Molecular origins of lung cancer: prospects for personalized prevention and therapy.

The first Meeting on "Molecular Origins of Lung Cancer--Prospects for Personalized Prevention and Therapy" was held from January 10 to 14, 2010 in San Diego, California. The purpose of the meeting was to discuss important basic, translational, and clinical work aimed at improving lung cancer prevention, detection, and treatment. Topics included drug design, target identification, early detection, cancer stem cells, microRNAs, genome wide approaches to determining risk and outcome, mouse models, and tumor microenvironment.

Treatment with HIF-1alpha antagonist PX-478 inhibits progression and spread of orthotopic human small cell lung cancer and lung adenocarcinoma in mice.

Introduction: PX-478 is a potent small-molecule inhibitor of hypoxia-inducible factor 1alpha (HIF-1alpha). In prior preclinical studies, it had antitumor activity against various solid tumors in subcutaneous xenografts but had no measurable activity against a non-small cell lung cancer (NSCLC) xenograft. To determine the effectiveness of PX-478 against lung tumors, we investigated HIF-1alpha expression in several lung cancer cell lines, both in vitro and in vivo, and treated orthotopic mouse models of human lung cancer with PX-478.

Chemoradiotherapy with or without AE-941 in stage III non-small cell lung cancer: a randomized phase III trial.

BACKGROUND AE-941 is a standardized aqueous shark cartilage extract with antiangiogenic properties that has previously been evaluated in phase I and II clinical trials. Our objective was to determine the effect of adding AE-941 to chemoradiotherapy on overall survival of patients with unresectable stage III non-small cell lung cancer (NSCLC). METHODS A randomized, double-blinded, placebo-controlled, phase III clinical trial was designed to test the efficacy of AE-941 in unresectable stage III NSCLC patients who were treated with chemoradiotherapy.

Phase I dose-escalation study of recombinant human Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer.

Purpose: Apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL)-a member of the tumor necrosis factor cytokine family-induces apoptosis by activating the extrinsic pathway through the proapoptotic death receptors DR4 and DR5. Recombinant human Apo2L/TRAIL (rhApo2L/TRAIL) has broad potential as a cancer therapy. To the best of our knowledge, this is the first in-human clinical trial to assess the safety, tolerability, pharmacokinetics, and antitumor activity of multiple intravenous doses of rhApo2L/TRAIL in patients with advanced cancer.

Tobacco and cancer: an American Association for Cancer Research policy statement.

The evidence against tobacco use is clear, incontrovertible, and convincing; so is the need for urgent and immediate action to stem the global tide of tobacco-related death and suffering and to improve public health. The American Association for Cancer Research makes an unequivocal call to all who are concerned about public health to take the following immediate steps:Increase the investment in tobacco-related research, commensurate with the enormous toll that tobacco use takes on human health, to provide the scientific evidence to drive the development of effective policies and treatments necessary to dramatically reduce tobacco use and attendant disease. Develop new evidence-based strategies to more effectively prevent the initiation of tobacco use, especially for youth and young adults.

Comparison of patient outcomes according to histology among pemetrexed-treated patients with stage IIIB/IV non-small-cell lung cancer in two phase II trials.

Introduction: Recent phase III studies in advanced non-small-cell lung cancer (NSCLC) have demonstrated differential efficacy for pemetrexed according to NSCLC histology. The results of 2 phase II studies of pemetrexed and a platinum agent (carboplatin or oxaliplatin) were pooled to determine whether outcomes in the studies differed by tumor histology.

Patients And Methods: Chemotherapy-naive patients with stage IIIB/IV NSCLC received pemetrexed 500 mg/m2 plus carboplatin area under the curve of 6 (n = 89) or pemetrexed 500 mg/m2 plus oxaliplatin 120 mg/m2 (n = 41); both regimens were administered every 21 days.

Molecular pharmacology and antitumor activity of PHT-427, a novel Akt/phosphatidylinositide-dependent protein kinase 1 pleckstrin homology domain inhibitor.

Phosphatidylinositol 3-kinase/phosphatidylinositide-dependent protein kinase 1 (PDPK1)/Akt signaling plays a critical role in activating proliferation and survival pathways within cancer cells. We report the molecular pharmacology and antitumor activity of PHT-427, a compound designed to bind to the pleckstrin homology (PH) binding domain of signaling molecules important in cancer. Although originally designed to bind the PH domain of Akt, we now report that PHT-427 also binds to the PH domain of PDPK1.

HMGB1 and RAGE in inflammation and cancer.

The immune system has evolved to respond not only to pathogens, but also to signals released from dying cells. Cell death through necrosis induces inflammation, whereas apoptotic cell death provides an important signal for tolerance induction. High mobility group box 1 (HMGB1) is a DNA-binding nuclear protein, released actively following cytokine stimulation as well as passively during cell death; it is the prototypic damage-associated molecular pattern (DAMP) molecule and has been implicated in several inflammatory disorders.

A phase I safety and pharmacokinetic study of the death receptor 5 agonistic antibody PRO95780 in patients with advanced malignancies.

Purpose: PRO95780 is a fully human IgG1 monoclonal antibody that triggers the extrinsic apoptosis pathway through death receptor 5. This first-in-human study assessed the safety, tolerability, pharmacokinetics, and any early evidence of efficacy of PRO95780 in patients with advanced malignancies.

Experimental Design: Target concentrations were predicted to occur at 10 mg/kg.

Pharmacokinetic study of the phase III, randomized, double-blind, multicenter trial (TRIBUTE) of paclitaxel and carboplatin combined with erlotinib or placebo in patients with advanced Non-small Cell Lung Cancer (NSCLC).

Purpose: To assess the pharmacokinetics and evaluate potential drug-drug interactions between erlotinib, paclitaxel and carboplatin.

Experimental Design: 1,079 previously untreated patients with advanced NSCLC were enrolled and randomized in a phase III trial (TRIBUTE) to receive either erlotinib or placebo in combination with paclitaxel 200 mg/m2 IV over 3 h and carboplatin at a calculated dose to achieve an AUC 6 mg∙min/mL. To determine possible drug-drug interaction with this combination, a subset of 24 (12 erlotinib, 12 placebo) patients were enrolled onto an intensive pharmacokinetic (IPK) substudy group at a single site.

VeriStrat classifier for survival and time to progression in non-small cell lung cancer (NSCLC) patients treated with erlotinib and bevacizumab.

We applied an established and commercially available serum proteomic classifier for survival after treatment with erlotinib (VeriStrat) in a blinded manner to pretreatment sera obtained from recurrent advanced NSCLC patients before treatment with the combination of erlotinib plus bevacizumab. We found that VeriStrat could classify these patients into two groups with significantly better or worse outcomes and may enable rational selection of patients more likely to benefit from this costly and potentially toxic regimen.

Surgery: Future directions in multimodality therapy for NSCLC.

Patients with stage III non-small-cell lung cancer (nSclc) comprise a heterogeneous population; the role of surgical resection in this setting has been controversial. Albain and colleagues recently demonstrated that trimodality therapy with lobectomy had clinical benefit for patients with pathologic nodal N2 stage III nSclc. we discuss the trial and its implications for future lung cancer therapy.

[Telemedicine assisted diet and diagnosis management in food hypersensitivity].

Several studies have shown that the current prevalence of food allergy in Western Europe is about 4% and will further increase. Because of missing therapeutic alternatives, food allergy patients are required to identify individual allergens in the daily food by carefully reading the product's ingredient lists. Experiences with other chronic diseases show that a combination of telemedicine and Disease Management (DM) could have a positive impact on medical outcome and health related costs.

[Histamine intolerance mimics anorexia nervosa].

Histamine intolerance is a clinically heterogeneous disease. We present a woman who suffered from weight loss, diarrhea, abdominal pain, headache, flushing and bronchial asthma for several years. When placed on a histamine-poor diet, she experienced weight gain and improvement of other all signs and symptoms, supporting the diagnosis of histamine intolerance.

Integration of molecular profiling into the lung cancer clinic.

Individuals from five thoracic oncology centers in the United States recently met to discuss how to integrate molecular profiling into the care of all patients with carcinoma of the lung. Lung cancer is an area of medical oncology in which clinicians are beginning to use specific tumor-associated molecular aberrations to assign and/or prioritize targeted therapies for patients. At this early stage, multiple hurdles remain before molecular profiling becomes a routine part of thoracic oncology practice.

Short-term effects of salt exposure on the maize chloroplast protein pattern.

It is of fundamental importance to understand the physiological differences leading to salt resistance and to get access to the molecular mechanisms underlying this physiological response. The aim of this work was to investigate the effects of short-term salt exposure on the proteome of maize chloroplasts in the initial phase of salt stress (up to 4 h). It could be shown that sodium ions accumulate quickly and excessively in chloroplasts in the initial phase of moderate salt stress.

Phase II study of vinorelbine and docetaxel in the treatment of advanced non-small-cell lung cancer as frontline and second-line therapy.

Objectives: Combination chemotherapy with third-generation, nonplatinum agents (ie, gemcitabine, vinorelbine, taxanes, or camptothecins) represents a well-tolerated frontline treatment option for metastatic non-small-cell lung cancer and might play a role as salvage therapy as well. The aim of this phase 2 study was to investigate the use of docetaxel and vinorelbine in the frontline and second-line setting in patients with incurable non-small-cell lung cancer.

Patients And Methods: Seventy-eight patients (42 untreated, 36 previously treated) were administered vinorelbine (20 mg/m) on days 1 and 8 and docetaxel (75 mg/m for untreated patients; 60 mg/m for previously treated patients for cycle 1, increased to 75 mg/m for the subsequent cycles in the absence of grade 3 fever/neutropenia) on day 8, repeated every 21 days, with routine filgrastim support.

Targeted drug delivery strategies to treat lung metastasis.

Background: Most cancer patients die of metastatic disease, and in a high proportion of cases, from lung metastasis. Methods to target therapy to metastatic disease in general and specifically to lung metastasis are required.

Objective: To describe the current and potential tools for the treatment of lung metastasis.

Summary of selected presentations from the 8th annual targeted therapy in lung cancer symposium.

Lung cancer is the leading cause of cancer-related death in the United States. Outcomes for patients with lung cancer have reached a plateau with cytotoxic chemotherapy. Lung cancer remains very much at the vanguard of the new revolution in cancer therapy using molecular targets.

Safety, pharmacokinetics, and antitumor activity of AMG 386, a selective angiopoietin inhibitor, in adult patients with advanced solid tumors.

PURPOSE AMG 386 is an investigational peptide-Fc fusion protein (ie, peptibody) that inhibits angiogenesis by preventing the interaction of angiopoietin-1 and angiopoietin-2 with their receptor, Tie2. This first-in-human study evaluated the safety, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of AMG 386 in adults with advanced solid tumors. PATIENTS AND METHODS Patients in sequential cohorts received weekly intravenous AMG 386 doses of 0.

Substituted benzimidazoles: A novel chemotype for small molecule hKSP inhibitors.

Substituted benzimidazoles were profiled as inhibitors of kinesin spindle protein (KSP), an increasingly important target for the development of anticancer drugs. This series demonstrated the monoastral phenotypic response and was found to be active in both enzymatic and cellular-based assays.

Tumor blood flow measured by perfusion computed tomography and 15O-labeled water positron emission tomography: a comparison study.

Objectives: To compare blood flow measurements of tumors assessed by perfusion computed tomography (pCT) and the clinical gold standard of 15O-labeled water positron emission tomography (15O-PET).

Methods: Blood flows were estimated by pCT (4-row multidetector, CT Perfusion 3.1) and 15O-PET (Posicam, first-pass model) in 14 patients with solid tumors, totaling 22 index tumors and 57 matched pairs of examinations.

Baseline vascular endothelial growth factor concentration as a potential predictive marker of benefit from vandetanib in non-small cell lung cancer.

Purpose: Vandetanib [vascular endothelial growth factor (VEGF) receptor/epidermal growth factor receptor/RET inhibitor] has shown improvements in progression-free survival (PFS) in advanced non-small cell lung cancer in three randomized phase II studies: vandetanib versus gefitinib (study 3), docetaxel +/- vandetanib (study 6), and carboplatin-paclitaxel and/or vandetanib (study 7). In study 7, vandetanib monotherapy was inferior to carboplatin-paclitaxel. We performed an exploratory retrospective analysis of the relationship between baseline circulating VEGF concentrations and PFS.