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Rossi A.,S.G. Moscati Hospital | Torri V.,Laboratory of Methodology for Biomedical Research | Garassino M.C.,Fondazione IRCCS | Porcu L.,Laboratory of Methodology for Biomedical Research | Galetta D.,National Cancer Research Center Giovanni Paolo
Cancer Treatment Reviews | Year: 2014

Breast, colorectal and lung cancers represent the three most incident forms of cancer worldwide. Among these three "big killers", lung cancer is considered the one with the worst prognosis due to its high mortality even in early stages. Due to their more favorable prognosis, breast and colorectal cancers might appear to have benefited from major advances. Most oncologists who are faced with metastatic non-small cell lung cancer (NSCLC) find the reported results very frustrating when compared with those for metastatic breast (MBC) and colorectal cancers (MCRC). The aim of this analysis was to quantify and compare the relative magnitude of overall survival (OS) improvements in the first-line approaches in metastatic NSCLC, MBC and MCRC through the analysis of the main landmark meta-analyses and randomized clinical trials (RCTs) of commercially available drugs. Five items were considered and analyzed for each cancer. Moreover we evaluated the real clinical impact of the results reported by each item on the entire population; for each "big killer" an overall hazard ratio (HR) was estimated: 0.88 (95%+ CI: 0.72-1.07) for MBC, 0.94 (95%+ CI: 0.82-1.07) for MCRC, and about 0.80 (95%+ CI: 0.73-0.90) for advanced NSCLC. We showed that, in the last decades, these three tumors had important and constant OS improvements reached step by step. The relative magnitude of OS improvement seems higher in metastatic NSCLC than MBC and MCRC. © 2013 Elsevier Ltd.

Bellizzi A.,University of Bari | Greco M.R.,University of Bari | Rubino R.,University of Bari | Paradiso A.,National Cancer Research Center Giovanni Paolo | And 4 more authors.
International Journal of Oncology | Year: 2015

Triple negative breast cancer (TNBC) patients cannot be treated with endocrine therapy or targeted therapies due to lack of related receptors. These patients overexpress the epidermal growth factor receptor (EGFR), but are resistant to tyrosine kinase inhibitors (TKIs) and anti-EGFR therapies. Mechanisms suggested for resistance to TKIs include EGFR independence, mutations and alterations in EGFR and in its downstream signalling pathways. Ligand-induced endocytosis and degradation of EGFR play important roles in the downregulation of the EGFR signal suggesting that its activity could be regulated by targeting its trafficking. Evidence in normal cells showing that the scaffolding protein Na+/H+ exchanger regulatory factor 1 (NHERF1) can associate with EGFR to regulate its trafficking, led us to hypothesize that NHERF1 expression levels could regulate EGFR trafficking and functional expression in TNBC cells and, in this way, modulate its role in progression and response to treatment. We investigated the subcellular localization of NHERF1 and its interaction with EGFR in a metastatic basal like TNBC cell model, MDA-MB-231, and the role of forced NHERF1 overexpression and/or stimulation with EGF on the sensitivity to EGFR specific TKI treatment with gefitinib. Stimulation with EGF induces an interaction of NHERF1 with EGFR to regulate its localization, degradation and function. NHERF1 overexpression is sufficient to drive its interaction with EGFR in non-stimulated conditions, inhibits EGFR degradation and increases its retention time in the plasma membrane. Importantly, NHERF1 overexpression strongly sensitized the cell to the pharmacological inhibition by gefitinib of EGFR-driven growth, motility and invadopodia-dependent ECM proteolysis. The further determination of how the NHERF1-EGFR interaction is regulated may improve our understanding of TNBC resistance to the action of existing anticancer drugs.

Novello S.,University of Turin | Capelletto E.,University of Turin | Cortinovis D.,Medical Oncology | Tiseo M.,University of Parma | And 5 more authors.
Translational Lung Cancer Research | Year: 2014

Introduction: The introduction of targeted therapies in non-small cell lung cancer (NSCLC) treatment has led to emerging toxicities, whose management and impact on quality-of-life (QoL) is not clearly defined. Aim of this Italian multicenter survey was to highlight any discrepancy between patients' and clinicians' perception of such toxicities in order to improve their management. Methods: From October 2013 to April 2014, 133 NSCLC advanced patients, treated with targeted therapies, were consecutively enrolled to assess toxicities and QoL with dedicated questionnaires. One hundred and sixteen patients were included in the final analysis, having attended three consecutive evaluations (T0, T1, T2), starting at least 15 days after the biological treatment. The survey required monthly compilation of both physicians and patients' questionnaires, basing adverse event evaluation on CTCAE version 4.0. Results: Most of the patients received either an EGFR-TKI or an anaplastic lymphoma kinase (ALK) inhibitor as targeted therapy (84.5% and 13.8%, respectively). At every checkpoint (T0, T1, T2) a significant difference in terms of perception of targeted therapies-related toxicities of any type and grade was described (P value =0.0001 in all cases). This difference was more pronounced for skin toxicity, fatigue and diarrhea. Furthermore, also the assessment of QoL revealed contrasting data between patients and clinicians, mainly QoL reported as good by the majority of patients and daily activities considered as slightly influenced by targeted therapies. Conclusions: In our knowledge, this is the first prospective survey in patients and doctors specifically designed for targeted therapies in advanced NSCLC. The results show an underestimation of toxicities by clinicians when compared with patients, the difference being greater for adverse events more strongly associated with daily life and QoL. Further studies are needed to confirm our first results. The discrepancy in perception of targeted therapies-related toxicities should be a result from which to start thinking about a new approach in their management. © Translational lung cancer research. All rights reserved.

Numico G.,U. Parini General Hospital | Trogu A.,U. Parini General Hospital | Cristofano A.,U. Parini General Hospital | Mozzicafreddo A.,U. Parini General Hospital | And 3 more authors.
Supportive Care in Cancer | Year: 2014

Purpose: Chemotherapy near the end of life is frequently considered as an indicator of inappropriate aggressiveness. We were interested in revising our prescribing habits and in analyzing the reasons for offering active treatment to patients with advanced cancer.Methods: We examined the electronic medical records of all the cancer patients died in the Italian Region of Valle d’Aosta in a 1-year period and extracted all the available clinical data. From the 350 deceased patients, we selected the 141 to whom active treatment had been given during the natural history of their disease.Results: Among the patients undergoing any active treatment, the median number of days from the last administration to death was 75. Thirty-seven patients (26.2 %) had their last treatment administration during the 4 weeks before death and 20 (14.2 %) during the last 2 weeks. Fourteen patients (9.9 %) started treatment during the last 4 weeks. When the patients undergoing treatment in the last 4 weeks of life were compared with those subject to earlier withdrawal, only age and pretreatment were statistically significantly different. Most of the treatment choices were considered appropriate, and earlier treatment withdrawal could have been advised only in a minority of the cases.Conclusions: Our data were at the lower range when compared with the available literature. Uncertainties in prognostication and the possibility of response to treatment can justify chemotherapy prescriptions in selected cases. We suggest that the focus should move to the provision of adequate and timely supportive care. © 2014, Springer-Verlag Berlin Heidelberg.

Porcelli L.,National Cancer Research Center Giovanni Paolo | Quatrale A.E.,National Cancer Research Center Giovanni Paolo | Mantuano P.,National Cancer Research Center Giovanni Paolo | Leo M.G.,Health-U | And 6 more authors.
Molecular Oncology | Year: 2013

Cancer cells may use PARP enzymes and Homologous Recombination to repair single and double strand breaks caused by genotoxic insults. In this study, the PARP-1 inhibitor Rucaparib was utilized to increase the sensitivity to chemoradiotherapy treatment in BRCA-2-deficient and -proficient pancreatic cancer cells. We used the pancreatic cancer cell lines, Capan-1 with mutated BRCA-2 and Panc-1, AsPC-1 and MiaPaCa-2 with BRCA-1/2 wild type. Cells were treated with Rucaparib and/or radiotherapy (4-10 Gy) plus Gemcitabine then the capability to proliferate was evaluated by colony formation, cell counting and MTT assays. Flow cytometry, immunocytochemistry and western blotting were utilized to assess cell response to Rucaparib plus irradiation. The antitumour effectiveness of combining the PARP-1 inhibitor before, together and after radiotherapy evidenced the first as the optimal schedule in blocking cell growth. Pre-exposure to Rucaparib increased the cytotoxicity of Gemcitabine plus radiotherapy by heavily inducing the accumulation of cells in G2/M phase, impairing mitosis and finally inducing apoptosis and authophagy. The upregulation of p-Akt and downregulation of p53 were evidenced in MiaPaCa-2 which displayed replication stress features. For the first time, the rationale of using a PARP inhibitor as chemoradiosensitizer in pancreatic cancer models has been hypothesized and demonstrated. © 2012 Federation of European Biochemical Societies.

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