Alberto Zambelli

Azienda Ospedaliera Papa Giovanni XXIII, Bérgamo, Lombardy, Italy

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Publications (5)27.01 Total impact

  • Annals of Oncology 05/2015; 26(suppl 3):iii11-iii11. DOI:10.1093/annonc/mdv116.05 · 6.58 Impact Factor
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    ABSTRACT: The majority of patients with stage III-IV epithelial ovarian cancer (EOC) relapse after initially responding to platinum-based chemotherapy, and develop resistance. The genomic features involved in drug resistance are unknown. To unravel some of these features we investigated the mutational profile of genes involved in pathways related to drug sensitivity in a cohort of matched tumors obtained at first (Ft-S), and second surgery (Sd-S). Matched biopsies (33) taken at Ft-S and Sd-S were selected from the "Pandora" tumor tissue collection. DNA libraries for 65 genes were generated using the TruSeq Custom Amplicon kit and sequenced on MiSeq (Illumina). Data were analyzed using a high performance cluster computing platform (Cloud4CARE project) and independently validated. A total of 2270 somatic mutations were identified (89.85% SNPs and 8.19% indels, 1.92% unknown). Homologous recombination genes and TP53 were mutated in the majority of Ft-S, while ATM, ATR, TOP2A and TOP2B were mutated in the entire dataset. Only 2% of mutations were conserved between matched Ft-S and Sd-S. Mutations detected at second surgery clustered patients in two groups characterized by different mutational profiles in genes associated with homologous recombination, PI3K, miRNA biogenesis and signal transduction. There was a low level of concordance between Ft-S and Sd-S in terms of genes involved in key processes of tumor growth and drug resistance. This result , suggests the importance of future longitudinal analyses to improve the clinical management of relapsed EOC. © The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
    Annals of Oncology 04/2015; DOI:10.1093/annonc/mdv164 · 6.58 Impact Factor
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    ABSTRACT: Preclinical data indicate there is strong synergism of action against Ewing sarcoma in sequential treatment with trabectedin followed by irinotecan and it appears to be related to a selective blockade of the transcription factor EWS-FLI1. This combination was evaluated in Ewing sarcoma patient who was progressing with standard therapies. Trabectedin was given as a 24-h iv infusion on day 1 at the dose of 1 mg/sqm, and irinotecan 75 mg/sqm on day 2 and then on days 2 and 4, every 3 weeks from the seventh course. The therapy was well tolerated with transient hematological toxicity and transaminitis and induced stabilization of the disease lasting for 11 courses, with clinical improvement and marked reduction of the need for opioids. However, shortly before the 12th course, sudden death occurred, possibly due to cerebral stroke, presumably not related to the drug treatment. The encouraging clinical benefit observed with the combination and its good tolerability deserves further investigation in Ewing sarcoma.
    Cancer Chemotherapy and Pharmacology 03/2015; DOI:10.1007/s00280-015-2726-7 · 2.57 Impact Factor
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    ABSTRACT: Triple negative breast cancers, which are defined by lack of expression of estrogen, progesterone, or HER2 receptors, represent approximately 15% of all breast cancers, although they account for a much higher proportional of breast cancer mortality. This is due both to their innate aggressive biological characteristics, but also to lack of effective therapies. Conventional chemotherapy is currently the only treatment option, thus there is a critical need to find new and effective targeted therapies in this disease. While investigation of agents such as poly (ADP-ribose) polymerase (PARP) inhibitors and EGFR inhibitors continues, results from recent clinical trials indicate that these therapies are not as active in sporadic triple negative breast cancers as initially hoped. It is important therefore to consider other emerging therapeutic agents. Mutation in p53 is found in the vast majority of triple negative breast cancers, and as such is a target of particular interest. Within this review, several agents with potential activity against aberrant p53 signaling have been considered, as a novel approach to finding an effective targeted therapy for this aggressive breast cancer subtype.
    Cancer Treatment Reviews 01/2013; DOI:10.1016/j.ctrv.2012.12.001 · 6.47 Impact Factor
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    ABSTRACT: BACKGROUND: The present study is aimed to identify genetic pathways correlated with chemoresistance in epithelial ovarian cancer (EOC). METHODS: We compared the molecular profiles of 23 tumour biopsies of stage III-IV (training set) at primary surgery, before chemotherapy, to the profile from the same patients at second surgery, after several lines of platinum (Pt)-based chemotherapy when the tumours were resistant. In the hypothesis that identified markers were related to Pt-resistance and to prognosis, we validated this signature in 52 EOC taken at primary surgery (validation set) selected to be either very sensitive to the first line therapy, i.e. not relapsing before one year from the end of therapy, or resistant, i.e. relapsing within 6months from the end of therapy. RESULTS: In the training set, we identified a resistance signature indicative of the activation of epithelial to mesenchymal transition (EMT) by transforming growth factor (TGF)-beta pathway. We then validated this signature in 52 EOC taken at primary surgery (validation set). Some genes involved in EMT, such as BMP and activin membrane-bound inhibitor (BAMBI), and mir-141 resulted in association with overall or progression free survival. CONCLUSION: Some genes involved in EMT were associated to overall or progression free survival, suggesting EMT as vital to the resistance mechanisms.
    European journal of cancer (Oxford, England: 1990) 08/2012; 49(2). DOI:10.1016/j.ejca.2012.06.026 · 4.82 Impact Factor