17 results on '"Stefania Napolitano"'
Search Results
2. It is finally time for adjuvant therapy in melanoma
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Floriana Morgillo, Giuseppe Argenziano, Teresa Troiani, Erika Martinelli, Fortunato Ciardiello, Gabriella Brancaccio, Stefania Napolitano, Napolitano, S., Brancaccio, G., Argenziano, G., Martinelli, E., Morgillo, F., Ciardiello, F., and Troiani, T.
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Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Antineoplastic Agents ,Ipilimumab ,Target therapy ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Adjuvant therapy ,Humans ,Radiology, Nuclear Medicine and imaging ,030212 general & internal medicine ,Adverse effect ,Melanoma ,business.industry ,MEK inhibitor ,Antibodies, Monoclonal ,General Medicine ,Immunotherapy ,Adjuvant treatment ,medicine.disease ,Neoadjuvant Therapy ,Nivolumab ,Chemotherapy, Adjuvant ,030220 oncology & carcinogenesis ,New strategie ,business ,Pembrolizumab ,Adjuvant ,medicine.drug - Abstract
Although melanoma is amenable to early detection, there has been no decline in the mortality rate of this disease and the prognosis of patients with high-risk primary melanoma or with macroscopic nodal involvement remains poor. The best option for patients with higher-risk melanoma is to receive effective adjuvant therapy in order to reduce their chances of recurrence. Multiple systemic therapeutic agents have been tested as adjuvant therapy for melanoma with durable benefits seen only with interferon- to date. More recently ipilimumab at the high dose of 10 mg/kg has shown a significant improvement in terms of Relapse free survival and Overall survival for stage III melanoma patients but at a significant cost in terms of immune-related toxicities. More recently, novel treatment options have emerged. The results from the latest trials with immunotherapy (PD-1 inhibitors) and molecular targeted therapy (BRAF inhibitor + MEK inhibitor) have revolutionized the management of adjuvant treatment for melanoma. As the results from these trials will mature in the next years, a change in the landscape of adjuvant treatment for melanoma is expected, resulting in new challenges in treatment decisions such as optimizing patients’ selection through predictive and prognostic biomarkers, and management of treatment related adverse events, in particular immune related toxicities.
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- 2018
3. 13P Synergistic activity of PARP inhibitor and ATR inhibitor in melanoma cell lines may depend on BRAF-V600 mutation status
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Giulia Martini, V. Caputo, N. Zanaletti, P. Vitale, Erika Martinelli, Valentina Belli, V. De Falco, Paola Vitiello, Davide Ciardiello, Teresa Troiani, Stefania Napolitano, Emilio Francesco Giunta, Giuseppe Argenziano, and M. Terminiello
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Oncology ,business.industry ,Melanoma cell line ,PARP inhibitor ,BRAF V600 Mutation ,Cancer research ,Medicine ,Hematology ,business - Published
- 2020
4. Immunotherapy in colorectal cancer: is the long-awaited revolution finally happening?
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C. Borrelli, Fernando Paragliola, Stefania Napolitano, Carminia Maria Della Corte, G. Arrichiello, Erika Martinelli, Giulia Martini, Valeria Nacca, L. Poliero, Arrichiello, Gianluca, Poliero, Luca, Borrelli, Carola, Paragliola, Fernando, Nacca, Valeria, Napolitano, Stefania, Corte, Carminia Maria Della, Martini, Giulia, and Martinelli, Erika
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Male ,Oncology ,Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,Immune checkpoint inhibitors ,medicine.medical_treatment ,Population ,Complex disease ,Internal medicine ,medicine ,Humans ,education ,RC254-282 ,education.field_of_study ,business.industry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Microsatellite instability ,Immunotherapy ,medicine.disease ,digestive system diseases ,Clinical trial ,Female ,DNA mismatch repair ,Colorectal Neoplasms ,business - Abstract
Immunotherapy has recently become a major treatment modality for several types of solid tumours, achieving remarkable and long-lasting remissions. In metastatic colorectal cancer patients (mCRC), immune checkpoint inhibitors (ICIs) were found to be effective as treatment for deficient mismatch repair (dMMR)/ microsatellite instability high (MSI-H) tumours and received regulatory approval for this indication. However, mCRC is a complex disease and dMMR/MSI-H tumours represent a minority of the cases; therefore, new strategies are needed to extend the benefits of immunotherapy to a larger population of patients. This review explores the immunological differences between dMMR/MSI-H and proficient mismatch repair (pMMR)/ microsatellite instability low (MSI-L) tumours, focuses on new proposed biomarkers to predict response to immunotherapy and illustrates results reported from the main clinical trials with immunotherapeutic agents in CRC, addressing the most promising approaches being currently developed.
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- 2021
5. P-200 Bone metastases from colorectal cancer correlate with biological characteristics of primary tumors: A retrospective analysis from a single institution
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C. Borrelli, N. Zanaletti, Paola Vitiello, G. Arrichiello, P. Vitale, Stefania Napolitano, M. Terminiello, L. Poliero, Emilio Francesco Giunta, D. Ciardiello, V. De Falco, Teresa Troiani, V. Caputo, Claudia Cardone, Fortunato Ciardiello, Giulia Martini, and Erika Martinelli
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Oncology ,medicine.medical_specialty ,Colorectal cancer ,business.industry ,Internal medicine ,Retrospective analysis ,medicine ,Hematology ,Single institution ,medicine.disease ,business - Published
- 2020
6. Triple blockade of EGFR, MEK and PD-L1 as effective antitumor treatment in PD-L1 overexpressing, MEK inhibitor resistant colon cancer cells
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Nunzia Matrone, Paola Vitiello, Erika Martinelli, Fortunato Ciardiello, Giusi Barra, Davide Ciardiello, Mimmo Turano, Stefania Napolitano, Scott Kopetz, Teresa Troiani, Valentina Belli, V. De Falco, M. Terminiello, A.S. Muddassir, Emilio Francesco Giunta, and Maria Furia
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biology ,business.industry ,Colorectal cancer ,medicine.medical_treatment ,MEK inhibitor ,Hematology ,Immunotherapy ,Gene signature ,medicine.disease ,Gene expression profiling ,Oncology ,Downregulation and upregulation ,PD-L1 ,medicine ,biology.protein ,Cancer research ,business ,EGFR inhibitors - Abstract
Background Molecular mechanisms driving acquired resistance to anti-EGFR therapies in metastatic Colorectal Cancer (mCRC) are complex but generally involve the activation of the downstream RAS-RAF-MEK-MAPK pathway. Methods In order to understand the mechanism underlying MEK inhibitor (MEKi) resistance, we generated three different MEKi resistant models, two all RAS WT (SW48-MR and LIM1215-MR) and one mutated in RAS (HCT116-MR). Results These models showed features related to the gene signature of Colorectal Cancer CMS4 with upregulation of immune pathway as confirmed by Microarray and Western blot analysis. In particular, moving forward the MEKi phenotype we assisted to the loss of epithelial features and acquisition of mesenchymal markers and morphology. Moreover, this change in the morphology is accompanied by up-regulation of PD-L1 expression and activation of EGFR and its downstream pathway, independently of cell line status mutation. To extend these in vitro findings, we performed an in vivo study using MC38 and CT26 MEKi resistant syngeneic models that we have previously generated. Combined treatment of MEKi, EGFR inhibitor (EGFRi) and PD-L1inhibitor (PD-L1i) resulted in a marked inhibition of tumor growth in both MC38–MR and CT26-MR xenograft model. Conclusions These results suggest a strategy to potentially overcome immunotherapy resistance in CMS4-like tumors and to improve the efficacy of MEK inhibition by co-treatment with other agents providing an additional therapeutic strategy via modulation of host immune responses. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.
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- 2019
7. Immune competent somatic mosaic model of colorectal cancer
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David G. Menter, Teresa Troiani, Scott Kopetz, Federica Carbone, Stefania Napolitano, and Giannicola Genovese
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Cell cycle checkpoint ,business.industry ,medicine.medical_treatment ,Cancer ,Cre recombinase ,Hematology ,Immunotherapy ,medicine.disease ,Immune checkpoint ,Genetically modified organism ,Immune system ,Oncology ,Genome editing ,medicine ,Cancer research ,business - Abstract
Background Historically, immunotherapies have been tested in syngeneic mouse models and until now only limited CRC syngeneic cells are available. Animal models with functioning human immune systems are critically needed to more accurately evaluate checkpoint blockers delivery, therapeutic response, and to better define biomarker expression in the presence of a competent immune system. Methods To better address the efficacy of immune checkpoint therapy specifically in relation to presence of a BRAFmutation, we developed a novel platform for the generation of somatic mosaic models of CRC enabling (i) high-throughput generation of genetically complex syngeneic models of cancer, (ii) tracing studies through fluorescence reporters. Results Cdx2Cre/+ mice, expressing the Cre recombinaseunder the control of a human Cdx2 promoter/enhancer sequence have been crossed with the R26LSL-Cas9-Gfp strain to generate models allowing for tissue specific activation of Cas9 and Gfpreporter only in CDX2 positive cells. This strain has been crossed with BRAFFSF-V600E mice to generate the final model. 6-8 weeks old mice have then been transduced with AAV constructs expressing the FLPO recombinasethat can be activated by Cre recombinase and sgRNAs targeting APC, TP53, MLH1, MSH2and ARID1Aalone or combined, in order to model MSI CRC (APC-TP53-MLH1and ARID1A-MLH1conditional mosaic knock-outs) and MSS CRC (APC-TP53 conditional mosaic knock-out). Viral particles have been surgically delivered via subserosal cecal injection and mice monitored for tumor formation by IVIS imaging. 35 mice injected with 3 combinations of tumor suppressors provide a diverse immunology repetoire. Cell lines isolated from genetically modified mice will provide a physiologic relevant and feasible means to study the mechanisms of response and resistance to immunotherapies and to understand biological and molecular differences between BRAFmutated MSI and MSS tumors. Conclusions This project focuses on the identification and characterization of the functional drivers of CMS1CRC tumors leveraging in vivomosaic genome editing technologies and functional genetic labeling of malignant sub-populations emerging during disease progression and in response to therapy. Legal entity responsible for the study The authors. Funding MD Anderson Cancer Center. Disclosure All authors have declared no conflicts of interest.
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- 2019
8. IFN-γ/IL-10 ratio as predictive biomarker for response to anti-PD-1 therapy in metastatic melanoma patients
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Valentina Belli, P. Vitale, M. Terminiello, Stefania Napolitano, V. De Falco, Gabriella Brancaccio, Davide Ciardiello, N. Zanaletti, R. De Palma, Teresa Troiani, Paola Vitiello, Giusi Barra, V. Caputo, Emilio Francesco Giunta, Giuseppe Argenziano, and Fortunato Ciardiello
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medicine.medical_specialty ,Poor prognosis ,education.field_of_study ,Metastatic melanoma ,business.industry ,Mrna expression ,Anti pd 1 ,Population ,Hematology ,Oncology ,Internal medicine ,medicine ,Statistical analysis ,In patient ,business ,education ,health care economics and organizations ,Predictive biomarker - Abstract
Background Anti-PD-1 antibodies represent nowadays a first-choice therapy for metastatic melanoma patients. Despite impressive results in terms of PFS and OS, a proportion of patients does not respond to anti-PD-1 therapy with an overall poor prognosis. Identification of predictive biomarkers is considered an important unmet clinical need to avoid expensive and potentially harmful drugs in patients who will not respond to them. In the last years, many studies have evaluated the role of cytokines on both blood and tissue samples as predictive biomarkers for immunotherapy, with encouraging results. Methods Blood samples from 18 patients with metastatic melanoma treated with anti-PD-1 antibodies as first line therapy were collected at baseline. 8 patients were classified as non-responders (best response: PD excluding pseudo-progression with median PFS of 2 months) and 10 patients as responders (best response: PR or CR, with median PFS of 17 months). mRNA expression levels of the main pro- and anti-inflammatory cytokines were evaluated by Real time quantitative PCR in PBMCs obtained from baseline blood samples. Unpaired two-tailed t-test was used for statistical analysis. Results IFN-γ mRNA expression levels were higher in responder patients (p 0.05). Combining data for each patient, we noticed a correlation between higher levels of IFN-γ and lower levels of IL-10 for responders and vice versa. Starting from these findings, we observed that the IFN-γ/IL-10 ratio was higher (median: 43,3 vs 5,2) in responders (p Conclusions Our data suggest an interesting correlation between IFN-γ/IL-10 ratio and response to anti-PD-1 therapy in melanoma patients. This correlation seems to be stronger than using IFN-γ expression levels alone probably because of the influence of anti-inflammatory cytokines. Since this is an exploratory and retrospective analysis of 18 patients, a larger population should be tested to validate our results. Legal entity responsible for the study Dipartimento di Medicina di Precisione, Universita degli studi della Campania Luigi Vanvitelli. Funding Has not received any funding. Disclosure F. Ciardiello: Advisory / Consultancy: Roche; Advisory / Consultancy: Amgen; Advisory / Consultancy: Merck; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Bayer; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Servier; Advisory / Consultancy: BMS; Advisory / Consultancy: Cellgene; Advisory / Consultancy: Lilly; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Merck; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Takeda. T. Troiani: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): Servier; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Bayer. All other authors have declared no conflicts of interest.
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- 2019
9. Atypical haemolytic-uraemic syndrome in patient with metastatic colorectal cancer treated with fluorouracil and oxaliplatin: a case report and a review of literature
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Giuseppe Viscardi, Fortunato Ciardiello, N. Zanaletti, Salvatore Guastafierro, P. Vitale, Maria Giovanna Ferrara, Erika Martinelli, Vincenzo De Falco, Dario Ribero, Umberto Bracale, Emilio Francesco Giunta, Davide Ciardiello, Morena Fasano, Stefania Napolitano, Antonello Sica, Teresa Troiani, Umberto Falcone, Viscardi, G., Zanaletti, N., Ferrara, M. G., Sica, A., Falcone, U., Guastafierro, S., Bracale, U., Ribero, D., Fasano, M., Napolitano, S., Vitale, P., De Falco, V., Giunta, E. F., Martinelli, E., Ciardiello, D., Ciardiello, F., and Troiani, T.
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Cancer Research ,medicine.medical_specialty ,Colorectal cancer ,medicine.medical_treatment ,colorectal cancer ,Malignancy ,lcsh:RC254-282 ,Gastroenterology ,atypical haemolytic-uraemic syndrome ,eculizumab ,thrombotic microangiopathies ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Original Research ,Chemotherapy ,business.industry ,Cancer ,Eculizumab ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,Oxaliplatin ,Discontinuation ,Oncology ,Complication ,business ,medicine.drug - Abstract
Background. Thrombotic microangiopathies (TMA) are relatively rare but severe disorders characterised by non-immune haemolytic anaemia, thrombocytopaenia and organ failure. In patients with metastatic cancer, sporadic forms of TMA can be triggered by chemotherapeutic agents or can occur as complication of malignancy itself or of infections. Case report. Hereby, we report a case of a patient diagnosed with metastatic colorectal cancer who experienced an atypical haemolytic-uraemic syndrome (aHUS) during chemotherapy treatment with FOLFOX6 scheme. The use of eculizumab led to prompt recovery of laboratory parameters that was maintained despite treatment discontinuation due to appearance of pneumonia infectious. Additionally, genetic analyses revealed the presence in heterozygosis of CFH gene polymorphisms associated with aHUS. Conclusion. This case emphasises the importance of considering TMA as a possible diagnosis in patients with cancer presenting with haemolytic non-immune mediate anaemia and thrombocytopaenia associated with worsening of renal function. Prompt diagnosis is crucial for the requirement of its specific treatment that can impact on long-term outcome and prognosis.
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- 2019
10. Macrophage migration inhibitory factor overexpression is a mechanism of acquired resistance to anti-EGFR inhibitor cetuximab in human colorectal cancer cell line
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M. Terminiello, Valentina Belli, Stefania Napolitano, P. Vitale, N. Zanaletti, Emilio Francesco Giunta, Fortunato Ciardiello, Claudia Cardone, Erika Martinelli, Angela Chambery, Nunzia Matrone, Rosita Russo, V. De Falco, Teresa Troiani, and Paolo V. Pedone
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Acquired resistance ,Oncology ,Cetuximab ,business.industry ,Mechanism (biology) ,Cancer research ,Medicine ,Macrophage migration inhibitory factor ,Hematology ,business ,Colorectal cancer cell line ,medicine.drug ,EGFR inhibitors - Published
- 2018
11. A new natural compound identified through a metabolomic approach has cytotoxic activity against human colorectal cancer cell lines with acquired resistance to cetuximab
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Erika Martinelli, Valentina Belli, P. Vitale, Nunzia Matrone, Emilio Francesco Giunta, Teresa Troiani, N. Zanaletti, Stefania Napolitano, M. Terminiello, V. De Falco, Fortunato Ciardiello, and Paola Vitiello
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Cetuximab ,business.industry ,Colorectal cancer ,Natural compound ,Hematology ,medicine.disease ,Metabolomics ,Acquired resistance ,Oncology ,Cell culture ,medicine ,Cancer research ,Cytotoxic T cell ,business ,medicine.drug - Published
- 2018
12. The acquired resistance to the combination of the anti-EGFR cetuximab and the MEK-inhibitor refametinib in KRAS mutated colorectal cancer cell lines depends on PI3K-signalling
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N. Zanaletti, P. Vitale, Claudia Cardone, M. R. Diadema, Gianpaolo Papaccio, Floriana Morgillo, Teresa Troiani, Stefania Napolitano, Giulia Martini, Vincenzo Sforza, Fortunato Ciardiello, Emilio Francesco Giunta, Valentina Belli, V. De Falco, Nunzia Matrone, Davide Ciardiello, Erika Martinelli, Vincenzo Desiderio, and Paola Vitiello
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Oncology ,medicine.medical_specialty ,Cetuximab ,Colorectal cancer ,business.industry ,MEK inhibitor ,Hematology ,medicine.disease ,medicine.disease_cause ,Signalling ,Cell culture ,Internal medicine ,medicine ,KRAS ,Refametinib ,business ,PI3K/AKT/mTOR pathway ,medicine.drug - Published
- 2017
13. HER2 activation and epithelial-mesenchymal transition (EMT) are involved in the acquired resistance to cetuximab in combination with either regorafenib or refametinib
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Teresa Troiani, Floriana Morgillo, Vincenzo Sforza, Paola Vitiello, Valentina Belli, Claudia Cardone, Luca Pompella, Erika Martinelli, Giulia Martini, Marianna Luciana Ferrara, Fortunato Ciardiello, N. Zanaletti, Stefania Napolitano, P. Vitale, and C.M. Della Corte
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Cetuximab ,business.industry ,Hematology ,chemistry.chemical_compound ,Acquired resistance ,Oncology ,chemistry ,Regorafenib ,Cancer research ,Medicine ,Epithelial–mesenchymal transition ,business ,Refametinib ,medicine.drug - Published
- 2016
14. SYM004, a novel generation anti-EGFR inhibitor, is able to overcome acquired resistance to cetuximab such as MET activation, ERBB2 amplification and EGFR mutations, in colorectal cancer models
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Maria Domenica Castellone, Teresa Troiani, Floriana Morgillo, Valentina Belli, Giulia Martini, Claudia Cardone, Michele Orditura, Erika Martinelli, Fortunato Ciardiello, Stefania Napolitano, and A. Parascandolo
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Oncology ,medicine.medical_specialty ,Cetuximab ,business.industry ,Colorectal cancer ,Hematology ,medicine.disease ,ERBB2 Amplification ,Acquired resistance ,Egfr mutation ,Internal medicine ,medicine ,business ,medicine.drug ,EGFR inhibitors - Published
- 2016
15. AXL activation can promote resistance to MEK inhibition in a model of colorectal cancer (CRC)
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Davide Ciardiello, Valentina Belli, Emilio Francesco Giunta, Giulia Martini, Erika Martinelli, Marianna Luciana Ferrara, Claudia Cardone, Teresa Troiani, Stefania Napolitano, Vincenzo Sforza, Floriana Morgillo, Fortunato Ciardiello, and Paola Vitiello
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Oncology ,Colorectal cancer ,business.industry ,Cancer research ,medicine ,Hematology ,medicine.disease ,business - Published
- 2016
16. Phase III study of regorafenib versus placebo as maintenance therapy in RAS wild type metastatic colorectal cancer (RAVELLO trial)
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Giulia Martini, Fabiana Auricchio, Julien Taieb, Teresa Troiani, Andrés Cervantes, Erika Martinelli, Fortunato Ciardiello, Alfredo Falcone, Filippo Venturini, Jean-Yves Douillard, Stefania Napolitano, Annalisa Capuano, Vincenzo Sforza, Claudia Cardone, Claus-Henning Köhne, Josep Tabernero, and Gunnar Folprecht
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Response rate (survey) ,Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Colorectal cancer ,Wild type ,Hematology ,Pharmacology ,Placebo ,medicine.disease ,chemistry.chemical_compound ,Maintenance therapy ,chemistry ,Regorafenib ,Internal medicine ,Overall survival ,Medicine ,Progression-free survival ,business - Abstract
TPS789 Background: Treatment of metastatic colorectal cancer (mCRC) has improved due to the introduction of more active chemotherapies (CT) and novel targeted agents that have significantly increased response rate (RR), progression free survival (PFS) and overall survival (OS). Recently, CORRECT and CONCUR trials have demonstrated both activity and efficacy of regorafenib, a small multi-kinase inhibitor, as monotherapy in pretreated mCRC. The wide range of action of regorafenib makes it an ideal candidate for monotherapy in earlier disease treatment lines in which different pathways could be involved in the acquisition of resistance. To improve long term efficacy of first line therapy several therapeutic approaches of maintenance treatment have been explored in mCRC. Methods: RAVELLO is an academic randomized, double-blind, placebo-controlled, multi-center, phase III study designed to evaluate efficacy and safety of regorafenib as maintenance treatment after first line therapy. Eligible patients: pathologically confirmed mCRC RAS wild type (KRAS and NRAS genes) treated with a first line fluoropyrimidine-based CT in combination with an anti-EGFR (epidermal growth factor receptor) monoclonal antibody for a minimum of 4 to a maximum of 8 months, with a stratification by response to the first line treatment (complete response/partial response or stable disease). 480 patients will be enrolled and randomly assigned in a 1:1 ratio to receive 160 mg regorafenib or placebo per os, every day for 3 weeks of every 4 weeks cycle, until disease progression or unacceptable toxicity. Primary endpoint is PFS. With a two-tailed alpha error of 0.05, the study will have 90% power to detect a 3-month prolongation of median PFS from randomization (corresponding to a hazard ratio of progression of 0.67 with 6-month median PFS expected in the control arm). Secondary endopoint are OS, safety, and biomarker correlative studies. Currently, one patient has been enrolled and is on treatment. EudraCT number: 2013-005428-41. Clinical trial information: 2013-005428-41.
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- 2015
17. Met Activation by Autocrine Loop Rescues Colon Cancer Cells From Sensitivity to EGFR Inhibition
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Floriana Morgillo, Anna Nappi, Donata Vitagliano, Fortunato Ciardiello, Teresa Troiani, Vincenzo Sforza, Anna Capasso, Liberato Berrino, Erika Martinelli, and Stefania Napolitano
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MAPK/ERK pathway ,TGF alpha ,biology ,Cetuximab ,business.industry ,Hematology ,Oncology ,Epidermal growth factor ,Cancer cell ,Cancer research ,biology.protein ,Medicine ,Hepatocyte growth factor ,Epidermal growth factor receptor ,business ,Autocrine signalling ,medicine.drug - Abstract
Background Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), is active in K-RAS wild type colorectal cancer (CRC). However, initially in responding patients cancer cells would become resistant to EGFR inhibition by the activation of alternative growth controlling pathways including the hepatocyte growth factor (HGF)/MET-dependent signal. Methods mRNA expression profiles of cetuximab-sensitive human GEO colon cancer cells and of their cetuximab-resistant derived GEO-CR cells were analyzed by microarrays. Protein expression levels were evaluated by western blot (WB). Growth factors were measure in the culture medium by Luminex technology. The in vitro antitumor activity of MET inhibitor (METi), was tested in a panel of ten human colon cancer cell lines by MTT assay. Results Evaluation of gene expression profile identified a series of genes that were up-regulated in GEO-CR cells possibly involved in acquired resistance to EGFR inhibition. Among these we found several genes involved in the MET pathway. WB analysis detected activated, phosphorylated MET in GEO-CR but not in GEO and in the other colon cancer cell lines tested. We also found in GEO-CR cells up-regulation of EGFR ligands such as transforming growth factor – α (TGFa) and Heparin Binding- Epidermal Growth Factor (HB-EGF). We further observed expression of HGF in GEO-CR cells, supporting HGF/MET autocrine activation following acquired resistance to cetuximab treatment. In fact, the RAS/RAF/MEK/MAPK pathway was constitutively active despite of EGFR inhibition by cetuximab in GEO-CR cells possibly due to HGF-induced MET activation. Treatment with a potent and selective METi was able to overcome cetuximab resistance in GEO-CR cells and causes cell growth inhibition. Conclusion These results suggest that autocrine activation of HGF/MET could be a relevant therapeutic target in colorectal cancer patients that become resistant to anti-EGFR treatment. Disclosure All authors have declared no conflicts of interest.
- Published
- 2012
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