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  • American Association for Cancer Research (AACR)  (5)
  • 1
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    Online Resource
    Abstract 3176: Recurrent SETBP1 mutations in atypical chronic myeloid leukemia abrogate an ubiquitination site and dysregulate SETBP1 protein levels.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3176-3176
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 3176-3176
    Abstract: Atypical Chronic Myeloid Leukemia (aCML) shares clinical and laboratory features with Chronic Myeloid Leukemia (CML), but it lacks the pathognomonic BCR-ABL1 fusion. The molecular pathogenesis of this disease has remained elusive and the outcome dismal. To investigate the molecular pathogenesis of aCML, we applied exome sequencing and RNA-SEQ to aCML, with the aim of identifying novel recurrent driver mutations. Whole-exome sequencing of 9 aCML patients(pts) revealed the presence of 70 unique mutations, including recurrent alterations of SETBP1 in 3 cases: 2 cases with a G870S and a case with a D868N alteration were found. Targeted resequencing in 70 aCMLs, 574 pts with different hematological malignancies and 344 cell lines, identified SETBP1 mutations in 17/70 aCML (24.3%; 95% CI: 16-35%), 4/30 (13%) MDS/MPN-u, 3/82 (3.6%) CMML and 0/100 MDS. aCML pts with SETBP1 mutations had higher white blood cell counts (p=0.008) and worse prognosis (p=0.01) when tested in multivariate analysis. The SETBP1 gene encodes for a predominantly nuclear protein with a predicted MW of 170kDa. Germline mutations of SETBP1 were previously described in pts affected by the Schinzel-Giedion syndrome (SGS), a rare disease characterized by bone, muscle and cardiac abnormalities and neuroepithelial neoplasms. The vast majority of aCML SETBP1 mutations (85%) was located between residues 858 and 871 and were identical to the germline changes seen in pts with SGS. This region may be critical for ubiquitin binding and for subsequent protein degradation, since the Eukaryotic Linear Motif identified a putative functional site (aa. 868-873) for beta-TrCP, the substrate recognition subunit of the E3 ubiquitin ligase. The prediction was experimentally validated using biotinylated, phosphorylated peptides encompassing this region (aa 859-879): while the wild type (wt) peptide could efficiently bind beta-TrCP, a peptide presenting G870S was incapable of binding this subunit, indicating a possible alteration in SETBP1 protein stability caused by the mutation. In line with the known binding model of beta-TrCP, dephosphorylated peptides failed to bind beta-TrCP, therefore confirming the specificity of the interaction. In agreement with these findings, TF1 cells transduced with SETBP1 G870S showed increased SETBP1 and SET protein levels, decreased PP2A activity and increased proliferation rates when compared to cells expressing the wt SETBP1 gene. Mutated SETBP1 represents a novel oncogene specifically present in aCML and closely related diseases. These data allow for a better understanding of the molecular pathogenesis of this disease; they provide evidence that SETBP1 mutations might be a new biomarker for future diagnosis and classification of aCML and related diseases, and indicate a potential strategy to develop new treatment modalities for malignancies caused by mutated SETBP1. Citation Format: Rocco Piazza, Simona Valletta, Nils Winkelmann, Sara Redaelli, Roberta Spinelli, Alessandra Pirola, Laura Antolini, Luca Mologni, Carla Donadoni, Elli Papaemmanuil, Susanne Schnittger, Kim Dong-Wook, Jacqueline Boultwood, Fabio Rossi, Giuseppe Gaipa, Greta De Martini, Paola Francia di Celle, Hyun Gyung Jang, Valeria Fantin, Graham R. Bignell, Vera Magistroni, Torsten Haferlach, Enrico Maria Pogliani, Peter Campbell, Andrew J. Chase, William J. Tapper, Nick C.P. Cross, Carlo Gambacorti Passerini. Recurrent SETBP1 mutations in atypical chronic myeloid leukemia abrogate an ubiquitination site and dysregulate SETBP1 protein levels. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3176. doi:10.1158/1538-7445.AM2013-3176
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-3176
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    3D-Informed Targeting of the Trop-2 Signal-Activation Site Drives Selective Cancer Vulnerability
    American Association for Cancer Research (AACR) ; 2023
    In:  Molecular Cancer Therapeutics Vol. 22, No. 6 ( 2023-06-01), p. 790-804
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 22, No. 6 ( 2023-06-01), p. 790-804
    Abstract: Next-generation Trop-2–targeted therapy against advanced cancers is hampered by expression of Trop-2 in normal tissues. We discovered that Trop-2 undergoes proteolytic activation by ADAM10 in cancer cells, leading to the exposure of a previously inaccessible protein groove flanked by two N-glycosylation sites. We designed a recognition strategy for this region, to drive selective cancer vulnerability in patients. Most undiscriminating anti–Trop-2 mAbs recognize a single immunodominant epitope. Hence, we removed it by deletion mutagenesis. Cancer-specific, glycosylation-prone mAbs were selected by ELISA, bio-layer interferometry, flow cytometry, confocal microscopy for differential binding to cleaved/activated, wild-type and glycosylation site–mutagenized Trop-2. The resulting 2G10 mAb family binds Trop-2–expressing cancer cells, but not Trop-2 on normal cells. We humanized 2G10 by state-of-the-art complementarity determining region grafting/re-modeling, yielding Hu2G10. This antibody binds cancer-specific, cleaved/activated Trop-2 with Kd & lt; 10−12 mol/L, and uncleaved/wtTrop-2 in normal cells with Kd 3.16×10−8 mol/L, thus promising an unprecedented therapeutic index in patients. In vivo, Hu2G10 ablates growth of Trop-2–expressing breast, colon, prostate cancers, but shows no evidence of systemic toxicity, paving the way for a paradigm shift in Trop-2–targeted therapy.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-22-0352
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 3
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    Abstract PD15-04: Trop-2 inactivation of E-cadherin drives triple negative breast cancer relapse
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 4_Supplement ( 2021-02-15), p. PD15-04-PD15-04
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 4_Supplement ( 2021-02-15), p. PD15-04-PD15-04
    Abstract: Hundreds of proteins/genes have been linked to the metastatic phenotype. However, consistent markers of tumour aggressiveness and metastatic potential in breast cancer patients were not identified, not even including proteomic analysis and large-scale genome sequencing.Metastasis-associated genes were predicted to include not only drivers of the metastatic phenotype, but also secondary events, together with adaptive, counterbalancing changes. Thus, to identify candidates with a required role in metastatic diffusion, we looked for genes that were concordantly dysregulated across orthogonal cancer metastasis settings. This led us to identify Trop-2 as uniquely upregulated and associated to metastasis in experimental models of breast cancer, as well as in other solid tumors. We identified functional inactivation of E-cadherin by Trop-2 as the main motor of metastatic diffusion of such metastatic systems. Trop-2 binding to E-cadherin inactivated its cell-cell adhesion function, through release from the cytoskeleton, for activation of β-catenin transcriptional activity. This led to anti-apoptotic signaling, increased cell migration capacity and enhanced cancer cell survival. We showed that this mechanism led to metastatic diffusion of xenotransplants growing in immunosuppressed mice. An E-cadherin-inactivation metastasis program was then shown to be recapitulated in breast cancer patients, as well as in other solid tumors, over 24 independent case series, encompassing 13,042 primary tumours. Aggressive triple-negative breast cancers were shown to be driven toward global relapse by Trop-2 overexpression, through E-cadherin inactivation and activation of β-catenin transcriptional activity. No disease recurrence was observed in control cases over +12 years of follow-up. These finding lead to a novel paradigm of a Trop-2-driven, E-cadherin-inactivation program as a main metastasis driver in solid tumors. This may open far-reaching perspectives in diagnostic procedures and anti-cancer therapies. Citation Format: Saverio Alberti, Marco Trerotola, Valeria Relli, Rossano Lattanzio, Martina Ceci, Khouloud Boujnah, Valeria Garbo, Antonino Moschella, Patrizia Querzoli, Massimo Pedriali, Laura Antolini, Emanuela Guerra. Trop-2 inactivation of E-cadherin drives triple negative breast cancer relapse [abstract]. In: Proceedings of the 2020 Sa n Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD15-04.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS20-PD15-04
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
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    Online Resource
    Abstract 2993: Patterns of recurrent mutations in SETBP1 mutated and wild-type atypical Chronic Myeloid Leukemia patients.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2993-2993
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 2993-2993
    Abstract: Atypical Chronic Myeloid Leukemia (aCML) is a heterogeneous disorder belonging to the group of myelodysplastic/myeloproliferative (MDS/MPN) syndromes. The molecular pathogenesis of this disease is still unclear and the outcome is poor with no improvement over the last 20 years. We applied whole exome sequencing approach in 9 aCML patient samples in order to identify possible recurrent alterations. The analysis revealed the presence of unique mutations in 70 genes with 3 cases of SETBP1 alterations. Some of the genes identified as mutated in the initial set of 9 patients (IDH2, MTA2, EPHB3, ETNK1, GATA2, IRAK4) and having a score higher than 1 in the oncogenic GeneRanker database were resequenced in a cohort of 40 aCML patients (15 with and 25 without SETBP1 mutations). With the exception of IDH2, no other gene was found mutated in any case apart from the index patient. Evaluation on a larger cohort of 70 aCML samples revealed recurrent SETBP1 mutations in 24.3% of cases (see designated abstract). To test the relationship between SETBP1 variants and mutations in oncogenes known to be involved in myeloid malignancies, mutations in ASXL1, CBL, CEBPA, DNMT3A, EED, EZH2, FLT3, IDH1/2, JAK2, JARID2, NPM1, N/KRAS, RBBP4, RUNX1, SF3B1, SUZ12, TET2 and WT1 were evaluated in a population of 61 aCML patients (14 with and 47 without SETBP1 mutations) by Sanger sequencing. Overall we identified 60 mutations in 14 genes: 28 were missense point mutations, 13 nonsense point mutations, 15 missense ins/del and 4 ins/del leading to a premature stop codon. No mutations were found in IDH1, RBBP4, NPM1, JAK2, FLT3, DNMT3A. Mutations in ASXL1 were present in 14 patients and appeared more frequent in patients with mutated SETBP1 (36% vs 19%) while the 15 TET2 mutations were more prevalent in patients with SETBP1 WT than in mutated samples(28% vs. 14%). Further associations will be presented at the meeting, although further analysis on larger cohorts of patients will be necessary to determine the significance of this differences. Additional data on epigenetic signature of aCML will clarify the role of epigenetic dysregulation in aCML and related diseases. Citation Format: Sara Redaelli, Simona Valletta, Rocco Piazza, Nils Winkelmann, Roberta Spinelli, Alessandra Pirola, Laura Antolini, Luca Mologni, Carla Donadoni, Elli Papaemmanuil, Susanne Schnittger, Kim Dong-Wook, Jacqueline Boultwood, Fabio Rossi, Giuseppe Gaipa, Greta De Martini, Paola Francia di Celle, Hyun Gyung Jang, Valeria Fantin, Graham R. Bignell, Vera Magistroni, Torsten Haferlach, Enrico Maria Pogliani, Peter Campbell, Andrew J. Chase, William J. Tapper, Nick C.P. Cross, Carlo Gambacorti Passerini. Patterns of recurrent mutations in SETBP1 mutated and wild-type atypical Chronic Myeloid Leukemia patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2993. doi:10.1158/1538-7445.AM2013-2993
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-2993
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
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    Online Resource
    Axillary Lymph Node Nanometastases Are Prognostic Factors for Disease-Free Survival and Metastatic Relapse in Breast Cancer Patients
    American Association for Cancer Research (AACR) ; 2006
    In:  Clinical Cancer Research Vol. 12, No. 22 ( 2006-11-15), p. 6696-6701
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 12, No. 22 ( 2006-11-15), p. 6696-6701
    Abstract: Purpose: Early breast cancer presents with a remarkable heterogeneity of outcomes. Undetected, microscopic lymph node tumor deposits may account for a significant fraction of this prognostic diversity. Thus, we systematically evaluated the presence of lymph node tumor cell deposits ≤0.2 mm in diameter [pN0(i+), nanometastases] and analyzed their prognostic effect. Experimental Design: Single-institution, consecutive patients with 8 years of median follow-up (n = 702) were studied. To maximize chances of detecting micrometastases and nanometastases, whole-axilla dissections were analyzed. pN0 cases (n = 377) were systematically reevaluated by lymph node (n = 6676) step-sectioning and anticytokeratin immunohistochemical analysis. The risk of first adverse events and of distant relapse of bona fide pN0 patients was compared with that of pN0(i+), pN1mi, and pN1 cases. Results: Minimal lymph node deposits were revealed in 13% of pN0 patients. The hazard ratio for all adverse events of pN0(i+) versus pN0(i−) was 2.51 (P = 0.00019). Hazards of pN1mi and pN0(i+) cases were not significantly different. A multivariate Cox model showed a hazard ratio of 2.16 for grouped pN0(i+)/pN1mi versus pN0(i−) (P = 0.0005). Crude cumulative incidence curves for metastatic relapse were also significantly different (Gray's test χ2 = 5.54, P = 0.019). Conclusion: Nanometastases are a strong risk factor for disease-free survival and for metastatic relapse. These findings support the inclusion of procedures for nanometastasis detection in tumor-node-metastasis staging.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-06-0569
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2006
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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