermal growth factor-like growth factor, epiregulin and amphiregulin). As heparin-binding epidermal growth factor-like growth factor was induced before epiregulin and amphiregulin upon insulin stimulation, we speculated that the insulin-induced heparin-binding epidermal growth factor-like growth factor initiated the activation of HER1, and that this in turn led to increased expression of epiregulin and amphiregulin and thereby to continued activation of HER1. Earlier reports have shown that insulin-like growth factor receptor can activate HER1 via its ligand heparin-binding epidermal growth factor-like growth factor. In accord with this, we found that treatment of RT4 cells with recombinant heparin-binding epidermal growth factor-like growth factor mimicked the effect of insulin, with induction of mRNA for the three ligands. However, the insulin-induced increase in mRNA expression of amphiregulin and epiregulin could not be prevented by the heparin-binding epidermal growth factor-like growth factor inhibitor CRM197, demonstrating that heparin-binding epidermal growth factor-like growth factor is not essential for the insulin-induced increase in the expression of these ligands. In conclusion, we show that insulin-induced growth in RT4 cells requires activated HER1. Furthermore, activation of HER1 is required for the insulin-induced increase in expression of the HER1 ligands heparin-binding epidermal growth factor-like growth factor, amphiregulin and epiregulin.

Concomitant inhibition of epidermal growth factor and vascular endothelial growth factor receptor tyrosine kinases reduces growth and metastasis of human salivary adenoid cystic carcinoma in an orthotopic nude mouse model

We hypothesized that epidermal growth factor (EGF) receptor (EGFR) activation and vascular endothelial growth factor (VEGF)-induced angiogenic signals are important for the progression and metastasis of human salivary adenoid cystic carcinoma (ACC). To test this hypothesis, we evaluated the therapeutic effect of AEE788, a dual inhibitor of EGF and VEGF receptor (VEGFR) tyrosine kinases, on human salivary ACC. In clinical specimens of salivary ACC, EGF and VEGF signaling proteins were expressed at markedly higher levels than in adjacent normal glandular tissues. We examined the effects of AEE788 on salivary ACC cell growth and apoptosis and on the phosphorylation of EGFR and VEGFR-2 in salivary ACC cells. Treatment of salivary ACC cells with AEE788, alone or in combination with chemotherapy, led to growth inhibition, induction of apoptosis, and dose-dependent inhibition of EGFR and VEGFR-2 phosphorylation. To determine the in vivo antitumor effects of AEE788, nude mice with orthotopic parotid tumors were randomized to receive oral AEE788 alone, paclitaxel alone, cisplatin alone, a combination of AEE788 plus paclitaxel, a combination of AEE788 plus cisplatin, or a placebo. AEE788 inhibited tumor growth and prevented lung metastasis in nude mice. To study the mechanism of interaction between AEE788 and chemotherapy, AEE788 was found to potentiate growth inhibition and apoptosis of ACC tumor cells mediated by chemotherapy. Tumors of mice treated with AEE788 and AEE788 plus chemotherapy exhibited down-regulation of activated EGFR and VEGFR-2, increased tumor and endothelial cell apoptosis, and decreased microvessel density, which correlated with a decrease in the level of matrix metalloproteinase-9 and matrix metalloproteinase-2 expression and a decrease in the incidence of vascular metastasis. These data show that EGFR and VEGFR can be molecular targets for therapy of salivary ACC.

Second-Line Treatment of Non-small Cell Lung Cancer: Big Targets, Small Progress; Small Targets, Big Progress?

In the current issue of the Journal of Thoracic Oncology, Noble and colleagues provide an excellent comprehensive review of systemic treatment for patients with advanced non-small cell lung cancer (NSCLC) previously treated with chemotherapy. The authors conclude that sufficient evidence exists for the routine use of either single-agent pemetrexed or docetaxel or erlotinib and that insufficient evidence exists for the routine use of other agents or combinations. I concur with these conclusions. However, whereas these agents result in prolonged survival and improved quality of life for some patients, the overall gains are modest at best. In fact, most patients still receive either no benefit or minimal benefits from treatment, and, for those who benefit, the duration of benefit is weeks to months, not months to years. We can and must do better, but how? An ideal starting point would be to enroll all eligible, willing patients into clinical trials that test new agents, combinations, and strategies. As with the first-line treatment of NSCLC with cytotoxics, a plateau has been reached with chemotherapy in the secondand third-line settings. We must take a cue from other recent successes in oncology in which molecularly targeted agents are given to carefully selected patient populations based on disease and tumor characteristics. In the last year, several agents have offered hope that these advances are forthcoming. I will mention just four, although there are dozens of other promising agents in the same class or others with differing mechanisms of action currently under investigation. Angiogenesis plays a vital role in tumor survival, and bevacizumab has already been proven effective in patients with NSCLC in the first-line setting. However, what is the role of continuing anti-angiogenic therapy beyond first line? Sorafenib is a multi-kinase inhibitor whose targets include the Ras signaling pathway and the vascular endothelial growth factor (VEGF) receptors. A phase II study (n 52) of sorafenib in patients with previously treated NSCLC was recently reported by Gatzemeier et al.1 Of the patients, 59% were reported to have stable disease, including 31% who had objective regression of disease. The authors reported that patients with higher VEGF levels had worse outcomes and that VEGF levels declined with treatment. Sunitinib is also a multi-kinase inhibitor that targets the angiogenesis receptors of VEGF and PDGF. A phase II study (n 63) by Socinski et al.2 included patients with advanced NSCLC who had received at least one prior chemotherapy regimen, including 57% who were receiving sunitinib as at least third-line therapy. Overall, 9.5% achieved a partial response, and an additional 42.9% had stable disease. Remarkably, 45 of 56 patients (80.4%) with disease evaluation reported had tumor regression at some point during treatment. These trials excluded patients treated with bevacizumab in the first-line setting. With the forthcoming, expected broad use of bevacizumab in the first-line setting, one must logically ask whether inhibition of the VEGF receptor intracellular tyrosine kinase will be effective in someone who has previously received bevacizumab. ZD6474 is a dual kinase inhibitor that targets both the epidermal growth factor (EGFR) and VEGFR. Natale et al.3 reported the results of a randomized phase II study (n 168) of gefitinib versus ZD6474. At the time of disease progression, crossover to the other agent was allowed. The hazard rate for progression-free survival (the primary

Rapamycin synergizes with the epidermal growth factor receptor inhibitor erlotinib in non–small-cell lung, pancreatic, colon, and breast tumors

The receptor for epidermal growth factor (EGFR) is overexpressed in many cancers. One important signaling pathway regulated by EGFR is the phosphatidylinositol 3'-kinase (PI3K)-phosphoinositide-dependent kinase 1-Akt pathway. Activation of Akt leads to the stimulation of antiapoptotic pathways, promoting cell survival. Akt also regulates the mammalian target of rapamycin (mTOR)-S6K-S6 pathway to control cell growth in response to growth factors and nutrients. Recent reports have shown that the sensitivity of non-small-cell lung cancer cell lines to EGFR inhibitors such as erlotinib (Tarceva, OSI Pharmaceuticals) is dependent on inhibition of the phosphatidylinositol 3'-kinase-phosphoinositide-dependent kinase 1-Akt-mTOR pathway. There can be multiple inputs to this pathway as activity can be regulated by other receptors or upstream mutations. Therefore, inhibiting EGFR alone may not be sufficient for substantial inhibition of all tumor cells, highlighting the need for multipoint intervention. Herein, we sought to determine if rapamycin, an inhibitor of mTOR, could enhance erlotinib sensitivity for cell lines derived from a variety of tissue types (non-small-cell lung, pancreatic, colon, and breast). Erlotinib could inhibit extracellular signal-regulated kinase, Akt, and S6 only in cell lines that were the most sensitive. Rapamycin could fully inhibit S6 in all cell lines, but this was accompanied by activation of Akt phosphorylation. However, combination with erlotinib could down-modulate rapamycin-stimulated Akt activity. Therefore, in select cell lines, inhibition of both S6 and Akt was achieved only with the combination of erlotinib and rapamycin. This produced a synergistic effect on cell growth inhibition, observations that extended in vivo using xenograft models. These results suggest that combining rapamycin with erlotinib might be clinically useful to enhance response to erlotinib.

Tyrosine phosphorylation of p145met mediated by EGFR and Src is required for serum-independent survival of human bladder carcinoma cells

Here we address the molecular mechanism of serum-independent survival and growth of human bladder carcinoma cell line 5637. Serum starvation promoted tyrosine phosphorylation of a 145-kDa protein and activation of the tyrosine kinase Src and the receptor for epidermal growth factor (EGFR) over a slow time course (>8 hours). The phosphorylated 145-kDa protein was identified as the beta-subunit of c-Met/hepatocyte growth factor (HGF) receptor, p145(met), in which tyrosine residues 1003, 1234, and 1235 were phosphorylated. Inhibitors of Src (PP2, SU6656) or EGFR (AG99), but not p145(met) (K252a), effectively blocked tyrosine phosphorylation of p145(met) and promoted cell death accompanied by activation of caspase-like proteases. Conditioned medium from the serum-starved 5637 cells or purified EGF readily promoted the activation of Src and EGFR, and tyrosine phosphorylation of p145(met) in normally grown 5637 cells, suggesting that autocrine signaling of EGFR ligands is responsible for signal transduction events in serum-starved cells. Consistent with this idea, a monoclonal antibody against EGFR that would interfere with the ligand binding to EGFR blocked tyrosine phosphorylation events and promoted the caspase activation and cell death in serum-free conditions. Such apoptotic cell death was also induced by pretreatment of cells with a high concentration of HGF that downregulated endogenous p145(met). Nevertheless, Cu2+ ions, competitive inhibitors for HGF-binding to p145(met), did not show any effect on cellular functions in serum-free conditions. These results suggest that the serum-independent growth of 5637 cells involves the transmembrane signaling cascade via EGFR ligand(s) (but not HGF), EGFR, Src and p145(met).

Tratamiento de la erupción acneiforme por inhibidores del factor de crecimiento epidérmico con tetraciclinas orales

Introduction Epidermal growth factor inhibitors (EGFR) are new antineoplastic agents that are increasingly being developed. They are basically used as second line treatment in advanced stage tumors. Appearance of a facial acneiform rash in patients treated with these drugs is common and characteristic. The literature proposes multiple topical and systemic treatment options. Up to now, there is no clear evidence on any of them. Patients and methods A descriptive study of 6 patients who were treated with 100 mg daily dose of doxyclycline for 3 weeks was conducted. Clinical characteristics of the patients and treatment efficacy were analyzed. Results Five of the six patients achieved total resolution of the acneiform rash with this treatment. One patient achieved partial response. After long follow-up periods and in spite of following treatment with the EGFR inhibitors, no relapse was observed. Conclusions Doxycycline is suggested as an effective treatment in this disease. Even though it is a short series, the results in our patients support this efficacy.