18 results on '"Buscarino M"'
Search Results
2. P2.08 Emergence of Kras Mutations and Acquired Resistance to Anti Egfr Therapy in Colorectal Cancer
- Author
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Misale, S., primary, Yaeger, R., additional, Hobor, S., additional, Scala, E., additional, Janakiraman, M., additional, Liska, D., additional, Valtorta, E., additional, Schiavo, R., additional, Buscarino, M., additional, Siravergna, G., additional, Bencardino, K., additional, Cercek, A., additional, Chen, C., additional, Veronese, S., additional, Zanon, C., additional, Sartore-Bianchi, A., additional, Gambacorta, M., additional, Gallicchio, M., additional, Vakiani, E., additional, Boscaro, V., additional, Medico, E., additional, Weiser, M., additional, Siena, S., additional, di Nicolantonio, F., additional, Solit, D., additional, and Bardelli, A., additional more...
- Published
- 2012
- Full Text
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Catalog
3. Therapeutics
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Azimi, A., primary, Kuznecovs, S., additional, Kuznecovs, J., additional, Blazejczyk, A., additional, Switalska, M., additional, Chlopicki, S., additional, Marcinek, A., additional, Gebicki, J., additional, Wietrzyk, J., additional, Egyhazi, S., additional, Azimi, A., additional, Ghasghgaei, S., additional, Frostvik Stolt, M., additional, Hertzman Johansson, C., additional, Hansson, J., additional, Delage, J. D., additional, Li, H., additional, Lu, H., additional, Cazin, L. H., additional, Vannier, J. P., additional, Drouet, L., additional, Dupuy, E., additional, Soria, J., additional, Varin, R., additional, Soria, C., additional, Castle, J., additional, Kreiter, S., additional, Diekmann, J., additional, Lower, M., additional, van der Roemer, N., additional, de Graaf, J., additional, Selmi, S., additional, Diken, M., additional, Boegel, S., additional, Paret, C., additional, Koslowski, M., additional, Kuhn, A. N., additional, Britten, C. M., additional, Huber, C., additional, Tureci, O., additional, Sahin, U., additional, Procopio, G., additional, Verzoni, E., additional, Testa, I., additional, de Braud, F., additional, Misale, S., additional, Yaeger, R., additional, Hobor, S., additional, Scala, E., additional, Janakiraman, M., additional, Liska, D., additional, Valtorta, E., additional, Schiavo, R., additional, Buscarino, M., additional, Siravergna, G., additional, Bencardino, K., additional, Cercek, A., additional, Chen, C., additional, Veronese, S., additional, Zanon, C., additional, Sartore-Bianchi, A., additional, Gambacorta, M., additional, Gallicchio, M., additional, Vakiani, E., additional, Boscaro, V., additional, Medico, E., additional, Weiser, M., additional, Siena, S., additional, di Nicolantonio, F., additional, Solit, D., additional, Bardelli, A., additional, Burbridge, M. F., additional, Dovat, S. P., additional, Song, C., additional, Payne, K. J., additional, Yang, L., additional, Cree, A., additional, Glaysher, M., additional, Bolton, L., additional, Johnson, P., additional, Atkey, N., additional, Torrance, C., additional, Bogush, T. A., additional, Dudko, E. A., additional, Shaturova, A. S., additional, Tikhomirov, M. V., additional, Bogush, E. A., additional, Polotsky, B. E., additional, Tjulandin, S. A., additional, Davydov, M. I., additional, Pernemalm, M., additional, Pawitan, Y., additional, Lazar, V., additional, Lundeberg, J., additional, Lehtio, J., additional, Rasul, A., additional, Ma, T., additional, Dyshlovoy, S. A., additional, Naeth, I., additional, Venz, S., additional, Fedorov, S. N., additional, Shubina, L. K., additional, Stonik, V. A., additional, Balabanov, S., additional, Honecker, F., additional, Kongpracha, P., additional, Tohtong, R., additional, Demidkina, V., additional, Kudryavtsev, V. A., additional, Kabakov, A. E., additional, Golan, T., additional, Atias, D., additional, Barshack, I., additional, Avivi, C., additional, Goldstein, R. S., additional, Berger, R., additional, Ben-Arieh, S., additional, Urban, D., additional, Maimon, N., additional, Leibowitz-Amit, R., additional, Keizman, D., additional, Biran, H., additional, Mishaeli, M., additional, Onn, A., additional, Gottfried, M., additional, Saraswati, S., additional, Agrawal, S. S., additional, Raval, P., additional, Patel, M., additional, Ganure, L., additional, Hanen, J. H., additional, Sonia, B. H. K., additional, Aya, M., additional, Zohra, H., additional, Touhami, M., additional, Cheng, X., additional, Shi, T. Y., additional, Yang, G., additional, Tu, X. Y., additional, Wu, X. H., additional, Wei, Q. Y., additional, Benboubker, H., additional, Zheng, B. Q., additional, Shi, Y. Q., additional, He, X. H., additional, Liang, L. H., additional, and Saied, G. M., additional more...
- Published
- 2012
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4. Bending Sensors Based on Thin Films of Semitransparent Bithiophene-Fulleropyrrolidine Bisadducts
- Author
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Michelangelo Gruttadauria, Vincenzo Campisciano, Giuseppe Arrabito, Michelangelo Scopelliti, Francesco Giacalone, Giovanni Saggio, Gianpiero Buscarino, Vito Errico, Bruno Pignataro, Clara Chiappara, and C. Chiappara, V. Campisciano, G. Arrabito, V. Errico, G. Saggio, G. Buscarino, M. Scopelliti, M. Gruttadauria, F. Giacalone, B. Pignataro more...
- Subjects
Materials science ,Fullerene ,piezoresistive sensors ,010405 organic chemistry ,Settore ING-INF/01 ,General Chemistry ,Bending ,Chronoamperometry ,bending ,010402 general chemistry ,01 natural sciences ,Piezoresistive effect ,0104 chemical sciences ,Electrical resistance and conductance ,X-ray photoelectron spectroscopy ,thin films ,thiophenes ,conjugated polymers ,Cyclic voltammetry ,Composite material ,Thin film ,Bending, conjugated polymers, piezoresistive sensors, thin films, thiophenes - Abstract
In this study, a novel bithiophene‐fulleropyrrolidine bisadducts system (bis‐Th2PC 60 ) was synthesized and electropolymerized by chronoamperometry onto flexible ITO/PET substrates. The resulting semitransparent thin film was characterized by XPS, FT‐IR, cyclic voltammetry and optical techniques, confirming the good outcome of the electropolymerization process. AFM investigations permitted to highlight an inherent disordered granular morphology, in which the grain‐to‐grain separation depends upon the application of bending. The electrical resistance of the thin film was characterized as function of bending (in the range 0°‐90°), showing promising responsivity to low bending angles (10°‐30°). The ΔR/R0 variations turn out to be 8%,16% and 20% for bending angles equal to 10°, 20° and 30°, respectively. This study represents a first step towards the understanding of piezoresistive properties in electropolymerized fullerenes‐based thin films, opening up applications as bending sensor. more...
- Published
- 2020
5. Genetic Characteristics and Long-Term Follow-Up of Slovenian Patients with RPGR Retinal Dystrophy.
- Author
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Hadalin V, Buscarino M, Sajovic J, Meglič A, Jarc-Vidmar M, Hawlina M, Volk M, and Fakin A
- Subjects
- Adult, Child, Female, Humans, Male, Eye Proteins genetics, Follow-Up Studies, Fundus Oculi, Mutation, Tomography, Optical Coherence, Slovenia, Cone-Rod Dystrophies, Retinal Dystrophies genetics, Retinitis Pigmentosa genetics
- Abstract
Genetic characteristics and a long-term clinical follow-up of 18 Slovenian retinitis pigmentosa GTPase regulator (RPGR) patients from 10 families with retinitis pigmentosa (RP) or cone/cone-rod dystrophy (COD/CORD) are reported. RP (eight families) was associated with two already known (p.(Ser407Ilefs*46) and p.(Glu746Argfs*23)) and five novel variants (c.1245+704_1415-2286del, p.(Glu660*), p.(Ala153Thr), c.1506+1G>T, and p.(Arg780Serfs*54)). COD (two families) was associated with p.(Ter1153Lysext*38). The median age of onset in males with RP (N = 9) was 6 years. At the first examination (median age of 32 years), the median best corrected visual acuity (BCVA) was 0.30 logMAR, and all patients had a hyperautofluorescent ring on fundus autofluorescence (FAF) encircling preserved photoreceptors. At the last follow-up (median age of 39 years), the median BCVA was 0.48 logMAR, and FAF showed ring constriction transitioning to patch in 2/9. Among females (N = 6; median age of 40 years), two had normal/near-normal FAF, one had unilateral RP (male pattern), and three had a radial and/or focal pattern of retinal degeneration. After a median of 4 years (4-21) of follow-up, 2/6 exhibited disease progression. The median age of onset in males with COD was 25 years. At first examination (median age of 35 years), the median BCVA was 1.00 logMAR, and all patients had a hyperautofluorescent FAF ring encircling foveal photoreceptor loss. At the last follow-up (median age of 42 years), the median BCVA was 1.30 logMAR, and FAF showed ring enlargement. The majority of the identified variants (75%; 6/8) had not been previously reported in other RPGR cohorts, which suggested the presence of distinct RPGR alleles in the Slovenian population. more...
- Published
- 2023
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6. A Genomic Analysis Workflow for Colorectal Cancer Precision Oncology.
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Corti G, Bartolini A, Crisafulli G, Novara L, Rospo G, Montone M, Negrino C, Mussolin B, Buscarino M, Isella C, Barault L, Siravegna G, Siena S, Marsoni S, Di Nicolantonio F, Medico E, and Bardelli A
- Subjects
- Antineoplastic Combined Chemotherapy Protocols pharmacology, Biomarkers, Tumor antagonists & inhibitors, Circulating Tumor DNA genetics, Circulating Tumor DNA isolation & purification, Colorectal Neoplasms blood, Colorectal Neoplasms genetics, Colorectal Neoplasms mortality, DNA Copy Number Variations, Gene Dosage, Genotyping Techniques, High-Throughput Nucleotide Sequencing, Humans, Italy, Lapatinib pharmacology, Lapatinib therapeutic use, Mutation, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local prevention & control, Patient Selection, Prognosis, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins p21(ras) antagonists & inhibitors, Proto-Oncogene Proteins p21(ras) genetics, Receptor, ErbB-2 antagonists & inhibitors, Receptor, ErbB-2 genetics, Trastuzumab pharmacology, Trastuzumab therapeutic use, Treatment Outcome, Workflow, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor genetics, Colorectal Neoplasms drug therapy, Genomics methods, Neoplasm Recurrence, Local diagnosis, Precision Medicine methods
- Abstract
Background: The diagnosis of colorectal cancer (CRC) is routinely accomplished through histopathologic examination. Prognostic information and treatment decisions are mainly determined by TNM classification, first defined in 1968. In the last decade, patient-specific CRC genomic landscapes were shown to provide important prognostic and predictive information. Therefore, there is a need for developing next generation sequencing (NGS) and bioinformatic workflows that can be routinely used for the assessment of prognostic and predictive biomarkers., Materials and Methods: To foster the application of genomics in the clinical management of CRCs, the IDEA workflow has been built to easily adapt to the availability of patient specimens and the clinical question that is being asked. Initially, IDEA deploys ad-hoc NGS assays to interrogate predefined genomic target sequences (from 600 kb to 30 Mb) with optimal detection sensitivity. Next, sequencing data are processed through an integrated bioinformatic pipeline to assess single nucleotide variants, insertions and deletions, gene copy-number alterations, and chromosomal rearrangements. The overall results are gathered into a user-friendly report., Results: We provide evidence that IDEA is capable of identifying clinically relevant molecular alterations. When optimized to analyze circulating tumor DNA, IDEA can be used to monitor response and relapse in the blood of patients with metastatic CRC receiving targeted agents. IDEA detected primary and secondary resistance mechanisms to ERBB2 blockade including sub-clonal RAS and BRAF mutations., Conclusions: The IDEA workflow provides a flexible platform to integrate NGS and bioinformatic tools for refined diagnosis and management of patients with advanced CRC., (Copyright © 2019 Elsevier Inc. All rights reserved.) more...
- Published
- 2019
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7. Emergence of MET hyper-amplification at progression to MET and BRAF inhibition in colorectal cancer.
- Author
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Oddo D, Siravegna G, Gloghini A, Vernieri C, Mussolin B, Morano F, Crisafulli G, Berenato R, Corti G, Volpi CC, Buscarino M, Niger M, Dunne PD, Rospo G, Valtorta E, Bartolini A, Fucà G, Lamba S, Martinetti A, Di Bartolomeo M, de Braud F, Bardelli A, Pietrantonio F, and Di Nicolantonio F more...
- Subjects
- Cell Line, Crizotinib, Disease Progression, Fatal Outcome, Gene Amplification, Humans, Indoles administration & dosage, Middle Aged, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins c-met antagonists & inhibitors, Pyrazoles administration & dosage, Pyridines administration & dosage, Rectal Neoplasms pathology, Sulfonamides administration & dosage, Vemurafenib, Antineoplastic Combined Chemotherapy Protocols therapeutic use, DNA, Neoplasm blood, Drug Resistance, Neoplasm genetics, Proto-Oncogene Proteins c-met genetics, Rectal Neoplasms drug therapy, Rectal Neoplasms genetics
- Abstract
Background: Combined MET and BRAF inhibition showed clinical benefit in a patient with rectal cancer carrying BRAF
V600E and MET amplification. However after 4 months, acquired resistance emerged and the patient deceased shortly after disease progression. The mechanism of resistance to this drug combination is unknown., Methods: We analysed plasma circulating tumour DNA obtained at progression by exome sequencing and digital PCR. MET gene and mRNA in situ hybridisation analyses in two bioptic specimens obtained at progression were used to confirm the plasma data., Results: We identified in plasma MET gene hyper-amplification as a potential mechanism underlying therapy resistance. Increased MET gene copy and transcript levels were detected in liver and lymph node metastatic biopsies. Finally, transduction of MET in BRAF mutant colorectal cancer cells conferred refractoriness to BRAF and MET inhibition., Conclusions: We identified in a rectal cancer patient MET gene hyper-amplification as mechanism of resistance to dual BRAF and MET inhibition. more...- Published
- 2017
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8. Acquired RAS or EGFR mutations and duration of response to EGFR blockade in colorectal cancer.
- Author
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Van Emburgh BO, Arena S, Siravegna G, Lazzari L, Crisafulli G, Corti G, Mussolin B, Baldi F, Buscarino M, Bartolini A, Valtorta E, Vidal J, Bellosillo B, Germano G, Pietrantonio F, Ponzetti A, Albanell J, Siena S, Sartore-Bianchi A, Di Nicolantonio F, Montagut C, and Bardelli A more...
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Immunological pharmacology, Clonal Evolution, Colorectal Neoplasms genetics, Female, Humans, Male, Middle Aged, Mutation, Antineoplastic Agents, Immunological therapeutic use, Colorectal Neoplasms drug therapy, Drug Resistance, Neoplasm genetics, ErbB Receptors antagonists & inhibitors, Genes, erbB-1, Genes, ras
- Abstract
Blockade of the epidermal growth factor receptor (EGFR) with the monoclonal antibodies cetuximab or panitumumab is effective in a subset of colorectal cancers (CRCs), but the emergence of resistance limits the efficacy of these therapeutic agents. At relapse, the majority of patients develop RAS mutations, while a subset acquires EGFR extracellular domain (ECD) mutations. Here we find that patients who experience greater and longer responses to EGFR blockade preferentially develop EGFR ECD mutations, while RAS mutations emerge more frequently in patients with smaller tumour shrinkage and shorter progression-free survival. In circulating cell-free tumour DNA of patients treated with anti-EGFR antibodies, RAS mutations emerge earlier than EGFR ECD variants. Subclonal RAS but not EGFR ECD mutations are present in CRC samples obtained before exposure to EGFR blockade. These data indicate that clonal evolution of drug-resistant cells is associated with the clinical outcome of CRC patients treated with anti-EGFR antibodies., Competing Interests: A.S.-B. is a member of advisory boards for Amgen, Bayer, Lilly and Sanofi. S.S. is a member of advisory boards for Amgen, Roche, Bayer, Sanofi, Eli Lilly and Merck. The remaining authors declare no competing financial interests. more...
- Published
- 2016
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9. Molecular Landscape of Acquired Resistance to Targeted Therapy Combinations in BRAF-Mutant Colorectal Cancer.
- Author
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Oddo D, Sennott EM, Barault L, Valtorta E, Arena S, Cassingena A, Filiciotto G, Marzolla G, Elez E, van Geel RM, Bartolini A, Crisafulli G, Boscaro V, Godfrey JT, Buscarino M, Cancelliere C, Linnebacher M, Corti G, Truini M, Siravegna G, Grasselli J, Gallicchio M, Bernards R, Schellens JH, Tabernero J, Engelman JA, Sartore-Bianchi A, Bardelli A, Siena S, Corcoran RB, and Di Nicolantonio F more...
- Subjects
- Colorectal Neoplasms drug therapy, Colorectal Neoplasms pathology, Gene Amplification, Humans, Signal Transduction, Colorectal Neoplasms genetics, Drug Resistance, Neoplasm genetics, Gene Dosage genetics, Proto-Oncogene Proteins B-raf genetics
- Abstract
Although recent clinical trials of BRAF inhibitor combinations have demonstrated improved efficacy in BRAF-mutant colorectal cancer, emergence of acquired resistance limits clinical benefit. Here, we undertook a comprehensive effort to define mechanisms underlying drug resistance with the goal of guiding development of therapeutic strategies to overcome this limitation. We generated a broad panel of BRAF-mutant resistant cell line models across seven different clinically relevant drug combinations. Combinatorial drug treatments were able to abrogate ERK1/2 phosphorylation in parental-sensitive cells, but not in their resistant counterparts, indicating that resistant cells escaped drug treatments through one or more mechanisms leading to biochemical reactivation of the MAPK signaling pathway. Genotyping of resistant cells identified gene amplification of EGFR, KRAS, and mutant BRAF, as well as acquired mutations in KRAS, EGFR, and MAP2K1 These mechanisms were clinically relevant, as we identified emergence of a KRAS G12C mutation and increase of mutant BRAF V600E allele frequency in the circulating tumor DNA of a patient at relapse from combined treatment with BRAF and MEK inhibitors. To identify therapeutic combinations capable of overcoming drug resistance, we performed a systematic assessment of candidate therapies across the panel of resistant cell lines. Independent of the molecular alteration acquired upon drug pressure, most resistant cells retained sensitivity to vertical MAPK pathway suppression when combinations of ERK, BRAF, and EGFR inhibitors were applied. These therapeutic combinations represent promising strategies for future clinical trials in BRAF-mutant colorectal cancer. Cancer Res; 76(15); 4504-15. ©2016 AACR., (©2016 American Association for Cancer Research.) more...
- Published
- 2016
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10. Tumor Heterogeneity and Lesion-Specific Response to Targeted Therapy in Colorectal Cancer.
- Author
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Russo M, Siravegna G, Blaszkowsky LS, Corti G, Crisafulli G, Ahronian LG, Mussolin B, Kwak EL, Buscarino M, Lazzari L, Valtorta E, Truini M, Jessop NA, Robinson HE, Hong TS, Mino-Kenudson M, Di Nicolantonio F, Thabet A, Sartore-Bianchi A, Siena S, Iafrate AJ, Bardelli A, and Corcoran RB more...
- Subjects
- Antibodies, Monoclonal therapeutic use, Cell Line, Tumor, Cetuximab therapeutic use, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology, DNA, Neoplasm blood, Humans, Liver Neoplasms genetics, Liver Neoplasms secondary, Molecular Targeted Therapy, Panitumumab, Precision Medicine, Treatment Outcome, Colorectal Neoplasms drug therapy, Drug Resistance, Neoplasm, Liver Neoplasms drug therapy, MAP Kinase Kinase 1 genetics, Mutation, Proto-Oncogene Proteins p21(ras) genetics
- Abstract
Unlabelled: How genomic heterogeneity associated with acquired resistance to targeted agents affects response to subsequent therapy is unknown. We studied EGFR blockade in colorectal cancer to assess whether tissue and liquid biopsies can be integrated with radiologic imaging to monitor the impact of individual oncogenic alterations on lesion-specific responses. Biopsy of a patient's progressing liver metastasis following prolonged response to cetuximab revealed a MEK1(K57T) mutation as a novel mechanism of acquired resistance. This lesion regressed upon treatment with panitumumab and the MEK inhibitor trametinib. In circulating tumor DNA (ctDNA), mutant MEK1 levels declined with treatment, but a previously unrecognized KRAS(Q61H) mutation was also identified that increased despite therapy. This same KRAS mutation was later found in a separate nonresponding metastasis. In summary, parallel analyses of tumor biopsies and serial ctDNA monitoring show that lesion-specific radiographic responses to subsequent targeted therapies can be driven by distinct resistance mechanisms arising within separate tumor lesions in the same patient., Significance: Molecular heterogeneity ensuing from acquired resistance drives lesion-specific responses to subsequent targeted therapies. Analysis of a single-lesion biopsy is inadequate to guide selection of subsequent targeted therapies. ctDNA profiles allow the detection of concomitant resistance mechanisms residing in separate metastases and assessment of the effect of therapies designed to overcome resistance., (©2015 American Association for Cancer Research.) more...
- Published
- 2016
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11. Clonal evolution and resistance to EGFR blockade in the blood of colorectal cancer patients.
- Author
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Siravegna G, Mussolin B, Buscarino M, Corti G, Cassingena A, Crisafulli G, Ponzetti A, Cremolini C, Amatu A, Lauricella C, Lamba S, Hobor S, Avallone A, Valtorta E, Rospo G, Medico E, Motta V, Antoniotti C, Tatangelo F, Bellosillo B, Veronese S, Budillon A, Montagut C, Racca P, Marsoni S, Falcone A, Corcoran RB, Di Nicolantonio F, Loupakis F, Siena S, Sartore-Bianchi A, and Bardelli A more...
- Subjects
- Alleles, Antibodies pharmacology, Antibodies therapeutic use, Antibodies, Neoplasm blood, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Clone Cells, Colorectal Neoplasms drug therapy, Colorectal Neoplasms pathology, DNA, Neoplasm blood, ErbB Receptors genetics, ErbB Receptors immunology, Humans, Mutation genetics, Proto-Oncogene Proteins genetics, Proto-Oncogene Proteins p21(ras), ras Proteins genetics, Clonal Evolution, Colorectal Neoplasms blood, Colorectal Neoplasms genetics, Drug Resistance, Neoplasm genetics, ErbB Receptors antagonists & inhibitors
- Abstract
Colorectal cancers (CRCs) evolve by a reiterative process of genetic diversification and clonal evolution. The molecular profile of CRC is routinely assessed in surgical or bioptic samples. Genotyping of CRC tissue has inherent limitations; a tissue sample represents a single snapshot in time, and it is subjected to spatial selection bias owing to tumor heterogeneity. Repeated tissue samples are difficult to obtain and cannot be used for dynamic monitoring of disease progression and response to therapy. We exploited circulating tumor DNA (ctDNA) to genotype colorectal tumors and track clonal evolution during treatment with the epidermal growth factor receptor (EGFR)-specific antibodies cetuximab or panitumumab. We identified alterations in ctDNA of patients with primary or acquired resistance to EGFR blockade in the following genes: KRAS, NRAS, MET, ERBB2, FLT3, EGFR and MAP2K1. Mutated KRAS clones, which emerge in blood during EGFR blockade, decline upon withdrawal of EGFR-specific antibodies, indicating that clonal evolution continues beyond clinical progression. Pharmacogenomic analysis of CRC cells that had acquired resistance to cetuximab reveals that upon antibody withdrawal KRAS clones decay, whereas the population regains drug sensitivity. ctDNA profiles of individuals who benefit from multiple challenges with anti-EGFR antibodies exhibit pulsatile levels of mutant KRAS. These results indicate that the CRC genome adapts dynamically to intermittent drug schedules and provide a molecular explanation for the efficacy of rechallenge therapies based on EGFR blockade. more...
- Published
- 2015
- Full Text
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12. The molecular landscape of colorectal cancer cell lines unveils clinically actionable kinase targets.
- Author
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Medico E, Russo M, Picco G, Cancelliere C, Valtorta E, Corti G, Buscarino M, Isella C, Lamba S, Martinoglio B, Veronese S, Siena S, Sartore-Bianchi A, Beccuti M, Mottolese M, Linnebacher M, Cordero F, Di Nicolantonio F, and Bardelli A more...
- Subjects
- Anaplastic Lymphoma Kinase, Cell Line, Tumor, Cetuximab, Colorectal Neoplasms genetics, Genes, erbB-1, Genetic Heterogeneity, Humans, Molecular Targeted Therapy, Proto-Oncogene Proteins c-ret metabolism, Receptor Protein-Tyrosine Kinases genetics, Receptor, Fibroblast Growth Factor, Type 2 metabolism, Colorectal Neoplasms enzymology, ErbB Receptors antagonists & inhibitors, Receptor Protein-Tyrosine Kinases metabolism
- Abstract
The development of molecularly targeted anticancer agents relies on large panels of tumour-specific preclinical models closely recapitulating the molecular heterogeneity observed in patients. Here we describe the mutational and gene expression analyses of 151 colorectal cancer (CRC) cell lines. We find that the whole spectrum of CRC molecular and transcriptional subtypes, previously defined in patients, is represented in this cell line compendium. Transcriptional outlier analysis identifies RAS/BRAF wild-type cells, resistant to EGFR blockade, functionally and pharmacologically addicted to kinase genes including ALK, FGFR2, NTRK1/2 and RET. The same genes are present as expression outliers in CRC patient samples. Genomic rearrangements (translocations) involving the ALK and NTRK1 genes are associated with the overexpression of the corresponding proteins in CRC specimens. The approach described here can be used to pinpoint CRCs with exquisite dependencies to individual kinases for which clinically approved drugs are already available. more...
- Published
- 2015
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13. Blockade of EGFR and MEK intercepts heterogeneous mechanisms of acquired resistance to anti-EGFR therapies in colorectal cancer.
- Author
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Misale S, Arena S, Lamba S, Siravegna G, Lallo A, Hobor S, Russo M, Buscarino M, Lazzari L, Sartore-Bianchi A, Bencardino K, Amatu A, Lauricella C, Valtorta E, Siena S, Di Nicolantonio F, and Bardelli A more...
- Subjects
- Drug Resistance, Neoplasm, ErbB Receptors genetics, ErbB Receptors metabolism, Gene Silencing, Humans, MAP Kinase Kinase Kinases genetics, Signal Transduction, Antineoplastic Agents therapeutic use, Colorectal Neoplasms drug therapy, ErbB Receptors antagonists & inhibitors, MAP Kinase Kinase Kinases antagonists & inhibitors
- Abstract
Colorectal cancers (CRCs) that are sensitive to the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab or panitumumab almost always develop resistance within several months of initiating therapy. We report the emergence of polyclonal KRAS, NRAS, and BRAF mutations in CRC cells with acquired resistance to EGFR blockade. Regardless of the genetic alterations, resistant cells consistently displayed mitogen-activated protein kinase kinase (MEK) and extracellular signal-regulated kinase (ERK) activation, which persisted after EGFR blockade. Inhibition of MEK1/2 alone failed to impair the growth of resistant cells in vitro and in vivo. An RNA interference screen demonstrated that suppression of EGFR, together with silencing of MEK1/2, was required to hamper the proliferation of resistant cells. Indeed, concomitant pharmacological blockade of MEK and EGFR induced prolonged ERK inhibition and severely impaired the growth of resistant tumor cells. Heterogeneous and concomitant mutations in KRAS and NRAS were also detected in plasma samples from patients who developed resistance to anti-EGFR antibodies. A mouse xenotransplant from a CRC patient who responded and subsequently relapsed upon EGFR therapy showed exquisite sensitivity to combinatorial treatment with MEK and EGFR inhibitors. Collectively, these results identify genetically distinct mechanisms that mediate secondary resistance to anti-EGFR therapies, all of which reactivate ERK signaling. These observations provide a rational strategy to overcome the multifaceted clonal heterogeneity that emerges when tumors are treated with targeted agents. We propose that MEK inhibitors, in combination with cetuximab or panitumumab, should be tested in CRC patients who become refractory to anti-EGFR therapies. more...
- Published
- 2014
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14. Emergence of KRAS mutations and acquired resistance to anti-EGFR therapy in colorectal cancer.
- Author
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Misale S, Yaeger R, Hobor S, Scala E, Janakiraman M, Liska D, Valtorta E, Schiavo R, Buscarino M, Siravegna G, Bencardino K, Cercek A, Chen CT, Veronese S, Zanon C, Sartore-Bianchi A, Gambacorta M, Gallicchio M, Vakiani E, Boscaro V, Medico E, Weiser M, Siena S, Di Nicolantonio F, Solit D, and Bardelli A more...
- Subjects
- Alleles, Antibodies, Monoclonal therapeutic use, Antibodies, Monoclonal, Humanized, Cell Line, Tumor, Cetuximab, Colorectal Neoplasms pathology, Disease Progression, Drug Resistance, Neoplasm genetics, Genes, ras genetics, Humans, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Panitumumab, Promoter Regions, Genetic genetics, Proto-Oncogene Proteins p21(ras), Antibodies, Monoclonal pharmacology, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, Drug Resistance, Neoplasm drug effects, ErbB Receptors antagonists & inhibitors, Mutation genetics, Proto-Oncogene Proteins genetics, ras Proteins genetics
- Abstract
A main limitation of therapies that selectively target kinase signalling pathways is the emergence of secondary drug resistance. Cetuximab, a monoclonal antibody that binds the extracellular domain of epidermal growth factor receptor (EGFR), is effective in a subset of KRAS wild-type metastatic colorectal cancers. After an initial response, secondary resistance invariably ensues, thereby limiting the clinical benefit of this drug. The molecular bases of secondary resistance to cetuximab in colorectal cancer are poorly understood. Here we show that molecular alterations (in most instances point mutations) of KRAS are causally associated with the onset of acquired resistance to anti-EGFR treatment in colorectal cancers. Expression of mutant KRAS under the control of its endogenous gene promoter was sufficient to confer cetuximab resistance, but resistant cells remained sensitive to combinatorial inhibition of EGFR and mitogen-activated protein-kinase kinase (MEK). Analysis of metastases from patients who developed resistance to cetuximab or panitumumab showed the emergence of KRAS amplification in one sample and acquisition of secondary KRAS mutations in 60% (6 out of 10) of the cases. KRAS mutant alleles were detectable in the blood of cetuximab-treated patients as early as 10 months before radiographic documentation of disease progression. In summary, the results identify KRAS mutations as frequent drivers of acquired resistance to cetuximab in colorectal cancers, indicate that the emergence of KRAS mutant clones can be detected non-invasively months before radiographic progression and suggest early initiation of a MEK inhibitor as a rational strategy for delaying or reversing drug resistance. more...
- Published
- 2012
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15. Inhibition of MEK and PI3K/mTOR suppresses tumor growth but does not cause tumor regression in patient-derived xenografts of RAS-mutant colorectal carcinomas.
- Author
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Migliardi G, Sassi F, Torti D, Galimi F, Zanella ER, Buscarino M, Ribero D, Muratore A, Massucco P, Pisacane A, Risio M, Capussotti L, Marsoni S, Di Nicolantonio F, Bardelli A, Comoglio PM, Trusolino L, and Bertotti A more...
- Subjects
- 1-Phosphatidylinositol 4-Kinase metabolism, Aged, Aged, 80 and over, Animals, Case-Control Studies, Cell Line, Tumor, Colon metabolism, Colon pathology, Colorectal Neoplasms metabolism, Colorectal Neoplasms pathology, Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors, Extracellular Signal-Regulated MAP Kinases metabolism, Female, Humans, Immunoenzyme Techniques, Liver Neoplasms metabolism, Liver Neoplasms secondary, Male, Mice, Mice, Inbred NOD, Mice, SCID, Middle Aged, Mitogen-Activated Protein Kinase Kinases metabolism, Protein Kinase Inhibitors pharmacology, Proto-Oncogene Proteins B-raf antagonists & inhibitors, Proto-Oncogene Proteins B-raf metabolism, Rectum metabolism, Rectum pathology, TOR Serine-Threonine Kinases metabolism, Xenograft Model Antitumor Assays, 1-Phosphatidylinositol 4-Kinase antagonists & inhibitors, Colorectal Neoplasms prevention & control, Genes, ras, Liver Neoplasms prevention & control, Mitogen-Activated Protein Kinase Kinases antagonists & inhibitors, Mutation genetics, TOR Serine-Threonine Kinases antagonists & inhibitors
- Abstract
Purpose: Gene mutations along the Ras pathway (KRAS, NRAS, BRAF, PIK3CA) occur in approximately 50% of colorectal cancers (CRC) and correlate with poor response to anti-EGF receptor (EGFR) therapies. We assessed the effects of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) and phosphoinositide 3-kinase (PI3K)/mTOR inhibitors, which neutralize the major Ras effectors, in patient-derived xenografts from RAS/RAF/PIK3CA-mutant metastatic CRCs (mCRC)., Experimental Design: Forty mCRC specimens harboring KRAS, NRAS, BRAF, and/or PIK3CA mutations were implanted in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Each xenograft was expanded into four treatment arms: placebo, the MEK inhibitor AZD6244, the PI3K/mTOR inhibitor, BEZ235, or AZD6244 + BEZ235. Cases initially treated with placebo crossed over to AZD6244, BEZ235, and the anti-EGFR monoclonal antibody cetuximab., Results: At the 3-week evaluation time point, cotreatment of established tumors with AZD6244 + BEZ235 induced disease stabilization in the majority of cases (70%) but did not lead to overt tumor regression. Monotherapy was less effective, with BEZ235 displaying higher activity than AZD6244 (disease control rates, DCRs: AZD6244, 27.5%; BEZ235, 42.5%). Triple therapy with cetuximab provided further advantage (DCR, 88%). The extent of disease control declined at the 6-week evaluation time point (DCRs: AZD6244, 13.9%; BEZ235, 16.2%; AZD6244 + BEZ235, 34%). Cross-analysis of mice harboring xenografts from the same original tumor and treated with each of the different modalities revealed subgroups with preferential sensitivity to AZD6244 (12.5%), BEZ235 (35%), or AZD6244 + BEZ235 (42.5%); another subgroup (10%) showed equivalent response to any treatment., Conclusions: The prevalent growth-suppressive effects produced by MEK and PI3K/mTOR inhibition suggest that this strategy may retard disease progression in patients. However, data offer cautionary evidence against the occurrence of durable responses., (©2012 AACR.) more...
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- 2012
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16. Delusional parasitosis in a female treated with mixed amphetamine salts: a case report and literature review.
- Author
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Buscarino M, Saal J, and Young JL
- Abstract
Objectives. To explore factors underlying the onset of delusional parasitosis; a condition in which an individual has a fixed, false belief that he/she is infested with insects. Case Description. MJ is a 57-year-old female who presents with symptoms of fatigue and AD/HD. Upon treatment with extended release mixed amphetamine salts, the patient displayed symptoms of delusional parasitosis. After eventual discontinuation of this medication, her delusions resolved. Comments. In order to maintain confidentiality, all identifying information was removed. To this end, please note that MJ is a fictitious name. more...
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- 2012
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17. A molecularly annotated platform of patient-derived xenografts ("xenopatients") identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer.
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Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C, Corà D, Di Nicolantonio F, Buscarino M, Petti C, Ribero D, Russolillo N, Muratore A, Massucco P, Pisacane A, Molinaro L, Valtorta E, Sartore-Bianchi A, Risio M, Capussotti L, Gambacorta M, Siena S, Medico E, Sapino A, Marsoni S, Comoglio PM, Bardelli A, and Trusolino L more...
- Subjects
- Aged, Aged, 80 and over, Animals, Antibodies, Monoclonal, Humanized, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Cetuximab, Colorectal Neoplasms genetics, Colorectal Neoplasms metabolism, Drug Resistance, Neoplasm, ErbB Receptors antagonists & inhibitors, ErbB Receptors genetics, ErbB Receptors metabolism, Female, Humans, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Middle Aged, Molecular Targeted Therapy, Prospective Studies, Receptor, ErbB-2 genetics, ras Proteins genetics, ras Proteins metabolism, Antibodies, Monoclonal pharmacology, Colorectal Neoplasms drug therapy, Colorectal Neoplasms enzymology, Receptor, ErbB-2 metabolism, Xenograft Model Antitumor Assays methods
- Abstract
Unlabelled: Only a fraction of patients with metastatic colorectal cancer receive clinical benefit from therapy with anti-epidermal growth factor receptor (EGFR) antibodies, which calls for the identification of novel biomarkers for better personalized medicine. We produced large xenograft cohorts from 85 patient-derived, genetically characterized metastatic colorectal cancer samples ("xenopatients") to discover novel determinants of therapeutic response and new oncoprotein targets. Serially passaged tumors retained the morphologic and genomic features of their original counterparts. A validation trial confirmed the robustness of this approach: xenopatients responded to the anti-EGFR antibody cetuximab with rates and extents analogous to those observed in the clinic and could be prospectively stratified as responders or nonresponders on the basis of several predictive biomarkers. Genotype-response correlations indicated HER2 amplification specifically in a subset of cetuximab-resistant, KRAS/NRAS/BRAF/PIK3CA wild-type cases. Importantly, HER2 amplification was also enriched in clinically nonresponsive KRAS wild-type patients. A proof-of-concept, multiarm study in HER2-amplified xenopatients revealed that the combined inhibition of HER2 and EGFR induced overt, long-lasting tumor regression. Our results suggest promising therapeutic opportunities in cetuximab-resistant patients with metastatic colorectal cancer, whose medical treatment in the chemorefractory setting remains an unmet clinical need., Significance: Direct transfer xenografts of tumor surgical specimens conserve the interindividual diversity and the genetic heterogeneity typical of the tumors of origin, combining the flexibility of preclinical analysis with the informative value of population-based studies. Our suite of patient-derived xenografts from metastatic colorectal carcinomas reliably mimicked disease response in humans, prospectively recapitulated biomarker-based case stratification, and identified HER2 as a predictor of resistance to anti-epidermal growth factor receptor antibodies and of response to combination therapies against HER2 and epidermal growth factor receptor in this tumor setting., (© 2011 AACR.) more...
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- 2011
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18. Increased detection sensitivity for KRAS mutations enhances the prediction of anti-EGFR monoclonal antibody resistance in metastatic colorectal cancer.
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Molinari F, Felicioni L, Buscarino M, De Dosso S, Buttitta F, Malatesta S, Movilia A, Luoni M, Boldorini R, Alabiso O, Girlando S, Soini B, Spitale A, Di Nicolantonio F, Saletti P, Crippa S, Mazzucchelli L, Marchetti A, Bardelli A, and Frattini M more...
- Subjects
- Aged, Base Sequence, Class I Phosphatidylinositol 3-Kinases, Colorectal Neoplasms diagnosis, Colorectal Neoplasms pathology, Drug Resistance, Neoplasm drug effects, Female, Gene Expression Regulation, Neoplastic, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Neoplasm Metastasis, PTEN Phosphohydrolase genetics, Phosphatidylinositol 3-Kinases genetics, Prognosis, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins p21(ras), Sensitivity and Specificity, Treatment Outcome, Antibodies, Monoclonal therapeutic use, Antineoplastic Agents therapeutic use, Colorectal Neoplasms drug therapy, ErbB Receptors antagonists & inhibitors, Mutation genetics, Proto-Oncogene Proteins genetics, ras Proteins genetics
- Abstract
Purpose: KRAS mutations represent the main cause of resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (MoAbs) in metastatic colorectal cancer (mCRC). We evaluated whether highly sensitive methods for KRAS investigation improve the accuracy of predictions of anti-EGFR MoAbs efficacy., Experimental Design: We retrospectively evaluated objective tumor responses in mCRC patients treated with cetuximab or panitumumab. KRAS codons 12 and 13 were examined by direct sequencing, MALDI-TOF MS, mutant-enriched PCR, and engineered mutant-enriched PCR, which have a sensitivity of 20%, 10%, 0.1%, and 0.1%, respectively. In addition, we analyzed KRAS codon 61, BRAF, and PIK3CA by direct sequencing and PTEN expression by immunohistochemistry., Results: In total, 111 patients were considered. Direct sequencing revealed mutations in codons 12 and 13 of KRAS in 43/111 patients (39%) and BRAF mutations in 9/111 (8%), with almost all of these occurring in nonresponder patients. Using highly sensitive methods, we identified up to 13 additional KRAS mutations compared with direct sequencing, all occurring in nonresponders. By analyzing PIK3CA and PTEN, we found that of these 13 patients, 7 did not show any additional alteration in the PI3K pathway., Conclusions: The application of highly sensitive methods for the detection of KRAS mutations significantly improves the identification of mCRC patients resistant to anti-EGFR MoAbs. more...
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- 2011
- Full Text
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