Hahne, J.C.
Lampis, A.
Valeri, N.
(2021). Vault RNAs: hidden gems in RNA and protein regulation. Cellular and molecular life sciences,
Vol.78
(4),
pp. 1487-1499.
show abstract
AbstractNon-coding RNAs are important regulators of differentiation during embryogenesis as well as key players in the fine-tuning of transcription and furthermore, they control the post-transcriptional regulation of mRNAs under physiological conditions. Deregulated expression of non-coding RNAs is often identified as one major contribution in a number of pathological conditions. Non-coding RNAs are a heterogenous group of RNAs and they represent the majority of nuclear transcripts in eukaryotes. An evolutionary highly conserved sub-group of non-coding RNAs is represented by vault RNAs, named since firstly discovered as component of the largest known ribonucleoprotein complexes called “vault”. Although they have been initially described 30 years ago, vault RNAs are largely unknown and their molecular role is still under investigation. In this review we will summarize the known functions of vault RNAs and their involvement in cellular mechanisms..
Knight, J.R.
Alexandrou, C.
Skalka, G.L.
Vlahov, N.
Pennel, K.
Officer, L.
Teodosio, A.
Kanellos, G.
Gay, D.M.
May-Wilson, S.
Smith, E.M.
Najumudeen, A.K.
Gilroy, K.
Ridgway, R.A.
Flanagan, D.J.
Smith, R.C.
McDonald, L.
MacKay, C.
Cheasty, A.
McArthur, K.
Stanway, E.
Leach, J.D.
Jackstadt, R.
Waldron, J.A.
Campbell, A.D.
Vlachogiannis, G.
Valeri, N.
Haigis, K.M.
Sonenberg, N.
Proud, C.G.
Jones, N.P.
Swarbrick, M.E.
McKinnon, H.J.
Faller, W.J.
Le Quesne, J.
Edwards, J.
Willis, A.E.
Bushell, M.
Sansom, O.J.
(2021). MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing eIF4E Phosphorylation and c-MYC Expression. Cancer discovery,
Vol.11
(5),
pp. 1228-1247.
Smyth, E.C.
Vlachogiannis, G.
Hedayat, S.
Harbery, A.
Hulkki-Wilson, S.
Salati, M.
Kouvelakis, K.
Fernandez-Mateos, J.
Cresswell, G.D.
Fontana, E.
Seidlitz, T.
Peckitt, C.
Hahne, J.C.
Lampis, A.
Begum, R.
Watkins, D.
Rao, S.
Starling, N.
Waddell, T.
Okines, A.
Crosby, T.
Mansoor, W.
Wadsley, J.
Middleton, G.
Fassan, M.
Wotherspoon, A.
Braconi, C.
Chau, I.
Vivanco, I.
Sottoriva, A.
Stange, D.E.
Cunningham, D.
Valeri, N.
(2021). EGFR amplification and outcome in a randomised phase III trial of chemotherapy alone or chemotherapy plus panitumumab for advanced gastro-oesophageal cancers. Gut,
Vol.70
(9),
pp. 1632-1641.
show abstract
ObjectiveEpidermal growth factor receptor (EGFR) inhibition may be effective in biomarker-selected populations of advanced gastro-oesophageal adenocarcinoma (aGEA) patients. Here, we tested the association between outcome and EGFR copy number (CN) in pretreatment tissue and plasma cell-free DNA (cfDNA) of patients enrolled in a randomised first-line phase III clinical trial of chemotherapy or chemotherapy plus the anti-EGFR monoclonal antibody panitumumab in aGEA (NCT00824785).DesignEGFR CN by either fluorescence in situ hybridisation (n=114) or digital-droplet PCR in tissues (n=250) and plasma cfDNAs (n=354) was available for 474 (86%) patients in the intention-to-treat (ITT) population. Tissue and plasma low-pass whole-genome sequencing was used to screen for coamplifications in receptor tyrosine kinases. Interaction between chemotherapy and EGFR inhibitors was modelled in patient-derived organoids (PDOs) from aGEA patients.ResultsEGFR amplification in cfDNA correlated with poor survival in the ITT population and similar trends were observed when the analysis was conducted in tissue and plasma by treatment arm. EGFR inhibition in combination with chemotherapy did not correlate with improved survival, even in patients with significant EGFR CN gains. Addition of anti-EGFR inhibitors to the chemotherapy agent epirubicin in PDOs, resulted in a paradoxical increase in viability and accelerated progression through the cell cycle, associated with p21 and cyclin B1 downregulation and cyclin E1 upregulation, selectively in organoids from EGFR-amplified aGEA.ConclusionEGFR CN can be accurately measured in tissue and liquid biopsies and may be used for the selection of aGEA patients. EGFR inhibitors may antagonise the antitumour effect of anthracyclines with important implications for the design of future combinatorial trials..
Lampis, A.
Hahne, J.C.
Gasparini, P.
Cascione, L.
Hedayat, S.
Vlachogiannis, G.
Murgia, C.
Fontana, E.
Edwards, J.
Horgan, P.G.
Terracciano, L.
Sansom, O.J.
Martins, C.D.
Kramer-Marek, G.
Croce, C.M.
Braconi, C.
Fassan, M.
Valeri, N.
(2021). MIR21-induced loss of junctional adhesion molecule A promotes activation of oncogenic pathways, progression and metastasis in colorectal cancer. Cell death & differentiation,
Vol.28
(10),
pp. 2970-2982.
show abstract
AbstractJunctional adhesion molecules (JAMs) play a critical role in cell permeability, polarity and migration. JAM-A, a key protein of the JAM family, is altered in a number of conditions including cancer; however, consequences of JAM-A dysregulation on carcinogenesis appear to be tissue dependent and organ dependent with significant implications for the use of JAM-A as a biomarker or therapeutic target. Here, we test the expression and prognostic role of JAM-A downregulation in primary and metastatic colorectal cancer (CRC) (n = 947). We show that JAM-A downregulation is observed in ~60% of CRC and correlates with poor outcome in four cohorts of stages II and III CRC (n = 1098). Using JAM-A knockdown, re-expression and rescue experiments in cell line monolayers, 3D spheroids, patient-derived organoids and xenotransplants, we demonstrate that JAM-A silencing promotes proliferation and migration in 2D and 3D cell models and increases tumour volume and metastases in vivo. Using gene-expression and proteomic analyses, we show that JAM-A downregulation results in the activation of ERK, AKT and ROCK pathways and leads to decreased bone morphogenetic protein 7 expression. We identify MIR21 upregulation as the cause of JAM-A downregulation and show that JAM-A rescue mitigates the effects of MIR21 overexpression on cancer phenotype. Our results identify a novel molecular loop involving MIR21 dysregulation, JAM-A silencing and activation of multiple oncogenic pathways in promoting invasiveness and metastasis in CRC..
Georgiou, A.
Stewart, A.
Vlachogiannis, G.
Pickard, L.
Valeri, N.
Cunningham, D.
Whittaker, S.R.
Banerji, U.
(2021). A phospho-proteomic study of cetuximab resistance in KRAS/NRAS/BRAFV600 wild-type colorectal cancer. Cellular oncology,
Vol.44
(5),
pp. 1197-1206.
show abstract
Abstract
Purpose
We hypothesised that plasticity in signal transduction may be a mechanism of drug resistance and tested this hypothesis in the setting of cetuximab resistance in patients with KRAS/NRAS/BRAFV600 wild-type colorectal cancer (CRC).
Methods
A multiplex antibody-based platform was used to study simultaneous changes in signal transduction of 55 phospho-proteins in 12 KRAS/NRAS/BRAFV600 wild-type CRC cell lines (6 cetuximab sensitive versus 6 cetuximab resistant) following 1 and 4 h in vitro cetuximab exposure. We validated our results in CRC patient samples (n = 4) using ex vivo exposure to cetuximab in KRAS/NRAS/BRAFV600 cells that were immunomagnetically separated from the serous effusions of patients with known cetuximab resistance.
Results
Differences in levels of phospho-proteins in cetuximab sensitive and resistant cell lines included reductions in phospho-RPS6 and phospho-PRAS40 in cetuximab sensitive, but not cetuximab resistant cell lines at 1 and 4 h, respectively. In addition, phospho-AKT levels were found to be elevated in 3/4 patient samples following ex vivo incubation with cetuximab for 1 h. We further explored these findings by studying the effects of combinations of cetuximab and two PI3K pathway inhibitors in 3 cetuximab resistant cell lines. The addition of PI3K pathway inhibitors to cetuximab led to a significantly higher reduction in colony formation capacity compared to cetuximab alone.
Conclusion
Our findings suggest activation of the PI3K pathway as a mechanism of cetuximab resistance in KRAS/NRAS/BRAFV600 wild-type CRC.
.
Tajan, M.
Hennequart, M.
Cheung, E.C.
Zani, F.
Hock, A.K.
Legrave, N.
Maddocks, O.D.
Ridgway, R.A.
Athineos, D.
Suárez-Bonnet, A.
Ludwig, R.L.
Novellasdemunt, L.
Angelis, N.
Li, V.S.
Vlachogiannis, G.
Valeri, N.
Mainolfi, N.
Suri, V.
Friedman, A.
Manfredi, M.
Blyth, K.
Sansom, O.J.
Vousden, K.H.
(2021). Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy. Nature communications,
Vol.12
(1).
show abstract
AbstractMany tumour cells show dependence on exogenous serine and dietary serine and glycine starvation can inhibit the growth of these cancers and extend survival in mice. However, numerous mechanisms promote resistance to this therapeutic approach, including enhanced expression of the de novo serine synthesis pathway (SSP) enzymes or activation of oncogenes that drive enhanced serine synthesis. Here we show that inhibition of PHGDH, the first step in the SSP, cooperates with serine and glycine depletion to inhibit one-carbon metabolism and cancer growth. In vitro, inhibition of PHGDH combined with serine starvation leads to a defect in global protein synthesis, which blocks the activation of an ATF-4 response and more broadly impacts the protective stress response to amino acid depletion. In vivo, the combination of diet and inhibitor shows therapeutic efficacy against tumours that are resistant to diet or drug alone, with evidence of reduced one-carbon availability. However, the defect in ATF4-response seen in vitro following complete depletion of available serine is not seen in mice, where dietary serine and glycine depletion and treatment with the PHGDH inhibitor lower but do not eliminate serine. Our results indicate that inhibition of PHGDH will augment the therapeutic efficacy of a serine depleted diet..
Carotenuto, P.
Amato, F.
Lampis, A.
Rae, C.
Hedayat, S.
Previdi, M.C.
Zito, D.
Raj, M.
Guzzardo, V.
Sclafani, F.
Lanese, A.
Parisi, C.
Vicentini, C.
Said-Huntingford, I.
Hahne, J.C.
Hallsworth, A.
Kirkin, V.
Young, K.
Begum, R.
Wotherspoon, A.
Kouvelakis, K.
Azevedo, S.X.
Michalarea, V.
Upstill-Goddard, R.
Rao, S.
Watkins, D.
Starling, N.
Sadanandam, A.
Chang, D.K.
Biankin, A.V.
Jamieson, N.B.
Scarpa, A.
Cunningham, D.
Chau, I.
Workman, P.
Fassan, M.
Valeri, N.
Braconi, C.
(2021). Modulation of pancreatic cancer cell sensitivity to FOLFIRINOX through microRNA-mediated regulation of DNA damage. Nature communications,
Vol.12
(1).
show abstract
AbstractFOLFIRINOX, a combination of chemotherapy drugs (Fluorouracil, Oxaliplatin, Irinotecan -FOI), provides the best clinical benefit in pancreatic ductal adenocarcinoma (PDAC) patients. In this study we explore the role of miRNAs (MIR) as modulators of chemosensitivity to identify potential biomarkers of response. We find that 41 and 84 microRNA inhibitors enhance the sensitivity of Capan1 and MiaPaCa2 PDAC cells respectively. These include a MIR1307-inhibitor that we validate in further PDAC cell lines. Chemotherapy-induced apoptosis and DNA damage accumulation are higher in MIR1307 knock-out (MIR1307KO) versus control PDAC cells, while re-expression of MIR1307 in MIR1307KO cells rescues these effects. We identify binding of MIR1307 to CLIC5 mRNA through covalent ligation of endogenous Argonaute-bound RNAs cross-linking immunoprecipitation assay. We validate these findings in an in vivo model with MIR1307 disruption. In a pilot cohort of PDAC patients undergoing FOLFIRONX chemotherapy, circulating MIR1307 correlates with clinical outcome..
Kühnl, A.
Peckitt, C.
Patel, B.
Ardeshna, K.M.
Macheta, M.P.
Radford, J.
Johnson, R.
Paneesha, S.
Barton, S.
Chau, I.
Begum, R.
Valeri, N.
Wotherspoon, A.
Du, Y.
Zerizer, I.
Cunningham, D.
(2020). R-GEM-Lenalidomide versus R-GEM-P as second-line treatment of diffuse large B-cell lymphoma: results of the UK NRCI phase II randomised LEGEND trial. Annals of hematology,
Vol.99
(1),
pp. 105-112.
Khakoo, S.
Carter, P.D.
Brown, G.
Valeri, N.
Picchia, S.
Bali, M.A.
Shaikh, R.
Jones, T.
Begum, R.
Rana, I.
Wotherspoon, A.
Terlizzo, M.
von Loga, K.
Kalaitzaki, E.
Saffery, C.
Watkins, D.
Tait, D.
Chau, I.
Starling, N.
Hubank, M.
Cunningham, D.
(2020). MRI Tumor Regression Grade and Circulating Tumor DNA as Complementary Tools to Assess Response and Guide Therapy Adaptation in Rectal Cancer. Clinical cancer research,
Vol.26
(1),
pp. 183-192.
Loupakis, F.
Depetris, I.
Biason, P.
Intini, R.
Prete, A.A.
Leone, F.
Lombardi, P.
Filippi, R.
Spallanzani, A.
Cascinu, S.
Bonetti, L.R.
Maddalena, G.
Valeri, N.
Sottoriva, A.
Zapata, L.
Salmaso, R.
Munari, G.
Rugge, M.
Dei Tos, A.P.
Golovato, J.
Sanborn, J.Z.
Nguyen, A.
Schirripa, M.
Zagonel, V.
Lonardi, S.
Fassan, M.
(2020). Prediction of Benefit from Checkpoint Inhibitors in Mismatch Repair Deficient Metastatic Colorectal Cancer: Role of Tumor Infiltrating Lymphocytes. The oncologist,
Vol.25
(6),
pp. 481-487.
show abstract
Abstract
Background
Immunotherapy with immune checkpoint inhibitors (ICIs) is highly effective in microsatellite instability–high (MSI-H) metastatic colorectal cancer (mCRC); however, specific predictive biomarkers are lacking.
Patients and Methods
Data and samples from 85 patients with MSI-H mCRC treated with ICIs were gathered. Tumor infiltrating lymphocytes (TILs) and tumor mutational burden (TMB) were analyzed in an exploratory cohort of “super” responders and “clearly” refractory patients; TILs were then evaluated in the whole cohort of patients. Primary objectives were the correlation between the number of TILs and TMB and their role as biomarkers of ICI efficacy. Main endpoints included response rate (RR), progression-free survival (PFS), and overall survival (OS).
Results
In the exploratory cohort, an increasing number of TILs correlated to higher TMB (Pearson's test, p = .0429). In the whole cohort, median number of TILs was 3.6 in responders compared with 1.8 in nonresponders (Mann-Whitney test, p = .0448). RR was 70.6% in patients with high number of TILs (TILs-H) compared with 42.9% in patients with low number of TILs (odds ratio = 3.20, p = .0291). Survival outcomes differed significantly in favor of TILs-H (PFS: hazard ratio [HR] = 0.42, p = .0278; OS: HR = 0.41, p = .0463).
Conclusion
A significant correlation between higher TMB and increased number of TILs was shown. A significantly higher activity and better PFS and OS with ICI in MSI-H mCRC were reported in cases with high number of TILs, thus supporting further studies of TIL count as predictive biomarker of ICI efficacy.
Implications for Practice
Microsatellite instability is the result of mismatch repair protein deficiency, caused by germline mutations or somatic modifications in mismatch repair genes. In metastatic colorectal cancer (mCRC), immunotherapy (with immune checkpoint inhibitors [ICIs]) demonstrated remarkable clinical benefit in microsatellite instability–high (MSI-H) patients. ICI primary resistance has been observed in approximately 25% of patients with MSI-H mCRC, underlining the need for predictive biomarkers. In this study, tumor mutational burden (TMB) and tumor infiltrating lymphocyte (TIL) analyses were performed in an exploratory cohort of patients with MSI-H mCRC treated with ICIs, demonstrating a significant correlation between higher TMB and increased number of TILs. Results also demonstrated a significant correlation between high number of TILs and clinical responses and survival benefit in a large data set of patients with MSI-H mCRC treated with ICI. TMB and TILs could represent predictive biomarkers of ICI efficacy in MSI-H mCRC and should be incorporated in future trials testing checkpoint inhibitors in colorectal cancer.
.
Fassan, M.
Realdon, S.
Cascione, L.
Hahne, J.C.
Munari, G.
Guzzardo, V.
Arcidiacono, D.
Lampis, A.
Brignola, S.
Dal Santo, L.
Agostini, M.
Bracon, C.
Maddalo, G.
Scarpa, M.
Farinati, F.
Zaninotto, G.
Valeri, N.
Rugge, M.
(2020). Circulating microRNA expression profiling revealed miR-92a-3p as a novel biomarker of Barrett’s carcinogenesis. Pathology - research and practice,
Vol.216
(5),
pp. 152907-152907.
Ratti, M.
Lampis, A.
Ghidini, M.
Salati, M.
Mirchev, M.B.
Valeri, N.
Hahne, J.C.
(2020). MicroRNAs (miRNAs) and Long Non-Coding RNAs (lncRNAs) as New Tools for Cancer Therapy: First Steps from Bench to Bedside. Targeted oncology,
Vol.15
(3),
pp. 261-278.
Amodio, V.
Yaeger, R.
Arcella, P.
Cancelliere, C.
Lamba, S.
Lorenzato, A.
Arena, S.
Montone, M.
Mussolin, B.
Bian, Y.
Whaley, A.
Pinnelli, M.
Murciano-Goroff, Y.R.
Vakiani, E.
Valeri, N.
Liao, W.-.
Bhalkikar, A.
Thyparambil, S.
Zhao, H.-.
de Stanchina, E.
Marsoni, S.
Siena, S.
Bertotti, A.
Trusolino, L.
Li, B.T.
Rosen, N.
Di Nicolantonio, F.
Bardelli, A.
Misale, S.
(2020). EGFR Blockade Reverts Resistance to KRASG12C Inhibition in Colorectal Cancer. Cancer discovery,
Vol.10
(8),
pp. 1129-1139.
Carotenuto, P.
Hedayat, S.
Fassan, M.
Cardinale, V.
Lampis, A.
Guzzardo, V.
Vicentini, C.
Scarpa, A.
Cascione, L.
Costantini, D.
Carpino, G.
Alvaro, D.
Ghidini, M.
Trevisani, F.
Te Poele, R.
Salati, M.
Ventura, S.
Vlachogiannis, G.
Hahne, J.C.
Boulter, L.
Forbes, S.J.
Guest, R.V.
Cillo, U.
Said‐Huntingford, I.
Begum, R.
Smyth, E.
Michalarea, V.
Cunningham, D.
Rimassa, L.
Santoro, A.
Roncalli, M.
Kirkin, V.
Clarke, P.
Workman, P.
Valeri, N.
Braconi, C.
(2020). Modulation of Biliary Cancer Chemo‐Resistance Through MicroRNA‐Mediated Rewiring of the Expansion of CD133+ Cells. Hepatology,
Vol.72
(3),
pp. 982-996.
Lampis, A.
Hahne, J.C.
Hedayat, S.
Valeri, N.
(2020). MicroRNAs as mediators of drug resistance mechanisms. Current opinion in pharmacology,
Vol.54,
pp. 44-50.
Acar, A.
Nichol, D.
Fernandez-Mateos, J.
Cresswell, G.D.
Barozzi, I.
Hong, S.P.
Trahearn, N.
Spiteri, I.
Stubbs, M.
Burke, R.
Stewart, A.
Caravagna, G.
Werner, B.
Vlachogiannis, G.
Maley, C.C.
Magnani, L.
Valeri, N.
Banerji, U.
Sottoriva, A.
(2020). Exploiting evolutionary steering to induce collateral drug sensitivity in cancer. Nature communications,
Vol.11
(1).
show abstract
AbstractDrug resistance mediated by clonal evolution is arguably the biggest problem in cancer therapy today. However, evolving resistance to one drug may come at a cost of decreased fecundity or increased sensitivity to another drug. These evolutionary trade-offs can be exploited using ‘evolutionary steering’ to control the tumour population and delay resistance. However, recapitulating cancer evolutionary dynamics experimentally remains challenging. Here, we present an approach for evolutionary steering based on a combination of single-cell barcoding, large populations of 108–109 cells grown without re-plating, longitudinal non-destructive monitoring of cancer clones, and mathematical modelling of tumour evolution. We demonstrate evolutionary steering in a lung cancer model, showing that it shifts the clonal composition of the tumour in our favour, leading to collateral sensitivity and proliferative costs. Genomic profiling revealed some of the mechanisms that drive evolved sensitivity. This approach allows modelling evolutionary steering strategies that can potentially control treatment resistance..
Anandappa, G.
Lampis, A.
Cunningham, D.
Khan, K.H.
Kouvelakis, K.
Vlachogiannis, G.
Hedayat, S.
Tunariu, N.
Rao, S.
Watkins, D.
Starling, N.
Braconi, C.
Darvish-Damavandi, M.
Lote, H.
Thomas, J.
Peckitt, C.
Kalaitzaki, R.
Khan, N.
Fotiadis, N.
Rugge, M.
Begum, R.
Rana, I.
Bryant, A.
Hahne, J.C.
Chau, I.
Fassan, M.
Valeri, N.
(2019). miR-31-3p Expression and Benefit from Anti-EGFR Inhibitors in Metastatic Colorectal Cancer Patients Enrolled in the Prospective Phase II PROSPECT-C Trial. Clinical cancer research,
Vol.25
(13),
pp. 3830-3838.
Visone, R.
Bacalini, M.G.
Franco, S.D.
Ferracin, M.
Colorito, M.L.
Pagotto, S.
Laprovitera, N.
Licastro, D.
Marco, M.D.
Scavo, E.
Bassi, C.
Saccenti, E.
Nicotra, A.
Grzes, M.
Garagnani, P.
Laurenzi, V.D.
Valeri, N.
Mariani-Costantini, R.
Negrini, M.
Stassi, G.
Veronese, A.
(2019). DNA methylation of shelf, shore and open sea CpG positions distinguish high microsatellite instability from low or stable microsatellite status colon cancer stem cells. Epigenomics,
Vol.11
(6),
pp. 587-604.
show abstract
Aim: To investigate the genome-wide methylation of genetically characterized colorectal cancer stem cell (CR-CSC) lines. Materials & methods: Eight CR-CSC lines were isolated from primary colorectal cancer (CRC) tissues, cultured and characterized for aneuploidy, mutational status of CRC-related genes and microsatellite instability (MSI). Genome-wide DNA methylation was assessed by MethylationEPIC microarray. Results: We describe a distinctive methylation pattern that is maintained following in vivo passages in immune-compromised mice. We identified an epigenetic CR-CSC signature associated with MSI. We noticed that the preponderance of the differentially methylated positions do not reside at CpG islands, but spread to shelf and open sea regions. Conclusion: Given that CRCs with MSI-high status have a lower metastatic potential, the identification of a MSI-related methylation signature could provide new insights and possible targets into metastatic CRC. .
Fontana, E.
Valeri, N.
(2019). Class(y) Dissection of BRAF Heterogeneity: Beyond Non-V600. Clinical cancer research,
Vol.25
(23),
pp. 6896-6898.
Fassan, M.
Cui, R.
Gasparini, P.
Mescoli, C.
Guzzardo, V.
Vicentini, C.
Munari, G.
Loupakis, F.
Lonardi, S.
Braconi, C.
Scarpa, M.
D'Angelo, E.
Pucciarelli, S.
Angriman, I.
Agostini, M.
D'Incá, R.
Farinati, F.
Gafà, R.
Lanza, G.
Frankel, W.L.
Croce, C.M.
Valeri, N.
Rugge, M.
(2019). miR-224 Is Significantly Upregulated and Targets Caspase-3 and Caspase-7 During Colorectal Carcinogenesis. Translational oncology,
Vol.12
(2),
pp. 282-291.
Khan, K.
Rane, J.K.
Cunningham, D.
Rao, S.
Watkins, D.
Starling, N.
Kalaitzaki, E.
Forster, M.
Braconi, C.
Valeri, N.
Gerlinger, M.
Chau, I.
(2019). Efficacy and Cardiotoxic Safety Profile of Raltitrexed in Fluoropyrimidines-Pretreated or High-Risk Cardiac Patients With GI Malignancies: Large Single-Center Experience. Clinical colorectal cancer,
Vol.18
(1),
pp. 64-71.e1.
Coati, I.
Lotz, G.
Fanelli, G.N.
Brignola, S.
Lanza, C.
Cappellesso, R.
Pellino, A.
Pucciarelli, S.
Spolverato, G.
Guzzardo, V.
Munari, G.
Zaninotto, G.
Scarpa, M.
Mastracci, L.
Farinati, F.
Realdon, S.
Pilati, P.
Lonardi, S.
Valeri, N.
Rugge, M.
Kiss, A.
Loupakis, F.
Fassan, M.
(2019). Claudin-18 expression in oesophagogastric adenocarcinomas: a tissue microarray study of 523 molecularly profiled cases. British journal of cancer,
Vol.121
(3),
pp. 257-263.
Salati, M.
Valeri, N.
Spallanzani, A.
Braconi, C.
Cascinu, S.
(2019). Oligometastatic gastric cancer: An emerging clinical entity with distinct therapeutic implications. European journal of surgical oncology,
Vol.45
(8),
pp. 1479-1482.
Pietrantonio, F.
Miceli, R.
Raimondi, A.
Kim, Y.W.
Kang, W.K.
Langley, R.E.
Choi, Y.Y.
Kim, K.-.
Nankivell, M.G.
Morano, F.
Wotherspoon, A.
Valeri, N.
Kook, M.-.
An, J.Y.
Grabsch, H.I.
Fucà, G.
Noh, S.H.
Sohn, T.S.
Kim, S.
Di Bartolomeo, M.
Cunningham, D.
Lee, J.
Cheong, J.-.
Smyth, E.C.
(2019). Individual Patient Data Meta-Analysis of the Value of Microsatellite Instability As a Biomarker in Gastric Cancer. Journal of clinical oncology,
Vol.37
(35),
pp. 3392-3400.
show abstract
PURPOSE In the CLASSIC and MAGIC trials, microsatellite instability (MSI)–high status was a favorable prognostic and potential negative predictive factor for neoadjuvant/adjuvant chemotherapy in resectable gastric cancer (GC). Given the low prevalence of MSI-high status in GC and its association with other positive prognostic variables, large data sets are needed to draw robust evidence of its prognostic/predictive value. PATIENTS AND METHODS We performed a multinational, individual-patient-data meta-analysis of the prognostic/predictive role of MSI in patients with resectable GC enrolled in the MAGIC, CLASSIC, ARTIST, and ITACA-S trials. Prognostic analyses used multivariable Cox models (MVM). The predictive role of MSI was assessed both in an all-comer population and in MAGIC and CLASSIC trials by MVM testing of the interaction of treatment (chemotherapy plus surgery v surgery) with MSI. RESULTS MSI status was available for 1,556 patients: 121 (7.8%) had MSI-high status; 576 were European, and 980 were Asian. In MSI-high versus MSI-low/microsatellite stable (MSS) comparisons, the 5-year disease-free survival (DFS) was 71.8% (95% CI, 63.8% to 80.7%) versus 52.3% (95% CI, 49.7% to 55.1%); the 5-year overall survival (OS) was 77.5% (95% CI, 70.0% to 85.8%) versus 59.3% (95% CI, 56.6% to 62.1%). In MVM, MSI was associated with longer DFS (hazard ratio [HR], 1.88; 95% CI, 1.28 to 2.76; P < .001) and OS (HR, 1.78; 95% CI, 1.17 to 2.73; P = .008), as were pT, pN, ethnicity, and treatment. Patients with MSI-low/MSS GC benefitted from chemotherapy plus surgery: the 5-year DFS compared with surgery only was 57% versus 41% (HR, 0.65; 95% CI, 0.53 to 0.79), and the 5-year OS was 62% versus 53% (HR, 0.75; 95% CI, 0.60 to 0.94). Conversely, those with MSI-high GC did not: the 5-year DFS was 70% versus 77% (HR, 1.27; 95% CI, 0.53 to 3.04), and the 5-year OS was 75% versus 83% (HR, 1.50; 95% CI, 0.55 to 4.12). CONCLUSION In patients with resectable primary GC, MSI is a robust prognostic marker that should be adopted as a stratification factor by clinical trials. Chemotherapy omission and/or immune checkpoint blockade should be investigated prospectively in MSI-high GCs according to clinically and pathologically defined risk of relapse. .
Khan, K.
Valeri, N.
Dearman, C.
Rao, S.
Watkins, D.
Starling, N.
Chau, I.
Cunningham, D.
(2019). Targeting EGFR pathway in metastatic colorectal cancer- tumour heterogeniety and convergent evolution. Critical reviews in oncology/hematology,
Vol.143,
pp. 153-163.
Schmidt, S.
Gay, D.
Uthe, F.W.
Denk, S.
Paauwe, M.
Matthes, N.
Diefenbacher, M.E.
Bryson, S.
Warrander, F.C.
Erhard, F.
Ade, C.P.
Baluapuri, A.
Walz, S.
Jackstadt, R.
Ford, C.
Vlachogiannis, G.
Valeri, N.
Otto, C.
Schülein-Völk, C.
Maurus, K.
Schmitz, W.
Knight, J.R.
Wolf, E.
Strathdee, D.
Schulze, A.
Germer, C.-.
Rosenwald, A.
Sansom, O.J.
Eilers, M.
Wiegering, A.
(2019). A MYC–GCN2–eIF2α negative feedback loop limits protein synthesis to prevent MYC-dependent apoptosis in colorectal cancer. Nature cell biology,
Vol.21
(11),
pp. 1413-1424.
Fanelli, G.N.
Loupakis, F.
Smyth, E.
Scarpa, M.
Lonardi, S.
Pucciarelli, S.
Munari, G.
Rugge, M.
Valeri, N.
Fassan, M.
(2019). Pathological Tumor Regression Grade Classifications in Gastrointestinal Cancers: Role on Patients’ Prognosis. International journal of surgical pathology,
Vol.27
(8),
pp. 816-835.
show abstract
Preoperative chemotherapy or combined radiotherapy and chemotherapy (CRT), followed by surgery, represents the standard approach for locally advanced esophageal, gastric, and rectal carcinomas. To adequately evaluate the effects of neoadjuvant CRT in the resection specimens, several histopathologic tumor regression grade (TRG) scoring systems have been introduced into clinical practice. The primary goal of these TRG systems relies on a correct prognostic stratification of patients in the attempt to help clinical decision-making and influence surgical strategies, postoperative adjuvant therapies, and surveillance intensity. However, most TRG systems suffer from poor reproducibility and low interobserver concordance rates. Many efforts have been made in the identification of alternative, robust, simple, and universally accepted TRG scoring systems, which would help in the comparison of different treatment strategies and in the standardization of multimodal therapies. The aim of this review is to analyze the most commonly used TRG systems in gastrointestinal cancers highlighting their pitfalls and usefulness, depending on the tumor type..
Valeri, N.
(2019). Streamlining Detection of Fusion Genes in Colorectal Cancer: Having “Faith” in Precision Oncology in the (Tissue) “Agnostic” Era. Cancer research,
Vol.79
(6),
pp. 1041-1043.
Moorcraft, S.Y.
Gonzalez de Castro, D.
Cunningham, D.
Jones, T.
Walker, B.A.
Peckitt, C.
Yuan, L.C.
Frampton, M.
Begum, R.
Eltahir, Z.
Wotherspoon, A.
Teixeira Mendes, L.S.
Hulkki Wilson, S.
Gillbanks, A.
Baratelli, C.
Fotiadis, N.
Patel, A.
Braconi, C.
Valeri, N.
Gerlinger, M.
Rao, S.
Watkins, D.
Chau, I.
Starling, N.
(2018). Investigating the feasibility of tumour molecular profiling in gastrointestinal malignancies in routine clinical practice. Annals of oncology,
Vol.29
(1),
pp. 230-236.
Lampis, A.
Carotenuto, P.
Vlachogiannis, G.
Cascione, L.
Hedayat, S.
Burke, R.
Clarke, P.
Bosma, E.
Simbolo, M.
Scarpa, A.
Yu, S.
Cole, R.
Smyth, E.
Mateos, J.F.
Begum, R.
Hezelova, B.
Eltahir, Z.
Wotherspoon, A.
Fotiadis, N.
Bali, M.A.
Nepal, C.
Khan, K.
Stubbs, M.
Hahne, J.C.
Gasparini, P.
Guzzardo, V.
Croce, C.M.
Eccles, S.
Fassan, M.
Cunningham, D.
Andersen, J.B.
Workman, P.
Valeri, N.
Braconi, C.
(2018). MIR21 Drives Resistance to Heat Shock Protein 90 Inhibition in Cholangiocarcinoma. Gastroenterology,
Vol.154
(4),
pp. 1066-1079.e5.
Smyth, E.
Khan, K.
Valeri, N.
(2018). Translational research and application of basic biology to clinical trial development in GI cancers. Annals of translational medicine,
Vol.6
(9),
pp. 164-164.
Davarzani, N.
Hutchins, G.G.
West, N.P.
Hewitt, L.C.
Nankivell, M.
Cunningham, D.
Allum, W.H.
Smyth, E.
Valeri, N.
Langley, R.E.
Grabsch, H.I.
(2018). Prognostic value of pathological lymph node status and primary tumour regression grading following neoadjuvant chemotherapy - results from the MRC OE02 oesophageal cancer trial. Histopathology,
Vol.72
(7),
pp. 1180-1188.
Khan, K.
Rata, M.
Cunningham, D.
Koh, D.-.
Tunariu, N.
Hahne, J.C.
Vlachogiannis, G.
Hedayat, S.
Marchetti, S.
Lampis, A.
Damavandi, M.D.
Lote, H.
Rana, I.
Williams, A.
Eccles, S.A.
Fontana, E.
Collins, D.
Eltahir, Z.
Rao, S.
Watkins, D.
Starling, N.
Thomas, J.
Kalaitzaki, E.
Fotiadis, N.
Begum, R.
Bali, M.
Rugge, M.
Temple, E.
Fassan, M.
Chau, I.
Braconi, C.
Valeri, N.
(2018). Functional imaging and circulating biomarkers of response to regorafenib in treatment-refractory metastatic colorectal cancer patients in a prospective phase II study. Gut,
Vol.67,
pp. 1484-1492.
show abstract
OBJECTIVE: Regorafenib demonstrated efficacy in patients with metastatic colorectal cancer (mCRC). Lack of predictive biomarkers, potential toxicities and cost-effectiveness concerns highlight the unmet need for better patient selection. DESIGN: Patients with RAS mutant mCRC with biopsiable metastases were enrolled in this phase II trial. Dynamic contrast-enhanced (DCE) MRI was acquired pretreatment and at day 15 post-treatment. Median values of volume transfer constant (Ktrans), enhancing fraction (EF) and their product KEF (summarised median values of Ktrans× EF) were generated. Circulating tumour (ct) DNA was collected monthly until progressive disease and tested for clonal RAS mutations by digital-droplet PCR. Tumour vasculature (CD-31) was scored by immunohistochemistry on 70 sequential tissue biopsies. RESULTS: Twenty-seven patients with paired DCE-MRI scans were analysed. Median KEF decrease was 58.2%. Of the 23 patients with outcome data, >70% drop in KEF (6/23) was associated with higher disease control rate (p=0.048) measured by RECIST V. 1.1 at 2 months, improved progression-free survival (PFS) (HR 0.16 (95% CI 0.04 to 0.72), p=0.02), 4-month PFS (66.7% vs 23.5%) and overall survival (OS) (HR 0.08 (95% CI 0.01 to 0.63), p=0.02). KEF drop correlated with CD-31 reduction in sequential tissue biopsies (p=0.04). RAS mutant clones decay in ctDNA after 8 weeks of treatment was associated with better PFS (HR 0.21 (95% CI 0.06 to 0.71), p=0.01) and OS (HR 0.28 (95% CI 0.07-1.04), p=0.06). CONCLUSIONS: Combining DCE-MRI and ctDNA predicts duration of anti-angiogenic response to regorafenib and may improve patient management with potential health/economic implications..
Ghidini, M.
Hahne, J.C.
Frizziero, M.
Tomasello, G.
Trevisani, F.
Lampis, A.
Passalacqua, R.
Valeri, N.
(2018). MicroRNAs as Mediators of Resistance Mechanisms to Small-Molecule Tyrosine Kinase Inhibitors in Solid Tumours. Target oncol,
Vol.13
(4),
pp. 423-436.
show abstract
Receptor tyrosine kinases (RTKs) are widely expressed transmembrane proteins that act as receptors for growth factors and other extracellular signalling molecules. Upon ligand binding, RTKs activate intracellular signalling cascades, and as such are involved in a broad variety of cellular functions including differentiation, proliferation, migration, invasion, angiogenesis, and survival under physiological as well as pathological conditions. Aberrant RTK activation can lead to benign proliferative conditions as well as to various forms of cancer. Indeed, more than 70% of the known oncogene and proto-oncogene transcripts involved in cancer code for RTKs. Consequently, these receptors are broadly studied as targets in the treatment of different tumours, and a large variety of small-molecule tyrosine kinase inhibitors (TKIs) are approved for therapy. In most cases, patients develop resistance to the TKIs within a short time. MicroRNAs are short (18-22 nucleotides) non-protein-coding RNAs that fine-tune cell homeostasis by controlling gene expression at the post-transcriptional level. Deregulation of microRNAs is common in many cancers, and increasing evidence exists for an important role of microRNAs in the development of resistance to therapies, including TKIs. In this review we focus on the role of microRNAs in mediating resistance to small-molecule TKIs in solid tumours..
Khan, K.H.
Cunningham, D.
Werner, B.
Vlachogiannis, G.
Spiteri, I.
Heide, T.
Mateos, J.F.
Vatsiou, A.
Lampis, A.
Damavandi, M.D.
Lote, H.
Huntingford, I.S.
Hedayat, S.
Chau, I.
Tunariu, N.
Mentrasti, G.
Trevisani, F.
Rao, S.
Anandappa, G.
Watkins, D.
Starling, N.
Thomas, J.
Peckitt, C.
Khan, N.
Rugge, M.
Begum, R.
Hezelova, B.
Bryant, A.
Jones, T.
Proszek, P.
Fassan, M.
Hahne, J.C.
Hubank, M.
Braconi, C.
Sottoriva, A.
Valeri, N.
(2018). Longitudinal Liquid Biopsy and Mathematical Modeling of Clonal Evolution Forecast Time to Treatment Failure in the PROSPECT-C Phase II Colorectal Cancer Clinical Trial. Cancer discov,
Vol.8,
pp. 1270-1285.
show abstract
Sequential profiling of plasma cell-free DNA (cfDNA) holds immense promise for early detection of patient progression. However, how to exploit the predictive power of cfDNA as a liquid biopsy in the clinic remains unclear. RAS pathway aberrations can be tracked in cfDNA to monitor resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. In this prospective phase II clinical trial of single-agent cetuximab in RAS wild-type patients, we combine genomic profiling of serial cfDNA and matched sequential tissue biopsies with imaging and mathematical modeling of cancer evolution. We show that a significant proportion of patients defined as RAS wild-type based on diagnostic tissue analysis harbor aberrations in the RAS pathway in pretreatment cfDNA and, in fact, do not benefit from EGFR inhibition. We demonstrate that primary and acquired resistance to cetuximab are often of polyclonal nature, and these dynamics can be observed in tissue and plasma. Furthermore, evolutionary modeling combined with frequent serial sampling of cfDNA allows prediction of the expected time to treatment failure in individual patients. This study demonstrates how integrating frequently sampled longitudinal liquid biopsies with a mathematical framework of tumor evolution allows individualized quantitative forecasting of progression, providing novel opportunities for adaptive personalized therapies.Significance: Liquid biopsies capture spatial and temporal heterogeneity underpinning resistance to anti-EGFR monoclonal antibodies in colorectal cancer. Dense serial sampling is needed to predict the time to treatment failure and generate a window of opportunity for intervention. Cancer Discov; 8(10); 1270-85. ©2018 AACR.See related commentary by Siravegna and Corcoran, p. 1213This article is highlighted in the In This Issue feature, p. 1195..
Sclafani, F.
Chau, I.
Cunningham, D.
Hahne, J.C.
Vlachogiannis, G.
Eltahir, Z.
Lampis, A.
Braconi, C.
Kalaitzaki, E.
De Castro, D.G.
Wotherspoon, A.
Capdevila, J.
Glimelius, B.
Tarazona, N.
Begum, R.
Lote, H.
Hulkki Wilson, S.
Mentrasti, G.
Brown, G.
Tait, D.
Oates, J.
Valeri, N.
(2018). KRAS and BRAF mutations in circulating tumour DNA from locally advanced rectal cancer. Scientific reports,
Vol.8
(1).
Sundar, R.
Miranda, S.
Rodrigues, D.N.
Chénard-Poirier, M.
Dolling, D.
Clarke, M.
Figueiredo, I.
Bertan, C.
Yuan, W.
Ferreira, A.
Chistova, R.
Boysen, G.
Perez, D.R.
Tunariu, N.
Mateo, J.
Wotherspoon, A.
Chau, I.
Cunningham, D.
Valeri, N.
Carreira, S.
de Bono, J.
(2018). Ataxia Telangiectasia Mutated Protein Loss and Benefit From Oxaliplatin-based Chemotherapy in Colorectal Cancer. Clinical colorectal cancer,
Vol.17
(4),
pp. 280-284.
Mensah, A.A.
Cascione, L.
Gaudio, E.
Tarantelli, C.
Bomben, R.
Bernasconi, E.
Zito, D.
Lampis, A.
Hahne, J.C.
Rinaldi, A.
Stathis, A.
Zucca, E.
Kwee, I.
Gattei, V.
Valeri, N.
Riveiro, M.E.
Bertoni, F.
(2018). Bromodomain and extra-terminal domain inhibition modulates the expression of pathologically relevant microRNAs in diffuse large B-cell lymphoma. Haematologica,
Vol.103
(12),
pp. 2049-2058.
Fassan, M.
Vianello, L.
Sacchi, D.
Fanelli, G.N.
Munari, G.
Scarpa, M.
Cappellesso, R.
Loupakis, F.
Lanza, C.
Salmaso, R.
Mescoli, C.
Valeri, N.
Agostini, M.
D’Angelo, E.
Lonardi, S.
Pucciarelli, S.
Veronese, N.
Luchini, C.
Rugge, M.
(2018). Assessment of intratumor immune-microenvironment in colorectal cancers with extranodal extension of nodal metastases. Cancer cell international,
Vol.18
(1).
Smyth, E.C.
Nyamundanda, G.
Cunningham, D.
Fontana, E.
Ragulan, C.
Tan, I.B.
Lin, S.J.
Wotherspoon, A.
Nankivell, M.
Fassan, M.
Lampis, A.
Hahne, J.C.
Davies, A.R.
Lagergren, J.
Gossage, J.A.
Maisey, N.
Green, M.
Zylstra, J.L.
Allum, W.H.
Langley, R.E.
Tan, P.
Valeri, N.
Sadanandam, A.
(2018). A seven-Gene Signature assay improves prognostic risk stratification of perioperative chemotherapy treated gastroesophageal cancer patients from the MAGIC trial. Annals of oncology,
Vol.29
(12),
pp. 2356-2362.
Fanelli, G.N.
Gasparini, P.
Coati, I.
Cui, R.
Pakula, H.
Chowdhury, B.
Valeri, N.
Loupakis, F.
Kupcinskas, J.
Cappellesso, R.
Fassan, M.
(2018). LONG-NONCODING RNAs in gastroesophageal cancers. Non-coding rna research,
Vol.3
(4),
pp. 195-212.
Lote, H.
Valeri, N.
Chau, I.
(2018). HER2 inhibition in gastro-oesophageal cancer: A review drawing on lessons learned from breast cancer. World j gastrointest oncol,
Vol.10,
pp. 159-171.
show abstract
Human epidermal growth factor receptor 2 (HER2)-inhibition is an important therapeutic strategy in HER2-amplified gastro-oesophageal cancer (GOC). A significant proportion of GOC patients display HER2 amplification, yet HER2 inhibition in these patients has not displayed the success seen in HER2 amplified breast cancer. Much of the current evidence surrounding HER2 has been obtained from studies in breast cancer, and we are only recently beginning to improve our understanding of HER2-amplified GOC. Whilst there are numerous licensed HER2 inhibitors in breast cancer, trastuzumab remains the only licensed HER2 inhibitor for HER2-amplified GOC. Clinical trials investigating lapatinib, trastuzumab emtansine, pertuzumab and MM-111 in GOC have demonstrated disappointing results and have not yet changed the treatment paradigm. Trastuzumab deruxtecan may hold promise and is currently being investigated in phase II trials. HER2 amplified GOC differs from breast cancer due to inherent differences in the HER2 amino-truncation and mutation rate, loss of HER2 expression, alterations in HER2 signalling pathways and differences in insulin-like growth factor-1 receptor and MET expression. Epigenetic alterations involving different microRNA profiles in GOC as compared to breast cancer and intrinsic differences in the immune environment are likely to play a role. The key to effective treatment of HER2 amplified GOC lies in understanding these mechanisms and tailoring HER2 inhibition for GOC patients in order to improve clinical outcomes..
Vlachogiannis, G.
Hedayat, S.
Vatsiou, A.
Jamin, Y.
Fernández-Mateos, J.
Khan, K.
Lampis, A.
Eason, K.
Huntingford, I.
Burke, R.
Rata, M.
Koh, D.-.
Tunariu, N.
Collins, D.
Hulkki-Wilson, S.
Ragulan, C.
Spiteri, I.
Moorcraft, S.Y.
Chau, I.
Rao, S.
Watkins, D.
Fotiadis, N.
Bali, M.
Darvish-Damavandi, M.
Lote, H.
Eltahir, Z.
Smyth, E.C.
Begum, R.
Clarke, P.A.
Hahne, J.C.
Dowsett, M.
de Bono, J.
Workman, P.
Sadanandam, A.
Fassan, M.
Sansom, O.J.
Eccles, S.
Starling, N.
Braconi, C.
Sottoriva, A.
Robinson, S.P.
Cunningham, D.
Valeri, N.
(2018). Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science,
Vol.359,
pp. 920-926.
show abstract
Patient-derived organoids (PDOs) have recently emerged as robust preclinical models; however, their potential to predict clinical outcomes in patients has remained unclear. We report on a living biobank of PDOs from metastatic, heavily pretreated colorectal and gastroesophageal cancer patients recruited in phase 1/2 clinical trials. Phenotypic and genotypic profiling of PDOs showed a high degree of similarity to the original patient tumors. Molecular profiling of tumor organoids was matched to drug-screening results, suggesting that PDOs could complement existing approaches in defining cancer vulnerabilities and improving treatment responses. We compared responses to anticancer agents ex vivo in organoids and PDO-based orthotopic mouse tumor xenograft models with the responses of the patients in clinical trials. Our data suggest that PDOs can recapitulate patient responses in the clinic and could be implemented in personalized medicine programs..
Smyth, E.C.
Wotherspoon, A.
Peckitt, C.
Gonzalez, D.
Hulkki-Wilson, S.
Eltahir, Z.
Fassan, M.
Rugge, M.
Valeri, N.
Okines, A.
Hewish, M.
Allum, W.
Stenning, S.
Nankivell, M.
Langley, R.
Cunningham, D.
(2017). Mismatch Repair Deficiency, Microsatellite Instability, and Survival: An Exploratory Analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) Trial. Jama oncol,
Vol.3
(9),
pp. 1197-1203.
show abstract
Importance: Mismatch repair (MMR) deficiency (MMRD) and microsatellite instability (MSI) are prognostic for survival in many cancers and for resistance to fluoropyrimidines in early colon cancer. However, the effect of MMRD and MSI in curatively resected gastric cancer treated with perioperative chemotherapy is unknown. Objective: To examine the association among MMRD, MSI, and survival in patients with resectable gastroesophageal cancer randomized to surgery alone or perioperative epirubicin, cisplatin, and fluorouracil chemotherapy in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. Design, Setting, and Participants: This secondary post hoc analysis of the MAGIC trial included participants who were treated with surgery alone or perioperative chemotherapy plus surgery for operable gastroesophageal cancer from July 1, 1994, through April 30, 2002. Tumor sections were assessed for expression of the MMR proteins mutL homologue 1, mutS homologue 2, mutS homologue 6, and PMS1 homologue 2. The association among MSI, MMRD, and survival was assessed. Main Outcomes and Measures: Interaction between MMRD and MSI status and overall survival (OS). Results: Of the 503 study participants, MSI results were available for 303 patients (283 with microsatellite stability or low MSI [median age, 62 years; 219 males (77.4%)] and 20 with high MSI [median age, 66 years; 14 males (70.0%)]). A total of 254 patients had MSI and MMR results available. Patients treated with surgery alone who had high MSI or MMRD had a median OS that was not reached (95% CI, 11.5 months to not reached) compared with a median OS among those who had neither high MSI nor MMRD of 20.5 months (95% CI, 16.7-27.8 months; hazard ratio, 0.42; 95% CI, 0.15-1.15; P = .09). In contrast, patients treated with chemotherapy plus surgery who had either high MSI or MMRD had a median OS of 9.6 months (95% CI, 0.1-22.5 months) compared with a median OS among those who were neither high MSI nor MMRD of 19.5 months (95% CI, 15.4-35.2 months; hazard ratio, 2.18; 95% CI, 1.08-4.42; P = .03). Conclusions and Relevance: In the MAGIC trial, MMRD and high MSI were associated with a positive prognostic effect in patients treated with surgery alone and a differentially negative prognostic effect in patients treated with chemotherapy. If independently validated, MSI or MMRD determined by preoperative biopsies could be used to select patients for perioperative chemotherapy..
Fassan, M.
Saraggi, D.
Balsamo, L.
Realdon, S.
Scarpa, M.
Castoro, C.
Coati, I.
Salmaso, R.
Farinati, F.
Guzzardo, V.
Arcidiacono, D.
Munari, G.
Gasparini, P.
Veronese, N.
Luchini, C.
Valeri, N.
Rugge, M.
(2017). Early miR-223 Upregulation in Gastroesophageal Carcinogenesis. Am j clin pathol,
Vol.147
(3),
pp. 301-308.
show abstract
Objectives: To test miR-223 upregulation during gastric (intestinal-type) and Barrett esophageal carcinogenesis. Methods: miR-223 expression was assessed by quantitative reverse transcription polymerase chain reaction in a series of 280 gastroesophageal biopsy samples representative of the whole spectrum of phenotypic changes involved in both carcinogenetic cascades. The results were further validated by in situ hybridization on multiple tissue specimens obtained from six surgically treated gastroesophageal adenocarcinomas. miR-223 expression was also assessed in plasma samples from 30 patients with early stage (ie, stages I and II) gastroesophageal adenocarcinoma and relative controls. Results: In both gastric and esophageal models, miR-223 expression significantly increased along with the severity of the considered lesions (analysis of variance, P < .001). Among atrophic gastritis and long-segment Barrett esophagus samples, miR-223 overexpression was significantly associated with the score of intestinal metaplasia. miR-223 plasma levels were significantly upregulated in patients with cancer compared with controls ( t test, both P < .001). Conclusions: miR-223 early upregulation observed in tissue samples and its diagnostic value in discriminating patients with early adenocarcinoma by plasma testing provide a solid rationale for further exploring the diagnostic reliability of this microRNA as a novel biomarker in gastroesophageal adenocarcinoma secondary prevention strategies..
Sundar, R.
Valeri, N.
Harrington, K.J.
Yap, T.A.
(2017). Combining Molecularly Targeted Agents: Is More Always Better?. Clinical cancer research,
Vol.23
(5),
pp. 1123-1125.
Saraggi, D.
Fassan, M.
Mescoli, C.
Scarpa, M.
Valeri, N.
Michielan, A.
D’Incá, R.
Rugge, M.
(2017). The molecular landscape of colitis-associated carcinogenesis. Digestive and liver disease,
Vol.49
(4),
pp. 326-330.
Ghidini, M.
Cascione, L.
Carotenuto, P.
Lampis, A.
Trevisani, F.
Previdi, M.C.
Hahne, J.C.
Said-Huntingford, I.
Raj, M.
Zerbi, A.
Mescoli, C.
Cillo, U.
Rugge, M.
Roncalli, M.
Torzilli, G.
Rimassa, L.
Santoro, A.
Valeri, N.
Fassan, M.
Braconi, C.
(2017). Characterisation of the immune-related transcriptome in resected biliary tract cancers. European journal of cancer,
Vol.86,
pp. 158-165.
Battersby, N.J.
Dattani, M.
Rao, S.
Cunningham, D.
Tait, D.
Adams, R.
Moran, B.J.
Khakoo, S.
Tekkis, P.
Rasheed, S.
Mirnezami, A.
Quirke, P.
West, N.P.
Nagtegaal, I.
Chong, I.
Sadanandam, A.
Valeri, N.
Thomas, K.
Frost, M.
Brown, G.
(2017). A rectal cancer feasibility study with an embedded phase III trial design assessing magnetic resonance tumour regression grade (mrTRG) as a novel biomarker to stratify management by good and poor response to chemoradiotherapy (TRIGGER): study protocol for a randomised controlled trial. Trials,
Vol.18
(1).
Smyth, E.
Zhang, S.
Cunningham, D.
Wotherspoon, A.
Soong, R.
Peckitt, C.
Valeri, N.
Fassan, M.
Rugge, M.
Okines, A.
Allum, W.
Stenning, S.
Nankivell, M.
Langley, R.
Tan, P.
(2017). Pharmacogenetic Analysis of the UK MRC (Medical Research Council) MAGIC Trial: Association of Polymorphisms with Toxicity and Survival in Patients Treated with Perioperative Epirubicin, Cisplatin, and 5-fluorouracil (ECF) Chemotherapy. Clinical cancer research,
Vol.23
(24),
pp. 7543-7549.
Tomasello, G.
Valeri, N.
Ghidini, M.
Smyth, E.C.
Liguigli, W.
Toppo, L.
Mattioli, R.
Curti, A.
Hahne, J.C.
Negri, F.M.
Panni, S.
Ratti, M.
Lazzarelli, S.
Gerevini, F.
Colombi, C.
Panni, A.
Rovatti, M.
Treccani, L.
Martinotti, M.
Passalacqua, R.
(2017). First-line dose-dense chemotherapy with docetaxel, cisplatin, folinic acid and 5-fluorouracil (DCF) plus panitumumab in patients with locally advanced or metastatic cancer of the stomach or gastroesophageal junction: final results and biomarker analysis from an Italian oncology group for clinical research (GOIRC) phase II study. Oncotarget,
Vol.8
(67),
pp. 111795-111806.
Saraggi, D.
Fassan, M.
Bornschein, J.
Farinati, F.
Realdon, S.
Valeri, N.
Rugge, M.
(2016). From Barrett metaplasia to esophageal adenocarcinoma: the molecular background. Histology and histopathology,
Vol.31
(1),
pp. 25-32.
Sclafani, F.
Chau, I.
Cunningham, D.
Lampis, A.
Hahne, J.C.
Ghidini, M.
Lote, H.
Zito, D.
Tabernero, J.
Glimelius, B.
Cervantes, A.
Begum, R.
De Castro, D.G.
Wilson, S.H.
Peckitt, C.
Eltahir, Z.
Wotherspoon, A.
Tait, D.
Brown, G.
Oates, J.
Braconi, C.
Valeri, N.
(2016). Sequence variation in mature microRNA-608 and benefit from neo-adjuvant treatment in locally advanced rectal cancer patients. Carcinogenesis,
Vol.37
(9),
pp. 852-857.
Smyth, E.C.
Fassan, M.
Cunningham, D.
Allum, W.H.
Okines, A.F.
Lampis, A.
Hahne, J.C.
Rugge, M.
Peckitt, C.
Nankivell, M.
Langley, R.
Ghidini, M.
Braconi, C.
Wotherspoon, A.
Grabsch, H.I.
Valeri, N.
(2016). Effect of Pathologic Tumor Response and Nodal Status on Survival in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy Trial. J clin oncol,
Vol.34
(23),
pp. 2721-2727.
show abstract
PURPOSE: The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial established perioperative epirubicin, cisplatin, and fluorouracil chemotherapy as a standard of care for patients with resectable esophagogastric cancer. However, identification of patients at risk for relapse remains challenging. We evaluated whether pathologic response and lymph node status after neoadjuvant chemotherapy are prognostic in patients treated in the MAGIC trial. MATERIALS AND METHODS: Pathologic regression was assessed in resection specimens by two independent pathologists using the Mandard tumor regression grading system (TRG). Differences in overall survival (OS) according to TRG were assessed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses using the Cox proportional hazards method established the relationships among TRG, clinical-pathologic variables, and OS. RESULTS: Three hundred thirty resection specimens were analyzed. In chemotherapy-treated patients with a TRG of 1 or 2, median OS was not reached, whereas for patients with a TRG of 3, 4, or 5, median OS was 20.47 months. On univariate analysis, high TRG and lymph node metastases were negatively related to survival (Mandard TRG 3, 4, or 5: hazard ratio [HR], 1.94; 95% CI, 1.11 to 3.39; P = .0209; lymph node metastases: HR, 3.63; 95% CI, 1.88 to 7.0; P < .001). On multivariate analysis, only lymph node status was independently predictive of OS (HR, 3.36; 95% CI, 1.70 to 6.63; P < .001). CONCLUSION: Lymph node metastases and not pathologic response to chemotherapy was the only independent predictor of survival after chemotherapy plus resection in the MAGIC trial. Prospective evaluation of whether omitting postoperative chemotherapy and/or switching to a noncross-resistant regimen in patients with lymph node-positive disease whose tumor did not respond to preoperative epirubicin, cisplatin, and fluorouracil may be appropriate..
Trevisani, F.
Ghidini, M.
Larcher, A.
Lampis, A.
Lote, H.
Manunta, P.
Alibrandi, M.T.
Zagato, L.
Citterio, L.
Dell’Antonio, G.
Carenzi, C.
Capasso, G.
Rugge, M.
Rigotti, P.
Bertini, R.
Cascione, L.
Briganti, A.
Salonia, A.
Benigni, F.
Braconi, C.
Fassan, M.
Hahne, J.C.
Montorsi, F.
Valeri, N.
(2016). MicroRNA 193b-3p as a predictive biomarker of chronic kidney disease in patients undergoing radical nephrectomy for renal cell carcinoma. Br j cancer,
Vol.115,
pp. 1343-1350.
show abstract
BACKGROUND: A significant proportion of patients undergoing radical nephrectomy (RN) for clear-cell renal cell carcinoma (RCC) develop chronic kidney disease (CKD) within a few years following surgery. Chronic kidney disease has important health, social and economic impact and no predictive biomarkers are currently available. MicroRNAs (miRs) are small non-coding RNAs implicated in several pathological processes. METHODS: Primary objective of our study was to define miRs whose deregulation is predictive of CKD in patients treated with RN. Ribonucleic acid from formalin-fixed paraffin embedded renal parenchyma (cortex and medulla isolated separately) situated >3 cm from the matching RCC was tested for miR expression using nCounter NanoString technology in 71 consecutive patients treated with RN for RCC. Validation was performed by RT-PCR and in situ hybridisation. End point was post-RN CKD measured 12 months post-operatively. Multivariable logistic regression and decision curve analysis were used to test the statistical and clinical impact of predictors of CKD. RESULTS: The overexpression of miR-193b-3p was associated with high risk of developing CKD in patients undergoing RN for RCC and emerged as an independent predictor of CKD. The addition of miR-193b-3p to a predictive model based on clinical variables (including sex and estimated glomerular filtration rate) increased the sensitivity of the predictive model from 81 to 88%. In situ hybridisation showed that miR-193b-3p overexpression was associated with tubule-interstitial inflammation and fibrosis in patients with no clinical or biochemical evidence of pre-RN nephropathy. CONCLUSIONS: miR-193b-3p might represent a useful biomarker to tailor and implement surveillance strategies for patients at high risk of developing CKD following RN..
Fassan, M.
Saraggi, D.
Balsamo, L.
Cascione, L.
Castoro, C.
Coati, I.
De Bernard, M.
Farinati, F.
Guzzardo, V.
Valeri, N.
Zambon, C.F.
Rugge, M.
(2016). Let-7c down-regulation in Helicobacter pylori-related gastric carcinogenesis. Oncotarget,
Vol.7
(4),
pp. 4915-4924.
Sclafani, F.
Chau, I.
Cunningham, D.
Peckitt, C.
Lampis, A.
Hahne, J.C.
Braconi, C.
Tabernero, J.
Glimelius, B.
Cervantes, A.
Begum, R.
Gonzalez De Castro, D.
Hulkki Wilson, S.
Eltahir, Z.
Wotherspoon, A.
Tait, D.
Brown, G.
Oates, J.
Valeri, N.
(2015). Prognostic role of the LCS6 KRAS variant in locally advanced rectal cancer: results of the EXPERT-C trial. Annals of oncology,
Vol.26
(9),
pp. 1936-1941.
Slattery, M.L.
Herrick, J.S.
Mullany, L.E.
Valeri, N.
Stevens, J.
Caan, B.J.
Samowitz, W.
Wolff, R.K.
(2015). An evaluation and replication of miRNAs with disease stage and colorectal cancer-specific mortality. Int j cancer,
Vol.137
(2),
pp. 428-438.
show abstract
MicroRNAs (miRNAs) have been implicated in colorectal cancer (CRC) development and associated with prognostic indicators such as disease stage and survival. Prognostic associations are often based on few individuals and imprecise. In this study, we utilize population-based data from 1,141 CRC cases to replicate previously reported associations between 121 miRNAs and disease stage and survival. The Agilent Human miRNA Microarray V19.0 was used to generate miRNA data following a stringent quality control protocol. Assessment of survival was done using Cox Proportional Hazard models adjusting for age, disease stage and tumor molecular phenotype. Five miRNAs were associated with more advanced disease stage; hsa-miR-145-5p and hsa-miR-31-5p showed increased expression with more advanced tumor stage, while hsa-miR-200b-3p, hsa-miR-215 and hsa-miR-451a had decreased expression with more advanced tumors. Thirteen miRNAs were associated with CRC mortality among individuals diagnosed with colon cancer while 14 were associated with CRC mortality after a diagnosis with rectal cancer. Strongest associations were observed for those miRNAs that were expressed in a small subset of tumors. Most notable associations were for hsa-miR-145-3p [hazard ratio (HR) 2.94, 95% confidence interval (CI) 1.54, 5.61], and hsa-miR-9-3p (HR 10.28, 95% CI 1.31, 80.84) with colon cancer and hsa-miR-335-5p (HR 0.17, 95% CI 0.05, 0.54) for rectal cancer. hsa-miR-374a-5p, hsa-miR-570-3p and hsa-miR-18a-5p significantly reduced the hazard of dying for all cases, regardless of tumor site. Our findings illustrate the need for a large sample to evaluate the association of miRNAs with survival and disease stage in order to determine associations by tumor site. .
Cordero, J.B.
Ridgway, R.A.
Valeri, N.
Nixon, C.
Frame, M.C.
Muller, W.J.
Vidal, M.
Sansom, O.J.
(2014). c-Src drives intestinal regeneration and transformation. Embo j,
Vol.33
(13),
pp. 1474-1491.
show abstract
The non-receptor tyrosine kinase c-Src, hereafter referred to as Src, is overexpressed or activated in multiple human malignancies. There has been much speculation about the functional role of Src in colorectal cancer (CRC), with Src amplification and potential activating mutations in up to 20% of the human tumours, although this has never been addressed due to multiple redundant family members. Here, we have used the adult Drosophila and mouse intestinal epithelium as paradigms to define a role for Src during tissue homeostasis, damage-induced regeneration and hyperplasia. Through genetic gain and loss of function experiments, we demonstrate that Src is necessary and sufficient to drive intestinal stem cell (ISC) proliferation during tissue self-renewal, regeneration and tumourigenesis. Surprisingly, Src plays a non-redundant role in the mouse intestine, which cannot be substituted by the other family kinases Fyn and Yes. Mechanistically, we show that Src drives ISC proliferation through upregulation of EGFR and activation of Ras/MAPK and Stat3 signalling. Therefore, we demonstrate a novel essential role for Src in intestinal stem/progenitor cell proliferation and tumourigenesis initiation in vivo. .
Ryan, B.M.
Wolff, R.K.
Valeri, N.
Khan, M.
Robinson, D.
Paone, A.
Bowman, E.D.
Lundgreen, A.
Caan, B.
Potter, J.
Brown, D.
Croce, C.
Slattery, M.L.
Harris, C.C.
(2014). An analysis of genetic factors related to risk of inflammatory bowel disease and colon cancer. Cancer epidemiol,
Vol.38
(5),
pp. 583-590.
show abstract
BACKGROUND AND AIMS: Patients with inflammatory bowel disease (IBD) have a higher risk of developing colorectal cancer than the general population. Genome-wide association studies have identified and replicated several loci associated with risk of IBD; however, it is currently unknown whether these loci are also associated with colon cancer risk. METHODS: We selected 15 validated SNPs associated with risk of either Crohn's disease, ulcerative colitis, or both in previous GWAS and tested whether these loci were also associated with colon cancer risk in a two-stage study design. RESULTS: We found that rs744166 in STAT3 was associated with colon cancer risk in two studies; however, the direction of the observation was reversed in TP53 mutant tumors possibly due to a nullification of the effect by mutant p53. The SNP, which lies within intron 1 of the STAT3 gene, was associated with lower expression of STAT3 mRNA in TP53 wild-type, but not mutant, tumors. CONCLUSIONS: These data suggest that the STAT3 locus is associated with both IBD and cancer. Further understanding the function of this variant in relation to TP53 could possibly explain the role of this gene in autoimmunity and cancer. Furthermore, an analysis of this locus, specifically in a population with IBD, could help to resolve the relationship between this SNP and cancer..
Valeri, N.
Braconi, C.
Gasparini, P.
Murgia, C.
Lampis, A.
Paulus-Hock, V.
Hart, J.R.
Ueno, L.
Grivennikov, S.I.
Lovat, F.
Paone, A.
Cascione, L.
Sumani, K.M.
Veronese, A.
Fabbri, M.
Carasi, S.
Alder, H.
Lanza, G.
Gafa', R.
Moyer, M.P.
Ridgway, R.A.
Cordero, J.
Nuovo, G.J.
Frankel, W.L.
Rugge, M.
Fassan, M.
Groden, J.
Vogt, P.K.
Karin, M.
Sansom, O.J.
Croce, C.M.
(2014). MicroRNA-135b Promotes Cancer Progression by Acting as a Downstream Effector of Oncogenic Pathways in Colon Cancer. Cancer cell,
Vol.25
(4),
pp. 469-483.
Fassan, M.
Dall'Olmo, L.
Galasso, M.
Braconi, C.
Pizzi, M.
Realdon, S.
Volinia, S.
Valeri, N.
Gasparini, P.
Baffa, R.
Souza, R.F.
Vicentini, C.
D'Angelo, E.
Bornschein, J.
Nuovo, G.J.
Zaninotto, G.
Croce, C.M.
Rugge, M.
(2014). Transcribed ultraconserved noncoding RNAs (T-UCR) are involved in Barrett's esophagus carcinogenesis. Oncotarget,
Vol.5
(16),
pp. 7162-7171.
Valeri, N.
Braconi, C.
Gasparini, P.
Grivennikow, S.
Hart, J.R.
Paone, A.
Lovat, F.
Fabbri, M.
Gafa', R.
Nuovo, G.
Lanza, G.
Frankel, W.
Vogt, P.K.
Groden, J.
Karin, M.
Croce, C.M.
(2012). Anti-miR-135b in colon cancer treatment: Results from a preclinical study. Journal of clinical oncology,
Vol.30
(4_suppl),
pp. 457-457.
show abstract
457 Background: MicroRNAs (miRs) are small non coding RNAs involved in cell homeostasis. miRs are deregulated in colorectal cancer (CRC). Our study aimed at identifying miRs with a driver role in carcinogenesis altered by similar mechanisms in both human and mouse CRC. Goal of the study was to use CRC mouse models for the pre-clinical development of anti-miRs as therapeutic drugs. Methods: Azoximetane (AOM)/Dextran-Sulfate (DSS) treated mice or CDX2-CRE/APC-/- mice were used to study inflammation-associated and sporadic APC-related CRC. Human Inflammatory Bowel Disease associated (n=30), and sporadic (n=90) CRC with their matched normal tissues were collected according to Good Clinical Practice recommendation and subjected to RNA extraction using Trizol. miR and gene expression profiling was assessed by nCounter technology (Nanostring Seattle). Anti-miR-135b and scrambled probes for in vivo studies were synthesized by Girindus. Results: miRs profiling from AOM/DSS and CDX2-CRE/APC-/- CRC. revealed that miR-135b is one of the most up-regulated miRs in both models. In humans miR-135b over-expression was found in both IBD and sporadic CRC and was associated with reduced Progression Free Survival and Overall Survival in CRC patients. Molecular studies in Mouse Embryo Fibroblast and human CRC cell lines highlighted the role of two major pathways in the upstream activation of miR-135b: APC-β-Catenin and SRC-PI3K. MiR-135b up-regulation resulted in reduced apoptosis and increased invasion and metastasis due to the down-regulation of TGFRB2, DAPK1, APC and HIF1AN. Silencing of miR-135b in vivo reduced tumor multiplicity and tumor load in the AOM/DSS CRC model. Mice treated with anti-miR-135b showed well differentiated tumors and microacinar pattern while tumors in the control groups showed low differentiation and adenomatous pattern. Conclusions: Our data suggest that miR-135b is a key molecule whose activation is downstream of oncogenes and oncosuppressor genes frequently altered in CRC. Our study defines specific pathways that converge on the activation of the same microrna. The “in vivo” silencing of miR-135 shows preclinical efficacy with low toxicity and represents the first in vivo study for the use of antimiRs in CRC treatment. .
Valeri, N.
Braconi, C.
Gasparini, P.
Grivennikow, S.
Hart, J.R.
Paone, A.
Lovat, F.
Fabbri, M.
Gafa', R.
Nuovo, G.
Lanza, G.
Frankel, W.
Vogt, P.K.
Groden, J.
Karin, M.
Croce, C.M.
(2012). Anti-miR-135b in colon cancer treatment: Results from a preclinical study. J clin oncol,
Vol.30
(4_suppl),
p. 457.
show abstract
457 Background: MicroRNAs (miRs) are small non coding RNAs involved in cell homeostasis. miRs are deregulated in colorectal cancer (CRC). Our study aimed at identifying miRs with a driver role in carcinogenesis altered by similar mechanisms in both human and mouse CRC. Goal of the study was to use CRC mouse models for the pre-clinical development of anti-miRs as therapeutic drugs. METHODS: Azoximetane (AOM)/Dextran-Sulfate (DSS) treated mice or CDX2-CRE/APC(-/-) mice were used to study inflammation-associated and sporadic APC-related CRC. Human Inflammatory Bowel Disease associated (n=30), and sporadic (n=90) CRC with their matched normal tissues were collected according to Good Clinical Practice recommendation and subjected to RNA extraction using Trizol. miR and gene expression profiling was assessed by nCounter technology (Nanostring Seattle). Anti-miR-135b and scrambled probes for in vivo studies were synthesized by Girindus. RESULTS: miRs profiling from AOM/DSS and CDX2-CRE/APC(-/-) CRC. revealed that miR-135b is one of the most up-regulated miRs in both models. In humans miR-135b over-expression was found in both IBD and sporadic CRC and was associated with reduced Progression Free Survival and Overall Survival in CRC patients. Molecular studies in Mouse Embryo Fibroblast and human CRC cell lines highlighted the role of two major pathways in the upstream activation of miR-135b: APC-β-Catenin and SRC-PI3K. MiR-135b up-regulation resulted in reduced apoptosis and increased invasion and metastasis due to the down-regulation of TGFRB2, DAPK1, APC and HIF1AN. Silencing of miR-135b in vivo reduced tumor multiplicity and tumor load in the AOM/DSS CRC model. Mice treated with anti-miR-135b showed well differentiated tumors and microacinar pattern while tumors in the control groups showed low differentiation and adenomatous pattern. CONCLUSIONS: Our data suggest that miR-135b is a key molecule whose activation is downstream of oncogenes and oncosuppressor genes frequently altered in CRC. Our study defines specific pathways that converge on the activation of the same microrna. The "in vivo" silencing of miR-135 shows preclinical efficacy with low toxicity and represents the first in vivo study for the use of antimiRs in CRC treatment..
Nuovo, G.J.
Garofalo, M.
Valeri, N.
Roulstone, V.
Volinia, S.
Cohn, D.E.
Phelps, M.
Harrington, K.J.
Vile, R.
Melcher, A.
Galanis, E.
Sehl, S.
Adair, R.
Scott, K.
Rose, A.
Toogood, G.
Coffey, M.C.
(2012). Reovirus-associated reduction of microRNA-let-7d is related to the increased apoptotic death of cancer cells in clinical samples. Mod pathol,
Vol.25
(10),
pp. 1333-1344.
show abstract
We analyzed the in situ molecular correlates of infection from cancer patients treated with reovirus. Melanoma, colorectal, and ovarian cancer samples from such patients showed variable infection of the cancer cells but not the intermingled benign cells. RT in situ PCR showed most cancer cells contained the viral genome with threefold less having productive viral infection as documented by either tubulin or reoviral protein co-expression. Productive infection in the cancer cells was strongly correlated with co-expression of p38 and caspase-3 as well as apoptosis-related death (P<0.001). The cancer cell apoptotic death was due to a marked viral-induced inhibition of microRNA-let-7d that, in turn, upregulated caspase-3 activity. In summary, reovirus shows a striking tropism to cancer cells in clinical samples. A rate-limiting factor of reovirus-induced cancer cell death is productive viral infection that operates via the marked reduction of microRNA-let-7d and concomitant elevated caspase-3 expression..
Ryan, B.M.
McClary, A.C.
Valeri, N.
Robinson, D.
Paone, A.
Bowman, E.D.
Robles, A.I.
Croce, C.
Harris, C.C.
(2012). rs4919510 in hsa-mir-608 is associated with outcome but not risk of colorectal cancer. Plos one,
Vol.7
(5),
p. e36306.
show abstract
BACKGROUND: Colorectal cancer is the third most incident cancer and cause of cancer-related death in the United States. MicroRNAs, a class of small non-coding RNAs, have been implicated in the pathogenesis and prognosis of colorectal cancer, although few studies have examined the relationship between germline mutation in the microRNAs with risk and prognosis. We therefore investigated the association between a SNP in hsa-mir-608, which lies within the 10q24 locus, and colorectal cancer. METHODS AND RESULTS: A cohort consisting of 245 cases and 446 controls was genotyped for rs4919510. The frequency of the GG genotype was significantly higher in African Americans (15%) compared to Caucasians (3%) controls. There was no significant association between rs4919510 and colorectal cancer risk (African American: OR(GG vs. CC) 0.89 [95% CI, 0.41-1.80]) (Caucasian: OR(GG vs. CC) 1.76, ([95% CI, 0.48-6.39]). However, we did observe an association with survival. The GG genotype was associated with an increased risk of death in Caucasians (HR(GG vs. CC) 3.54 ([95% CI, 1.38-9.12]) and with a reduced risk of death in African Americans (HR(GG vs. CC) 0.36 ([95% CI 0.12-1.07). CONCLUSIONS: These results suggest that rs4910510 may be associated with colorectal cancer survival in a manner that is dependent on race..
Valeri, N.
Gasparini, P.
Braconi, C.
Lovat, F.
Paone, A.
Fabbri, M.
Nuovo, G.
Fishel, R.
Croce, C.M.
(2011). Effect of miR-21 on resistance to 5-fluorouracil and regulation of MSH2. Journal of clinical oncology,
Vol.29
(4_suppl),
pp. 431-431.
show abstract
431 Background: MicroRNAs are small non coding RNAs controlling cell homeostasis. Defects in mismatch repair (MMR) genes cause resistance to 5-fluorouracil (5FU). miR-21 is up-regulated in colorectal cancer (CRC) and is associated with poor benefit from adjuvant 5FU. We aimed at studying if miR-21 may induce 5FU resistance by down-regulating MSH2. Methods: Fresh frozen (32) and paraffin-embedded (50) cases of CRC and matched normal tissues were studied for miR-21 expression (Northern Blotting and in situ Hybridization) and MSH2 expression (Western Blotting and Immunohistochemistry). CRC Colo-320DM, SW620 and isogenic Lovo cells with [Lovo(MSH2+)] and without MSH2 [Lovo(MSH2-)] were used. Pre-miR-21 was used for over-expression experiments. Luciferase vectors with MSH2 (Luc-MSH2) and MSH6 (Luc-MSH6) 3'UTRs downstream of the Luciferase gene were used. Cell cycle modifications after 5FU (10uM) were assessed by FACS analysis. Lentiviral vectors encoding for miR-21 or siRNA to MSH2 or empty vectors were used for stable infection. Stable clones were injected in the flank of nude mice. Mice were treated with 5FU i.p. for 2 weeks. Tumor volume was measured once a week and calculated according to the formula Volume=LxW2/2. Results: A statistically significant inverse correlation between miR-21 and MSH2 expression was observed by Parson's test in the two CRC cohorts. miR-21 over-expression caused reduction in MSH2 and MSH6 protein expression and in Luciferase activity after transfection with Luc-MSH2 or Luc-MSH6 vectors confirming that miR-21 directly regulates MSH2 and MSH6. miR-21 up-regulation reduced 5FU induced apoptosis and G2/M arrest at the same extent of siRNA to MSH2 in all MMR proficient cells while no significant effect was observed in Lovo(MSH2-). Complementation experiments with plasmid encoding for MSH2 promoted 5FU induced apoptosis that was inhibited by co-transfection with miR-21. Xenograft tumors over-expressing miR-21 or siRNA anti MSH2 achieved the same response to 5FU and both showed to be less responsive to 5FU than controls. Conclusions: miR-21 causes resistance to 5FU in a MSH2 dependent manner and might be a useful marker in predicting therapeutic outcome in CRC patients. No significant financial relationships to disclose. .
Braconi, C.
Kogure, T.
Valeri, N.
Gasparini, P.
Huang, N.
Nuovo, G.
Terracciano, L.
Croce, C.M.
Patel, T.
(2011). Effect of the ultraconserved noncoding RNA uc 338 on cellular growth of hepatocarcinoma. Journal of clinical oncology,
Vol.29
(4_suppl),
pp. 202-202.
show abstract
202 Background: The role of non-protein coding (nc)RNAs in cancer is unknown but emerging evidence suggests that deregulated expression of ncRNA may contribute to cancer pathogenesis. We sought to examine the role of ultraconserved ncRNA (ucRNA) that are 100% conserved across the human, rat and mouse genomes in hepatocellular cancers (HCC). Methods: Whole genome ucRNA expression profiling was performed using a custom microarray, and verified by real time PCR in cell lines and by in situ hybridization in a tissue microarray comprising of 221 human HCC, 72 non cirrhotic (NC) and 97 cirrhotic (C) liver tissues. ucRNA expression was manipulated with siRNA or plasmid-over-expressing ucRNA, and the effects on anchorage-dependent and independent growth, and cell cycle assessed using cell viability, soft agar assays and flow cytometry. Gene ontology analysis was performed by evaluating uc338-dependent changes on mRNA expression using Affymetrix chips. Results: 56 ucRNAs were aberrantly expressed with 33 increased and 23 decreased in HepG2 cells compared to non-malignant hepatocytes. The greatest change was observed with uc.338 (6.9-fold increase). uc.338 expression was significantly increased in several HCC cell lines. uc.338 expression was detected in 170 cases (77%) of HCC, with 62% of these showing a moderate to strong expression. Compared to non- malignant adjacent tissue, uc.338 expression was increased in 97/156 of HCC. The mean % of cells expressing uc.338 was 4% in NC liver, 15% in C and 24% in HCC. Inhibition of uc.338 reduced anchorage dependent and independent growth, and cell cycle progression in both human and murine malignant hepatocytes. Gene annotation enrichment analysis of mRNAs that were altered by inhibition of uc.338 expression identified the top over-represented GenMAPP pathways as: cell cycle, mRNA processing, RNA transcription, G1 to S cell cycle. Moreover, enforced expression of uc.338 increased cell growth in nonmalignant hepatocytes. Conclusions: These data showing that uc.338 is selectively overexpressed in HCC and promotes cell growth provides new insights into the role of RNA genes in HCC. No significant financial relationships to disclose. .
Voltan, R.
di Iasio, M.G.
Bosco, R.
Valeri, N.
Pekarski, Y.
Tiribelli, M.
Secchiero, P.
Zauli, G.
(2011). Nutlin-3 downregulates the expression of the oncogene TCL1 in primary B chronic lymphocytic leukemic cells. Clin cancer res,
Vol.17
(17),
pp. 5649-5655.
show abstract
PURPOSE: The oncogene TCL1 plays a key role in the development of B chronic lymphocytic leukemia (B-CLL), but it is not known whether TCL1 could be modulated by therapeutic approaches. EXPERIMENTAL DESIGN: B-CLL patient samples (n = 35) and B leukemic cell lines (EHEB, JVM2, JVM3, MEC1, MEC2, and BJAB) with different p53 status were exposed to Nutlin-3, a small-molecule inhibitor of the p53-MDM2 interaction. Modulations of the steady-state mRNA levels of TCL1 were analyzed by quantitative real-time PCR and Western blotting in both primary B-CLL samples and leukemic cell lines. In addition, transfection experiments with either p53 siRNA or with a TCL1 expression plasmid were carried out in the EHEB B-CLL cell line. RESULTS: Upon ex vivo treatment with Nutlin-3, TCL1 was significantly (P < 0.05) decreased in 23 of 28 B-CLL p53(wild-type). The functionality of the p53 pathway in the same leukemic cell samples was underscored by the concomitant ability of Nutlin-3 to significantly (P < 0.05) upregulate the p53 target gene MDM2 in the p53(wild-type) leukemic cells. The dependence of TCL1 downregulation by a functional p53 pathway was confirmed in a panel of B lymphoblastoid cell lines and by p53 knockdown experiments with p53 siRNA. The importance of TCL1 in promoting leukemic cell survival was underscored in transfection experiments, in which TCL1 overexpression significantly counteracted the Nutlin-3-mediated induction of apoptosis in EHEB. CONCLUSIONS: Our data indicate that the Nutlin-3 downregulates TCL1 mRNA and protein, which likely represents an important molecular determinant in the proapoptotic activity of Nutlin-3..
Valeri, N.
Gasparini, P.
Braconi, C.
Lovat, F.
Paone, A.
Fabbri, M.
Nuovo, G.
Fishel, R.
Croce, C.M.
(2011). Effect of miR-21 on resistance to 5-fluorouracil and regulation of MSH2. J clin oncol,
Vol.29
(4_suppl),
p. 431.
show abstract
431 Background: MicroRNAs are small non coding RNAs controlling cell homeostasis. Defects in mismatch repair (MMR) genes cause resistance to 5-fluorouracil (5FU). miR-21 is up-regulated in colorectal cancer (CRC) and is associated with poor benefit from adjuvant 5FU. We aimed at studying if miR-21 may induce 5FU resistance by down-regulating MSH2. METHODS: Fresh frozen (32) and paraffin-embedded (50) cases of CRC and matched normal tissues were studied for miR-21 expression (Northern Blotting and in situ Hybridization) and MSH2 expression (Western Blotting and Immunohistochemistry). CRC Colo-320DM, SW620 and isogenic Lovo cells with [Lovo(MSH2+)] and without MSH2 [Lovo(MSH2-)] were used. Pre-miR-21 was used for over-expression experiments. Luciferase vectors with MSH2 (Luc-MSH2) and MSH6 (Luc-MSH6) 3'UTRs downstream of the Luciferase gene were used. Cell cycle modifications after 5FU (10uM) were assessed by FACS analysis. Lentiviral vectors encoding for miR-21 or siRNA to MSH2 or empty vectors were used for stable infection. Stable clones were injected in the flank of nude mice. Mice were treated with 5FU i.p. for 2 weeks. Tumor volume was measured once a week and calculated according to the formula Volume=LxW(2)/2. RESULTS: A statistically significant inverse correlation between miR-21 and MSH2 expression was observed by Parson's test in the two CRC cohorts. miR-21 over-expression caused reduction in MSH2 and MSH6 protein expression and in Luciferase activity after transfection with Luc-MSH2 or Luc-MSH6 vectors confirming that miR-21 directly regulates MSH2 and MSH6. miR-21 up-regulation reduced 5FU induced apoptosis and G2/M arrest at the same extent of siRNA to MSH2 in all MMR proficient cells while no significant effect was observed in Lovo(MSH2-). Complementation experiments with plasmid encoding for MSH2 promoted 5FU induced apoptosis that was inhibited by co-transfection with miR-21. Xenograft tumors over-expressing miR-21 or siRNA anti MSH2 achieved the same response to 5FU and both showed to be less responsive to 5FU than controls. CONCLUSIONS: miR-21 causes resistance to 5FU in a MSH2 dependent manner and might be a useful marker in predicting therapeutic outcome in CRC patients. No significant financial relationships to disclose..
Braconi, C.
Kogure, T.
Valeri, N.
Gasparini, P.
Huang, N.
Nuovo, G.
Terracciano, L.
Croce, C.M.
Patel, T.
(2011). Effect of the ultraconserved noncoding RNA uc 338 on cellular growth of hepatocarcinoma. J clin oncol,
Vol.29
(4_suppl),
p. 202.
show abstract
202 Background: The role of non-protein coding (nc)RNAs in cancer is unknown but emerging evidence suggests that deregulated expression of ncRNA may contribute to cancer pathogenesis. We sought to examine the role of ultraconserved ncRNA (ucRNA) that are 100% conserved across the human, rat and mouse genomes in hepatocellular cancers (HCC). METHODS: Whole genome ucRNA expression profiling was performed using a custom microarray, and verified by real time PCR in cell lines and by in situ hybridization in a tissue microarray comprising of 221 human HCC, 72 non cirrhotic (NC) and 97 cirrhotic (C) liver tissues. ucRNA expression was manipulated with siRNA or plasmid-over-expressing ucRNA, and the effects on anchorage-dependent and independent growth, and cell cycle assessed using cell viability, soft agar assays and flow cytometry. Gene ontology analysis was performed by evaluating uc338-dependent changes on mRNA expression using Affymetrix chips. RESULTS: 56 ucRNAs were aberrantly expressed with 33 increased and 23 decreased in HepG2 cells compared to non-malignant hepatocytes. The greatest change was observed with uc.338 (6.9-fold increase). uc.338 expression was significantly increased in several HCC cell lines. uc.338 expression was detected in 170 cases (77%) of HCC, with 62% of these showing a moderate to strong expression. Compared to non- malignant adjacent tissue, uc.338 expression was increased in 97/156 of HCC. The mean % of cells expressing uc.338 was 4% in NC liver, 15% in C and 24% in HCC. Inhibition of uc.338 reduced anchorage dependent and independent growth, and cell cycle progression in both human and murine malignant hepatocytes. Gene annotation enrichment analysis of mRNAs that were altered by inhibition of uc.338 expression identified the top over-represented GenMAPP pathways as: cell cycle, mRNA processing, RNA transcription, G1 to S cell cycle. Moreover, enforced expression of uc.338 increased cell growth in nonmalignant hepatocytes. CONCLUSIONS: These data showing that uc.338 is selectively overexpressed in HCC and promotes cell growth provides new insights into the role of RNA genes in HCC. No significant financial relationships to disclose..
Fabbri, M.
Bottoni, A.
Shimizu, M.
Spizzo, R.
Nicoloso, M.S.
Rossi, S.
Barbarotto, E.
Cimmino, A.
Adair, B.
Wojcik, S.E.
Valeri, N.
Calore, F.
Sampath, D.
Fanini, F.
Vannini, I.
Musuraca, G.
Dell'Aquila, M.
Alder, H.
Davuluri, R.V.
Rassenti, L.Z.
Negrini, M.
Nakamura, T.
Amadori, D.
Kay, N.E.
Rai, K.R.
Keating, M.J.
Kipps, T.J.
Calin, G.A.
Croce, C.M.
(2011). Association of a microRNA/TP53 feedback circuitry with pathogenesis and outcome of B-cell chronic lymphocytic leukemia. Jama,
Vol.305
(1),
pp. 59-67.
show abstract
CONTEXT: Chromosomal abnormalities (namely 13q, 17p, and 11q deletions) have prognostic implications and are recurrent in chronic lymphocytic leukemia (CLL), suggesting that they are involved in a common pathogenetic pathway; however, the molecular mechanism through which chromosomal abnormalities affect the pathogenesis and outcome of CLL is unknown. OBJECTIVE: To determine whether the microRNA miR-15a/miR-16-1 cluster (located at 13q), tumor protein p53 (TP53, located at 17p), and miR-34b/miR-34c cluster (located at 11q) are linked in a molecular pathway that explains the pathogenetic and prognostic implications (indolent vs aggressive form) of recurrent 13q, 17p, and 11q deletions in CLL. DESIGN, SETTING, AND PATIENTS: CLL Research Consortium institutions provided blood samples from untreated patients (n = 206) diagnosed with B-cell CLL between January 2000 and April 2008. All samples were evaluated for the occurrence of cytogenetic abnormalities as well as the expression levels of the miR-15a/miR-16-1 cluster, miR-34b/miR-34c cluster, TP53, and zeta-chain (TCR)-associated protein kinase 70 kDa (ZAP70), a surrogate prognostic marker of CLL. The functional relationship between these genes was studied using in vitro gain- and loss-of-function experiments in cell lines and primary samples and was validated in a separate cohort of primary CLL samples. MAIN OUTCOME MEASURES: Cytogenetic abnormalities; expression levels of the miR-15a/miR-16-1 cluster, miR-34 family, TP53 gene, downstream effectors cyclin-dependent kinase inhibitor 1A (p21, Cip1) (CDKN1A) and B-cell CLL/lymphoma 2 binding component 3 (BBC3), and ZAP70 gene; genetic interactions detected by chromatin immunoprecipitation. RESULTS: In CLLs with 13q deletions the miR-15a/miR-16-1 cluster directly targeted TP53 (mean luciferase activity for miR-15a vs scrambled control, 0.68 relative light units (RLU) [95% confidence interval {CI}, 0.63-0.73]; P = .02; mean for miR-16 vs scrambled control, 0.62 RLU [95% CI, 0.59-0.65]; P = .02) and its downstream effectors. In leukemic cell lines and primary CLL cells, TP53 stimulated the transcription of miR-15/miR-16-1 as well as miR-34b/miR-34c clusters, and the miR-34b/miR-34c cluster directly targeted the ZAP70 kinase (mean luciferase activity for miR-34a vs scrambled control, 0.33 RLU [95% CI, 0.30-0.36]; P = .02; mean for miR-34b vs scrambled control, 0.31 RLU [95% CI, 0.30-0.32]; P = .01; and mean for miR-34c vs scrambled control, 0.35 RLU [95% CI, 0.33-0.37]; P = .02). CONCLUSIONS: A microRNA/TP53 feedback circuitry is associated with CLL pathogenesis and outcome. This mechanism provides a novel pathogenetic model for the association of 13q deletions with the indolent form of CLL that involves microRNAs, TP53, and ZAP70..
Braconi, C.
Valeri, N.
Kogure, T.
Gasparini, P.
Huang, N.
Nuovo, G.J.
Terracciano, L.
Croce, C.M.
Patel, T.
(2011). Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma. Proc natl acad sci u s a,
Vol.108
(2),
pp. 786-791.
show abstract
Although expression of non-protein-coding RNA (ncRNA) can be altered in human cancers, their functional relevance is unknown. Ultraconserved regions are noncoding genomic segments that are 100% conserved across humans, mice, and rats. Conservation of gene sequences across species may indicate an essential functional role, and therefore we evaluated the expression of ultraconserved RNAs (ucRNA) in hepatocellular cancer (HCC). The global expression of ucRNAs was analyzed with a custom microarray. Expression was verified in cell lines by real-time PCR or in tissues by in situ hybridization using tissue microarrays. Cellular ucRNA expression was modulated with siRNAs, and the effects on global gene expression and growth of human and murine HCC cells were evaluated. Fifty-six ucRNAs were aberrantly expressed in HepG2 cells compared with nonmalignant hepatocytes. Among these ucRNAs, the greatest change was noted for ultraconserved element 338 (uc.338), which was dramatically increased in human HCC compared with noncancerous adjacent tissues. Although uc.338 is partially located within the poly(rC) binding protein 2 (PCBP2) gene, the transcribed ncRNA encoding uc.338 is expressed independently of PCBP2 and was cloned as a 590-bp RNA gene, termed TUC338. Functional gene annotation analysis indicated predominant effects on genes involved in cell growth. These effects were experimentally demonstrated in both human and murine cells. siRNA to TUC338 decreased both anchorage-dependent and anchorage-independent growth of HCC cells. These studies identify a critical role for TUC338 in regulation of transformed cell growth and of transcribed ultraconserved ncRNA as a unique class of genes involved in the pathobiology of HCC..
Lovat, F.
Valeri, N.
Croce, C.M.
(2011). MicroRNAs in the pathogenesis of cancer. Semin oncol,
Vol.38
(6),
pp. 724-733.
show abstract
MicroRNAs (miRs) are small (19-25 nucleotides) non-protein-coding RNAs involved in development, differentiation, and aging; they act by inducing messenger RNA (mRNA) silencing through degradation, and post-transcriptional or decoy activity. miR profiles of human solid and hematologic malignancies have highlighted their potential value as tumor markers in cancer patient management. Different experimental lines of evidence have confirmed that deregulation of miRs not only results as consequence of cancer progression but also directly promotes tumor initiation and progression in a cause-effect manner. These findings reveal a potential and appealing role for miRs as cancer therapeutic targets. This review focuses on the causes and consequences of miR deregulation in carcinogenesis and tumor progression. The work aims at providing the molecular bases for the understanding of the potential role of miRs in the translational and clinical setting..
Braconi, C.
Kogure, T.
Valeri, N.
Nuovo, G.
Costinean, S.
Croce, C.M.
Patel, T.
(2011). Abstract 1178: Involvement of MEG3, a long non-coding RNA, in hepatocellular cancer (HCC). Cellular and molecular biology,
.
Braconi, C.
Kogure, T.
Valeri, N.
Huang, N.
Nuovo, G.
Costinean, S.
Negrini, M.
Miotto, E.
Croce, C.M.
Patel, T.
(2011). microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer. Oncogene,
Vol.30
(47),
pp. 4750-4756.
show abstract
The human genome is replete with long non-coding RNAs (lncRNA), many of which are transcribed and likely to have a functional role. Microarray analysis of >23,000 lncRNAs revealed downregulation of 712 (~3%) lncRNA in malignant hepatocytes, among which maternally expressed gene 3 (MEG3) was downregulated by 210-fold relative to expression in non-malignant hepatocytes. MEG3 expression was markedly reduced in four human hepatocellular cancer (HCC) cell lines compared with normal hepatocytes by real-time PCR. RNA in situ hybridization showed intense cytoplasmic expression of MEG3 in non-neoplastic liver with absent or very weak expression in HCC tissues. Enforced expression of MEG3 in HCC cells significantly decreased both anchorage-dependent and -independent cell growth, and induced apoptosis. MEG3 promoter hypermethylation was identified by methylation-specific PCR and MEG3 expression was increased with inhibition of methylation with either 5-Aza-2-Deoxycytidine, or siRNA to DNA Methyltransferase (DNMT) 1 and 3b in HCC cells. MiRNA-dependent regulation of MEG3 expression was studied by evaluating the involvement of miR-29, which can modulate DNMT 1 and 3. Overexpression of mir-29a increased expression of MEG3. GTL2, the murine homolog of MEG3, was reduced in liver tissues from hepatocyte-specific miR-29a/b1 knock-out mice compared with wild-type controls. These data show that methylation-dependent tissue-specific regulation of the lncRNA MEG3 by miR-29a may contribute to HCC growth and highlight the inter-relationship between two classes of non-coding RNA, miRNAs and lncRNAs, and epigenetic regulation of gene expression..
Braconi, C.
Valeri, N.
Gasparini, P.
Huang, N.
Taccioli, C.
Nuovo, G.
Suzuki, T.
Croce, C.M.
Patel, T.
(2010). Hepatitis C virus proteins modulate microRNA expression and chemosensitivity in malignant hepatocytes. Clin cancer res,
Vol.16
(3),
pp. 957-966.
show abstract
PURPOSE: Hepatocellular cancer (HCC) is highly resistant to chemotherapy and is associated with poor prognosis. Chronic hepatitis C virus (HCV) infection is a major cause of HCC. However, the effect of viral proteins in mediating chemosensitivity in tumor cells is unknown. We postulated that HCV viral proteins could modulate therapeutic responses by altering host cell microRNA (miRNA) expression. EXPERIMENTAL DESIGN: HepG2 malignant hepatocytes were stably transfected with full-length HCV genome (Hep-394) or an empty vector (Hep-SWX). MiRNA profiling was done by using a custom microarray, and the expression of selected miRNAs was validated by real-time PCR. Protein expression was assessed by Western blotting, whereas caspase activation was assessed by a luminometric assay. RESULTS: The IC(50) to sorafenib was lower in Hep-394 compared with Hep-SWX control cells. Alterations in miRNA expression occurred with 10 miRNAs downregulated >2-fold and 23 miRNAs upregulated >2-fold in Hep-394 cells compared with controls. Of these, miR-193b was overexpressed by 5-fold in Hep-394 cells. miR-193b was predicted to target Mcl-1, an antiapoptotic protein that can modulate the response to sorafenib. The expression of Mcl-1 was decreased, and basal caspase-3/7 activity and poly ADP ribose polymerase cleavage were increased in Hep-394 cells compared with controls. Moreover, transfection with precursors to miR-193b decreased both Mcl-1 expression and the IC(50) to sorafenib. CONCLUSIONS: Cellular expression of full-length HCV increases sensitivity to sorafenib by the miRNA-dependent modulation of Mcl-1 and apoptosis. Modulation of miRNA responses may be a useful strategy to enhance response to chemotherapy in HCC..
Braconi, C.
Kogure, T.
Valeri, N.
Huang, N.
Gasparini, P.
Nuovo, G.
Terracciano, L.
Croce, C.M.
Patel, T.
(2010). Ultraconserved non-coding RNAs are involved in human hepatocellular cancer growth. Cancer research,
Vol.70.
Cohn, D.E.
Fabbri, M.
Valeri, N.
Alder, H.
Ivanov, I.
Liu, C.-.
Croce, C.M.
Resnick, K.E.
(2010). Comprehensive miRNA profiling of surgically staged endometrial cancer. Am j obstet gynecol,
Vol.202
(6),
pp. 656.e1-656.e8.
show abstract
OBJECTIVE: We sought to determine a microRNA (miRNA) profile of surgically staged endometrial cancers. STUDY DESIGN: RNA was extracted from archival primary endometrial cancers, and an miRNA profile was established using a microarray and confirmed with real-time polymerase chain reaction. Targets of differentially expressed miRNAs were explored using real-time polymerase chain reaction and Western blot in endometrial cell lines. RESULTS: Endometrial cancer has an miRNA profile distinct from normal endometrium, even in patients with stage IA grade 1 tumors. This miRNA cancer profile was able to correctly assign a specimen as a malignancy with a sensitivity of 92%. Overexpressed miRNAs were predicted to target PTEN, and transfection of cell lines with these miRNAs led to down-regulation of PTEN expression. In advanced disease, an miRNA pattern distinct from early-stage disease was seen, and overexpression of mir-199c predicted improved cancer survival in this population. CONCLUSION: Endometrial cancer has a distinct miRNA profile, and miRNAs can be used as a predictive biomarker..
Valeri, N.
Gasparini, P.
Braconi, C.
Paone, A.
Lovat, F.
Fabbri, M.
Sumani, K.M.
Alder, H.
Amadori, D.
Patel, T.
Nuovo, G.J.
Fishel, R.
Croce, C.M.
(2010). MicroRNA-21 induces resistance to 5-fluorouracil by down-regulating human DNA MutS homolog 2 (hMSH2). Proc natl acad sci u s a,
Vol.107
(49),
pp. 21098-21103.
show abstract
The overexpression of microRNA-21 (miR-21) is linked to a number of human tumors including colorectal cancer, where it appears to regulate the expression of tumor suppressor genes including p21, phosphatase and tensin homolog, TGFβ receptor II, and B-cell leukemia/lymphoma 2 -associated X protein. Here we demonstrate that miR-21 targets and down-regulates the core mismatch repair (MMR) recognition protein complex, human mutS homolog 2 (hMSH2) and 6 (hMSH6). Colorectal tumors that express a high level of miR-21 display reduced hMSH2 protein expression. Cells that overproduce miR-21 exhibit significantly reduced 5-fluorouracil (5-FU)-induced G2/M damage arrest and apoptosis that is characteristic of defects in the core MMR component. Moreover, xenograft studies demonstrate that miR-21 overexpression dramatically reduces the therapeutic efficacy of 5-FU. These studies suggest that the down-regulation of the MMR mutator gene associated with miR-21 overexpression may be an important clinical indicator of therapeutic efficacy in colorectal cancer..
Valeri, N.
Gasparini, P.
Fabbri, M.
Braconi, C.
Veronese, A.
Lovat, F.
Adair, B.
Vannini, I.
Fanini, F.
Bottoni, A.
Costinean, S.
Sandhu, S.K.
Nuovo, G.J.
Alder, H.
Gafa, R.
Calore, F.
Ferracin, M.
Lanza, G.
Volinia, S.
Negrini, M.
McIlhatton, M.A.
Amadori, D.
Fishel, R.
Croce, C.M.
(2010). Modulation of mismatch repair and genomic stability by miR-155. Proc natl acad sci u s a,
Vol.107
(15),
pp. 6982-6987.
show abstract
Inactivation of mismatch repair (MMR) is the cause of the common cancer predisposition disorder Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), as well as 10-40% of sporadic colorectal, endometrial, ovarian, gastric, and urothelial cancers. Elevated mutation rates (mutator phenotype), including simple repeat instability [microsatellite instability (MSI)] are a signature of MMR defects. MicroRNAs (miRs) have been implicated in the control of critical cellular pathways involved in development and cancer. Here we show that overexpression of miR-155 significantly down-regulates the core MMR proteins, hMSH2, hMSH6, and hMLH1, inducing a mutator phenotype and MSI. An inverse correlation between the expression of miR-155 and the expression of MLH1 or MSH2 proteins was found in human colorectal cancer. Finally, a number of MSI tumors with unknown cause of MMR inactivation displayed miR-155 overexpression. These data provide support for miR-155 modulation of MMR as a mechanism of cancer pathogenesis..
Braconi, C.
Kogure, T.
Valeri, N.
Huang, N.
Gasparini, P.
Nuovo, G.
Terracciano, L.
Croce, C.M.
Patel, T.
(2010). Abstract 4086: Ultraconserved non-coding RNAs are involved in human hepatocellular cancer growth. Cellular and molecular biology,
.
Fabbri, M.
Adair, B.
Wernicke, D.
Garzon, R.
Valeri, N.
Cimmino, A.
Zanesi, N.
Croce, C.
(2009). MicroRNA 29 family restores estrogen receptor and selective estrogen receptors regulators (SERMs) sensitivity in breast cancer. Cancer research,
Vol.69.
Fabbri, M.
Valeri, N.
Calin, G.A.
(2009). MicroRNAs and genomic variations: from Proteus tricks to Prometheus gift. Carcinogenesis,
Vol.30
(6),
pp. 912-917.
show abstract
MicroRNAs (miRNAs) are small non-coding RNAs with regulatory functions. MiRNAs are aberrantly expressed in almost all human cancers, leading to abnormal levels of target genes. Recently, an increasing number of studies have addressed whether genomic variations including germ line or somatic mutations and single-nucleotide polymorphisms can count for miRNA abnormal expression by altering their biogenesis and/or affect the ability of miRNAs to bind to target messenger RNAs. Here, we provide an extensive review of the studies that have investigated variations occurring both in miRNA genes and in target genes and we discuss the possible clinical implications of these findings. Furthermore, we propose that sequence variations in miRNAs or interactor sites located in mRNAs can be involved in cancer predisposition..
Valeri, N.
Croce, C.M.
Fabbri, M.
(2009). Pathogenetic and clinical relevance of microRNAs in colorectal cancer. Cancer genomics proteomics,
Vol.6
(4),
pp. 195-204.
show abstract
Colorectal cancer (CRC) has been described as a multistep disease due to the progressive accumulation of mutations and chromosomal rearrangements involving critical oncogenes or oncosuppressors. MicroRNAs (miRNAs) are a class of small interfering RNAs frequently involved in the pathogenesis of cancer. Several genome-wide profiling studies have identified miRNAs deregulated in colorectal cancer. Many of these deregulated miRNAs contribute to CRC tumorigenesis and may help to understand CRC pathogenesis, prognosis and response to treatment. This review will focus on common mechanisms involved in miRNA alterations in CRC, their functional implication in CRC development and the potential use of miRNAs as prognostic and predictive surrogate markers for the management of CRC patients..
Valeri, N.
Vannini, I.
Fanini, F.
Calore, F.
Adair, B.
Fabbri, M.
(2009). Epigenetics, miRNAs, and human cancer: a new chapter in human gene regulation. Mamm genome,
Vol.20
(9-10),
pp. 573-580.
show abstract
Cancer is a genetic and epigenetic disease. MicroRNAs (miRNAs), a class of small noncoding RNAs, have been shown to be deregulated in many diseases including cancer. An intertwined connection between epigenetics and miRNAs has been supported by the recent identification of a specific subgroup of miRNAs called "epi-miRNAs" that can directly and indirectly modulate the activity of the epigenetic machinery. The complexity of this connection is enhanced by the epigenetic regulation of miRNA expression that generates a fine regulatory feedback loop. This review focuses on how epigenetics affects the miRNome and how the recently identified epi-miRNAs regulate the epigenome in human cancers, ultimately contributing to human carcinogenesis..
Resnick, K.E.
Fabbri, M.
Valeri, N.
Alder, H.
Taccioli, C.
Liu, C.-.
Cohn, D.E.
Croce, C.M.
(2008). MiRNA profile in stage 1, surgically staged endometrial cancer and predicted downstream targets. Gynecologic oncology,
Vol.108
(3),
pp. S11-S11.
Braconi, C.
Bracci, R.
Bearzi, I.
Bianchi, F.
Costagliola, A.
Catalani, R.
Mandolesi, A.
Ranaldi, R.
Galizia, E.
Cascinu, S.
Rossi, G.
Giustini, L.
Latini, L.
Valeri, N.
Cellerino, R.
(2008). KIT and PDGFRalpha mutations in 104 patients with gastrointestinal stromal tumors (GISTs): a population-based study. Ann oncol,
Vol.19
(4),
pp. 706-710.
show abstract
BACKGROUND: The prognostic significance of KIT or platelet-derived growth factor receptor alpha (PDGFRalpha) mutations in gastrointestinal stromal tumors (GISTs) is still controversial. PATIENTS AND METHODS: In all, 104 patients were diagnosed with GISTs by KIT immunoreactivity; tumor DNA was sequenced for the presence of mutations in KIT exons 9, 11, 13 and 17 and in PDGFRalpha exons 12 and 18. Disease-free survival (DFS) was analyzed in 85 radically resected patients. RESULTS: KIT mutations occurred in exon 11 (69), in exon 9 (11) and in exon 17 (1). PDGFRalpha mutations were detected in exon 18 (10) and in exon 12 (3). Ten GISTs were wild type. Exon 11 mutations were as follows: deletions in 42 cases and point mutations in 20 cases and insertions and duplications, respectively, in 2 and 5 cases. A better trend in DFS was evident for duplicated and point-mutated exon 11 KIT GISTs. There was a significant association between PDGFRalpha mutations, gastric location and lower mitotic index. Moreover, PDGFRalpha-mutated GISTs seemed to have a better outcome. CONCLUSIONS: Point mutations and duplications in KIT exon 11 are associated with a better clinical trend in DFS. PDGFRalpha-mutated GISTs are preferentially localized in the stomach and seem to have a favorable clinical behavior..
Braconi, C.
Bracci, R.
Bearzi, I.
Bianchi, F.
Sabato, S.
Mandolesi, A.
Belvederesi, L.
Cascinu, S.
Valeri, N.
Cellerino, R.
(2008). Insulin-like growth factor (IGF) 1 and 2 help to predict disease outcome in GIST patients. Ann oncol,
Vol.19
(7),
pp. 1293-1298.
show abstract
BACKGROUND: The expression of the insulin-like growth factor (IGF) system has never been studied in gastrointestinal stromal tumors (GISTs). PATIENTS AND METHODS: We studied the immunohistochemical expression of IGF1 receptor (IGFR-I), IGF1 and IGF2 in 94 samples of GISTs. IGF1 and IGF2 expression was scored in three classes: negative (N), moderate (M) and strong (S), according to staining intensity and extent. RESULTS: IGFR-I was overexpressed in all cases. IGF1 and IGF2 expression was absent in 25 and 48 cases, moderate in 29 and 16 cases and strong in 40 and 30 cases, respectively. Strong IGF1 expression significantly correlated with higher mitotic index (P = 0.0001), larger (P = 0.01), higher risk (P = 0.0002), metastatic (P = 0.0001) and relapsed (P = 0.04) GISTs. Strong IGF2 expression correlated with higher mitotic index (P = 0.05) and higher risk GISTs (P = 0.001). The Kaplan-Meier analysis (N versus M versus S) showed a significant worsening of the disease-free survival (DFS) with the increase of IGF1 (P = 0.02) and IGF2 (P = 0.02) expression. In the subgroup of patients with operated high-risk GISTs, there was a better trend in DFS for patients affected by GISTs with negative IGF1 and IGF2. CONCLUSIONS: The expression of IGF1 and IGF2 seems to predict relapse in GIST patients..
Cascinu, S.
Verdecchia, L.
Valeri, N.
Berardi, R.
Scartozzi, M.
(2006). New target therapies in advanced pancreatic cancer. Ann oncol,
Vol.17 Suppl 5,
pp. v148-v152.
show abstract
The recent elucidation both of the mechanisms involved in pancreatic cancer carcinogenesis and the related molecular events, has led to several distinct therapeutic advances, including many novel target agents, such as monoclonal antibodies against EGFR, EGFR-tyrosine kinase inhibitors, monoclonal antibody against VEGF, farnesyl transferase inhibitors, matrix metalloproteinase inhibitors, COX 2 inhibitors, and the development of gene therapy to target pancreatic cancer. This review highlights recent findings in the treatment of pancreatic cancer by using these novel therapeutic approaches..
Valeri, N.
Battelli, N.
Mariotti, C.
Santinelli, A.
Siquini, W.
Gusella, P.
Braconi, C.
Lippe, P.
Cascinu Prof, S.
(2006). CEA as a prognostic factor in locally advanced breast cancer patients undergoing neoadjuvant chemotherapy. J clin oncol,
Vol.24
(18_suppl),
p. 10705.
show abstract
10705 Background: CEA and CA 15.3 are most commonly used to evaluate disease progression in metastatic and recurrent breast cancer. Only few significant studies showed a potential predictive role of CEA and CA 15.3 in adjuvant or neoadjuvant setting. We evaluated the correlation between tumour markers level at diagnosis and outcome in locally advanced breast cancer patients treated with neoadjuvant chemotherapy. METHODS: Patients with locally advanced breast cancer (T > 3.5 cm and T4) at diagnosis entered the study. All patients had to have initial negative staging (chest X-ray, abdominal ultrasonography, bone scintigraphy and CT scan), whereas all patients who developed metastatic disease in sites which were uncertain during initial staging were excluded. Tumour markers at diagnosis were considered negative if CEA was inferior to 5 ng/ml and CA 15.3 inferior to 35 U/ml. All patients received neoadjuvant chemotherapy (4-6 cycles with regimens containing Anthracyclines and Taxanes or FEC). Most of patients underwent radical mastectomy followed by sequential radiation therapy and adjuvant chemotherapy and/or hormonotherapy in hormonal responsive patients. RESULTS: Fifty-three patients entered the study. At a median follow up of 73 months, 35 patients were disease free after adjuvant treatment (group A), whereas 18 patients developed metastatic disease during follow-up (group B). At diagnosis 14 patients had CA 15.3 greater than 34 U/ml (7 in group A and 7 in group B), 6 patients had CEA greater than 5 ng/ml (1 in group A and 5 in group B) and 18 patients had CEA or CA 15.3 greater than normal values (7 in group A and 11 in group B).We analyzed DFS and OS in patients with normal (CEA < 5 ng/ml, CA15.3 < 35 U/ml) and elevated (CEA ≥ 5 ng/ml, CA 15.3 ≥ 35 U/ml) tumour markers at diagnosis; DFS (p = 0.001) and OS (p = 0.03) were significantly reduced in patients with elevated CEA at diagnosis; differences were not statistically significant for CA 15.3 (p > 0.05). CONCLUSIONS: CEA levels before neoadjuvant treatment could represent an important prognostic factor and may influence the choice of treatment in locally advanced breast cancer patients . No significant financial relationships to disclose..
Hahne, J.
Valeri, N.
Non-coding RNAs and resistance to anticancer drugs in gastrointestinal tumours. Frontiers of oncology,
.
Hahne, J.
Ratti, M.
Lampis, A.
Passalacquab, R.
Valeri, N.
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Vlachogiannis, G.
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Assiotis, I.
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Khan, K.
Starling, N.
Cunningham, D.
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Lote, H.
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hahne, J.
Trevisani, F.
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Valeri, N.
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Carotenuto, P.
Braconi, C.
Wnt signalling modulates transcribed-ultraconserved
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Zaniboni, A.
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Indini, A.
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Dottorini, L.
Moleri, G.
Russo, A.
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Dondossola, D.
Valeri, N.
Ghidini, A.
Tomasello, G.
Petrelli, F.
A Review of Clinical Practice Guidelines and Treatment Recommendations for Cancer Care in the COVID-19 Pandemic. Cancers,
Vol.12
(9),
pp. 2452-2452.
show abstract
The COVID-19 pandemic has inevitably caused those involved in cancer care to change clinical practice in order to minimize the risk of infection while maintaining cancer treatment as a priority. General advice during the pandemic suggests that most patients continue with ongoing therapies or planned surgeries, while follow-up visits may instead be delayed until the resolution of the outbreak. We conducted a literature search using PubMed to identify articles published in English language that reported on care recommendations for cancer patients during the COVID-19 pandemic from its inception up to 1st June 2020, using the terms “(cancer or tumor) AND (COVID 19)”. Articles were selected for relevance and split into five categories: (1) personal recommendations of single or multiple authors, (2) recommendations of single authoritative centers, (3) recommendations of panels of experts or of multiple regional comprehensive centers, (4) recommendations of multicenter cooperative groups, (5) official guidelines or recommendations of health authorities. Of the 97 included studies, 10 were personal recommendations of single or multiple independent authors, 16 were practice recommendations of single authoritative cancer centers, 35 were recommendations provided by panel of experts or of multiple regional comprehensive centers, 19 were cooperative group position papers, and finally, 17 were official guidelines statements. The COVID-19 pandemic is a global emergency, and has rapidly modified our clinical practice. Delaying unnecessary treatment, minimizing toxicity, and identifying care priorities for surgery, radiotherapy, and systemic therapies must be viewed as basic priorities in the COVID-19 era..
Khan, K.
Gonzalez-Exposito, R.
Cunningham, D.
Koh, D.-.
Woolston, A.
Barber, L.
Griffiths, B.
Kouvelakis, K.
Calamai, V.
Bali, M.
Khan, N.
Bryant, A.
Saffery, C.
Dearman, C.
Begum, R.
Rao, S.
Starling, N.
Watkins, D.
Chau, I.
Braconi, C.
Valeri, N.
Gerlinger, M.
Fotiadis, N.
Diagnostic Accuracy and Safety of Coaxial System in Oncology Patients Treated in a Specialist Cancer Center With Prospective Validation Within Clinical Trial Data. Frontiers in oncology,
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Ghidini, M.
Lampis, A.
Mirchev, M.B.
Okuducu, A.F.
Ratti, M.
Valeri, N.
Hahne, J.C.
Immune-Based Therapies and the Role of Microsatellite Instability in Pancreatic Cancer. Genes,
Vol.12
(1),
pp. 33-33.
show abstract
Pancreatic cancer is one of the most aggressive malignancies with limited treatment options thus resulting in high morbidity and mortality. Among all cancers, with a five-year survival rates of only 2–9%, pancreatic cancer holds the worst prognostic outcome for patients. To improve the overall survival, an earlier diagnosis and stratification of cancer patients for personalized treatment options are urgent needs. A minority of pancreatic cancers belong to the spectrum of Lynch syndrome-associated cancers and are characterized by microsatellite instability (MSI). MSI is a consequence of defective mismatch repair protein functions and it has been well characterized in other gastrointestinal tumors such as colorectal and gastric cancer. In the latter, high levels of MSI are linked to a better prognosis and to an increased benefit to immune-based therapies. Therefore, the same therapies could offer an opportunity of treatment for pancreatic cancer patients with MSI. In this review, we summarize the current knowledge about immune-based therapies and MSI in pancreatic cancer..