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Genova, Italy

Marquez-Medina D.,University of Lleida | Popat S.,Lung Cancer Unit
Future Oncology | Year: 2016

Nonadvanced non-small-cell lung cancer (NSCLC) has a poor long-term survival from surgery or definitive radiation that is minimally improved with induction/adjuvant conventional chemotherapy. EGFR-tyrosine kinase inhibitors (TKIs), which provide a significant benefit for molecularly selected EGFR-mutant patients with advanced NSCLC, have been infrequently explored in nonadvanced NSCLC to date. Current published studies reported no significant benefit from adding EGFR-TKI to the induction/adjuvant setting. However, many of them present eventual biases such as unpowered statistics, lack of molecular selection, recruitment of low-risk NSCLC, low sample size or unsuitable control arms. Results, strengths and deficiencies of completed and ongoing trials were fully discussed. Similarly, the selection of patients and control arms, the duration and risks of EGFR-TKI therapies in early-stage NSCLC, the evaluation of response and the diagnosis of EGFR status were considered and analyzed. © 2016 Future Medicine Ltd. Source

Zismanov V.,Lung Cancer Research Laboratory | Zismanov V.,Tel Aviv University | Drucker L.,Meir Medical Center | Drucker L.,Tel Aviv University | And 3 more authors.
Pulmonary Pharmacology and Therapeutics | Year: 2013

Lung cancer remains the most common cause of cancer-related death in the world for which novel systemic treatments are urgently needed. Protein homeostasis that regulates protein levels and their fold is critical for cancer cell proliferation and survival. A complex network of cellular organelles and signaling cascades is involved in control of protein homeostasis including endoplasmic reticulum (ER). Thus, proteins in control of ER homeostasis are increasingly recognized as potential therapeutic targets. Molecular chaperone heat shock protein 90 (Hsp90) and histone deacetylase (HDAC) play an important role in ER homeostasis. Previous studies demonstrate that Hsp90 and HDAC inhibitors are individually functional against lung cancer. In this work we suggested that combined Hsp90 and HDAC inhibitors may elevate ER stress thereby enhancing the anti non small lung cancer (NSCLC) activity. Methods and results: Using an in vitro cell line model we demonstrated that 17-DMAG (HSP90 inhibitor) co-administration with PTACH (HDAC inhibitor) caused elevated ER stress (immunoblotting) (more than 110%↑, p < 0.05) accompanied by apoptotic cell death (Annexin V) (7-21%↑, p < 0.05). Moreover, 17-DMAG/PTACH treated cells lost the ability to migrate (scratch test) (57-85%↓ of scratch closure, p < 0.05). Conclusions: Our findings provide proof-of-concept that targeting ER homeostasis is therapeutically beneficial in lung cancer cell lines. Indeed, the elevated ER stress caused by 17-DMAG/PTACH combined treatment leads to increased cell death of NSCLC cell lines compared to the application of the drugs separately. © 2013 Elsevier Ltd. Source

Gregorc V.,Istituto di Ricovero e Cura a Carattere Scientifico | Novello S.,University of Turin | Lazzari C.,Istituto di Ricovero e Cura a Carattere Scientifico | Barni S.,Azienda Ospedaliera Treviglio | And 21 more authors.
The Lancet Oncology | Year: 2014

Background: An established multivariate serum protein test can be used to classify patients according to whether they are likely to have a good or poor outcome after treatment with EGFR tyrosine-kinase inhibitors. We assessed the predictive power of this test in the comparison of erlotinib and chemotherapy in patients with non-small-cell lung cancer. Methods: From Feb 26, 2008, to April 11, 2012, patients (aged ≥18 years) with histologically or cytologically confirmed, second-line, stage IIIB or IV non-small-cell lung cancer were enrolled in 14 centres in Italy. Patients were stratified according to a minimisation algorithm by Eastern Cooperative Oncology Group performance status, smoking history, centre, and masked pretreatment serum protein test classification, and randomly assigned centrally in a 1:1 ratio to receive erlotinib (150 mg/day, orally) or chemotherapy (pemetrexed 500 mg/m2, intravenously, every 21 days, or docetaxel 75 mg/m2, intravenously, every 21 days). The proteomic test classification was masked for patients and investigators who gave treatments, and treatment allocation was masked for investigators who generated the proteomic classification. The primary endpoint was overall survival and the primary hypothesis was the existence of a significant interaction between the serum protein test classification and treatment. Analyses were done on the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00989690. Findings: 142 patients were randomly assigned to chemotherapy and 143 to erlotinib, and 129 (91%) and 134 (94%), respectively, were included in the per-protocol analysis. 88 (68%) patients in the chemotherapy group and 96 (72%) in the erlotinib group had a proteomic test classification of good. Median overall survival was 9·0 months (95% CI 6·8-10·9) in the chemotherapy group and 7·7 months (5·9-10·4) in the erlotinib group. We noted a significant interaction between treatment and proteomic classification (pinteraction=0·017 when adjusted for stratification factors; pinteraction=0·031 when unadjusted for stratification factors). Patients with a proteomic test classification of poor had worse survival on erlotinib than on chemotherapy (hazard ratio 1·72 [95% CI 1·08-2·74], p=0·022). There was no significant difference in overall survival between treatments for patients with a proteomic test classification of good (adjusted HR 1·06 [0·77-1·46], p=0·714). In the group of patients who received chemotherapy, the most common grade 3 or 4 toxic effect was neutropenia (19 [15%] vs one [<1%] in the erlotinib group), whereas skin toxicity (one [<1%] vs 22 [16%]) was the most frequent in the erlotinib group. Interpretation: Our findings indicate that serum protein test status is predictive of differential benefit in overall survival for erlotinib versus chemotherapy in the second-line setting. Patients classified as likely to have a poor outcome have better outcomes on chemotherapy than on erlotinib. Funding: Italian Ministry of Health, Italian Association of Cancer Research, and Biodesix. © 2014 Elsevier Ltd. Source

Marquez-Medina D.,University of Lleida | Popat S.,Lung Cancer Unit
Clinical and Translational Oncology | Year: 2015

Malignant pleural effusion (MPE) represents 15–35 % of pleural effusions and markedly worsens the prognosis and quality of life of patients with cancer.Malignant mesothelioma (MM) and lung adenocarcinoma are the most frequent primary and secondary causes, respectively, of MPE. Effective treatments for cancer-related MPE are warranted in order to improve symptoms, reduce the number of invasive pleural procedures, and prolong patient life. Since angiogenesis plays a key role in MPE development, the potential role of bevacizumab and other anti-angiogenic therapies have been explored in this review. No relevant phase III trials have specifically analysed the benefit from adding bevacizumab to platinum-based chemotherapy in lung cancer-related MPE. However, small retrospective series reported 71.4–93.3 % MPE control rate, a reduction in invasive procedures, and a safe profile with this combination. Being approved for the first-line treatment of non-squamous advanced NSCLC, the addition of bevacizumab should be considered for patients presenting with MPE. In addition, further studies in this are recommended. In MM, the addition of bevacizumab to platinum-based chemotherapy did not meet primary endpoints in two phase II trials. However, the beneficial results on OS reported in comparison with historical cohorts and the statistically significant benefit on PFS and OS observed in the phase III MAPS trial foretell an eventual role for the combination of platinum/pemetrexed/bevacizumab as front-line systemic therapy for pleural MM. To date, no other anti-angiogenic drug has showed significant benefit in the treatment of patients with either MPE or MM. However, new promising drugs such as ramucirumab or recombinant human endostar warrant further investigation. © 2015 Federación de Sociedades Españolas de Oncología (FESEO) Source

De Luca A.,University of Rome Tor Vergata | Pellizzari Tregno F.,University of Rome Tor Vergata | Sau A.,University of Rome Tor Vergata | Pastore A.,Childrens Hospital Istituto di Ricovero e Cura a Carattere Scientifico Bambino Gesu | And 5 more authors.
Cancer Science | Year: 2013

Malignant pleural mesothelioma is a poorly responsive tumor known to overexpress the phase II detoxification enzyme glutathione-S-transferase, which catalyzes the conjugation between glutathione and platinum(II)-containing drugs. Therefore, we evaluated the effect of the strong glutathione S-transferase inhibitor NBDHEX on human mesothelioma cell lines (MSTO-211H, MPP89, MM-B1 and Mero 48a) featuring the most common mesothelioma phenotypes: epithelioid and biphasic. Even though a different response to NBDHEX was observed, the molecule was very effective on all cell lines tested, triggering a sustained activation of both JNK and p38, followed by caspase activation and apoptosis. NBDHEX also caused severe oxidative stress in the MPP89 cells and, to a lesser extent, in the MMB1 cells, while it did not cause a significant redox imbalance in the other cell lines. The efficacy of the drug was found to be comparable or even higher than that of cisplatin. Moreover, it showed synergistic or additive effects when used in combination with cisplatin. In conclusion, NBDHEX was effective on mesothelioma cell lines, with IC50 values in the low micromolar range (IC50 between 1 and 4 μM). These findings indicate that NBDHEX, alone or in combination with cisplatin, is a promising new strategy for treating this rare and aggressive malignancy. © 2012 Japanese Cancer Association. Source

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