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2. A KRAS variant is a biomarker of poor outcome, platinum chemotherapy resistance and a potential target for therapy in ovarian cancer

Author

Ratner, ES, Keane, FK, Lindner, R, Tassi, RA, Paranjape, T, Glasgow, M, Nallur, S, Deng, Y, Lu, L, Steele, L, Sand, S, Muller, R-U, Bignotti, E, Bellone, S, Boeke, M, Yao, X, Pecorelli, S, Ravaggi, A, Katsaros, D, Zelterman, D, Cristea, MC, Yu, H, Rutherford, TJ, Weitzel, JN, Neuhausen, SL, Schwartz, PE, Slack, FJ, Santin, AD, and Weidhaas, JB

Subjects
Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Cancer, Ovarian Cancer, Biotechnology, Rare Diseases, Women's Health, Clinical Research, Genetics, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, 3' Untranslated Regions, Aged, Antineoplastic Combined Chemotherapy Protocols, BRCA1 Protein, BRCA2 Protein, Biomarkers, Tumor, Carboplatin, Cell Line, Tumor, Cell Survival, Drug Resistance, Neoplasm, Female, Genotype, Humans, Kaplan-Meier Estimate, Middle Aged, Multivariate Analysis, Mutation, Neoplasms, Glandular and Epithelial, Ovarian Neoplasms, Paclitaxel, Polymorphism, Single Nucleotide, Prognosis, Proto-Oncogene Proteins, Proto-Oncogene Proteins p21(ras), RNA Interference, Treatment Outcome, ras Proteins, platinum resistance, KRAS variant, ovarian cancer, outcome, Clinical Sciences, Oncology & Carcinogenesis, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

Germline variants in the 3' untranslated region (3'UTR) of cancer genes disrupting microRNA (miRNA) regulation have recently been associated with cancer risk. A variant in the 3'UTR of the KRAS oncogene, referred to as the KRAS variant, is associated with both cancer risk and altered tumor biology. Here, we test the hypothesis that the KRAS variant can act as a biomarker of outcome in epithelial ovarian cancer (EOC), and investigate the cause of altered outcome in KRAS variant-positive EOC patients. As this variant seems to be associated with tumor biology, we additionally test the hypothesis that this variant can be directly targeted to impact cell survival. EOC patients with complete clinical data were genotyped for the KRAS variant and analyzed for outcome (n=536), response to neoadjuvant chemotherapy (n=125) and platinum resistance (n=306). Outcome was separately analyzed for women with known BRCA mutations (n=79). Gene expression was analyzed on a subset of tumors with available tissue. Cell lines were used to confirm altered sensitivity to chemotherapy associated with the KRAS variant. Finally, the KRAS variant was directly targeted through small-interfering RNA/miRNA oligonucleotides in cell lines and survival was measured. Postmenopausal EOC patients with the KRAS variant were significantly more likely to die of ovarian cancer by multivariate analysis (hazard ratio=1.67, 95% confidence interval: 1.09-2.57, P=0.019, n=279). Perhaps explaining this finding, EOC patients with the KRAS variant were significantly more likely to be platinum resistant (odds ratio=3.18, confidence interval: 1.31-7.72, P=0.0106, n=291). In addition, direct targeting of the KRAS variant led to a significant reduction in EOC cell growth and survival in vitro. These findings confirm the importance of the KRAS variant in EOC, and indicate that the KRAS variant is a biomarker of poor outcome in EOC likely due to platinum resistance. In addition, this study supports the hypothesis that these tumors have continued dependence on such 3'UTR lesions, and that direct targeting may be a viable future treatment approach.

Published
2012

5. Appropriate management of growth hormone deficiency during the age of transition: an Italian Delphi consensus statement

Author

Cannavo, S., Cappa, M., Ferone, D., Isidori, A. M., Loche, S., Salerno, M., Maghnie, M., Aimaretti, G., Ambrosio, M. R., Bellone, S., Caruso, M., Castello, R., Ceccato, F., Cerbone, T., Cherubini, V., de Carlo, E., De Sanctis, L., della Casa, S., Di Somma, C., Faienza, M. F., Gasco, V., Gaudino, R., Giacomozzi, C., Giavoli, C., Guazzarotti, L., Klain, A., Lania, A., Leonardi, D., Longhi, S., Lughetti, L., Maggio, M. C., Wasniewska, G. M., Mameli, C., Mauro, C., Giudice, E. M. D., Palermo, M. C. A., Parpagnoli, M., Persani, L., Pilotta, A., Pozzobon, G., Rochira, V., Rota, F., Sacco, M., Scarcella, S., Scavuzzo, F., Sinisi, A. A., Street, M. E., Tornese, G., Cannavò, S., Cappa, M., Ferone, D., Isidori, A. M., Loche, S., Salerno, M., Maghnie, M., Tornese, G., Cannavò, S, Cappa, M, Ferone, D, Isidori, A M, Loche, S, Salerno, M, Maghnie, M, and Maggio, Maria Cristina

Subjects
growth hormone deficiency, Settore MED/38 - Pediatria Generale E Specialistica, Endocrinology, age of transition, consensus, Italian Delphi consensus statement, Endocrinology, Diabetes and Metabolism, adolescent, growth hormone, transition, Transition age
Abstract

Growth hormone deficiency (GHD) describes the impairment of growth hormone (GH) secretion by the pituitary somatotroph cells. GHD may be congenital, with causes, including genetic alterations and structural brain malformations, or acquired, including midline tumours, cranial irradiation, traumatic brain injury, central nervous system infections and inflammatory conditions. GHD in children is characterised by short stature, delayed bone maturation and abnormalities in substrate metabolism, body composition, physical and psychosocial functioning, all of which improve with recombinant human GH (rhGH) therapy. The diagnosis of GHD is based on clinical signs and symptoms, biochemistry and imaging. Although GH stimulation tests are considered the mainstay of diagnostic investigations, the results must be interpreted with caution owing to the variability in cut-off values and reproducibility. Transition refers to the physical and psychosocial changes in adolescent patients during the mid-teens to late teens (usually 15–18 years of age) until about 6–7 years after achievement of adult height. During the transition age, only a small residual capacity of longitudinal growth is left, but body maturity is not yet complete. Discontinuation of rhGH treatment at the end of longitudinal growth in adolescents with permanent GHD is associated with decreased muscle strength and mass, increased body fat (mainly in the abdomen), the arrest or reversal of muscle mass and bone mass density (BMD) gain and lipid profile deterioration. For these reasons, patients whose GHD persists during the transition age need to continue rhGH treatment to obtain full somatic maturation and normalisation of body composition, BMD, quality of life (QoL) and lipid metabolism. There is some evidence that rhGH treatment during transition may result in improved growth and bone health, as well as a better prognosis for metabolic and cardiovascular risks in the long term. Since these patients need to continue treatment to complete their body development, a multidisciplinary approach is required to ensure continuity of care during the transfer from paediatric to adult endocrinology services. Guidelines for the diagnosis and treatment of young adults with GHD have been published by the American Association of Clinical Endocrinologists (AACE), American College of Endocrinology (ACE), Endocrine Society, European Society of Paediatric Endocrinology (ESPE), Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society and Endocrine Society of Australia. However, clinical practice lacks uniformity in terms of diagnosis and treatment of transition-age patients, the impact of GH replacement during transition has not been adequately assessed in randomised clinical trials (RCTs), validated questionnaires to assess QoL in patients on rhGH treatment in the transition period are not available and there is still uncertainty about the multidisciplinary approach during transition [8]. Hence, a structured transition protocol is essential to establish the best practice for transitioning adolescents with GHD to adult care. A study in Italy in 2015 identified a low level of awareness of these issues in clinical practice and real-world gaps in the management of GHD patients during transition. To address these gaps and assist endocrinologists (adult and paediatric) in the diagnosis and treatment of GHD in transition-age patients, a Delphi consensus process was undertaken to develop clinically relevant recommendations. The current consensus statements address the diagnosis of GHD, benefits of treatment, monitoring and management of transition-age patients with GHD, along with treatment adherence and safety concerns.

Published
2023

9. Updated Recommendations on Cardiovascular Prevention in 2022: An Executive Document of the Italian Society of Cardiovascular Prevention

Author

Volpe, M., Gallo, G., Modena, M. G., Ferri, C., Desideri, G., Tocci, G., Bellone, S., Bertolotti, M., Biffi, A., Consoli, A., Corsini, A., Nati, G., Pirro, M., Rubattu, S., Trimarco, B., de Kreutzenberg, S. V., and Volpe, R.

Subjects
Cardiovascular prevention, High blood pressure, Antiplatelet treatment, COVID-19, Diabetes, Hypercholesterolemia, Obesity
Published
2022

18. Prevention Italy 2021 - An update of the 2018 Consensus document and recommendations for the prevention of cardiovascular disease in Italy

Author

Battistoni, A., Gallo, G., Aragona, C. O., Barchiesi, F., Basolo, A., Bellone, S., Bellotti, P., Bertolotti, M., Bianco, A., Biffi, A., Borghi, C., Cicero, A. F. G., Consoli, A., Corsini, A., Desideri, G., Di Giacinto, B., Fernando, F., Ferri, C., Galiuto, L., Grassi, D., Grassi, G., Icardi, G., Indolfi, C., Lodi, E., Modena, M. G., Muiesan, M. L., Nati, G., Orsi, A., Palermi, S., Parati, G., Passantino, A., Patelli, A., Pelliccia, A., Pengo, M., Filardi, P. P., Perseghin, G., Pirro, M., Pontremoli, R., Rengo, G., Ricotti, R., Rizzoni, D., Rocca, B., Rotella, C., Rubattu, S., Salvetti, G., Sciacqua, A., Serdoz, A., Sirico, F., Squeo, M. R., Tocci, G., Trimarco, B., Vigili de Kreutzenberg, S., Volpe, R., and Volpe, M.

Subjects
Consensus, Italy, Humans, Risk Assessment, Risk Factors, Cardiovascular Diseases
Published
2021

20. A phase II evaluation of pembrolizumab in recurrent microsatellite instability-high (MSI-H) endometrial cancer patients with Lynch-like versus MLH-1 methylated characteristics (NCT02899793)

Author

Bellone, S., primary, Roque, D.M., additional, Siegel, E.R., additional, Buza, N., additional, Hui, P., additional, Bonazzoli, E., additional, Guglielmi, A., additional, Zammataro, L., additional, Nagarkatti, N., additional, Zaidi, S., additional, Lee, J., additional, Silasi, D.-A., additional, Huang, G.S., additional, Andikyan, V., additional, Damast, S., additional, Clark, M., additional, Azodi, M., additional, Schwartz, P.E., additional, Tymon-Rosario, J., additional, Harold, J., additional, Mauricio, D., additional, Zeybek, B., additional, Menderes, G., additional, Altwerger, G., additional, Ratner, E., additional, Alexandrov, L.B., additional, Iwasaki, A., additional, Kong, Y., additional, Song, E., additional, Dong, W., additional, Elvin, J., additional, Choi, J., additional, and Santin, A.D., additional

Published
2021
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23. Prevention Italy 2021 - An update of the 2018 Consensus document and recommendations for the prevention of cardiovascular disease in Italy [Prevenzione Italia 2021 Un update del Documento di consenso e raccomandazioni per la prevenzione cardiovascolare in Italia]

Author

Battistoni, A, Gallo, G, Aragona, C, Barchiesi, F, Basolo, A, Bellone, S, Bellotti, P, Bertolotti, M, Bianco, A, Biffi, A, Borghi, C, Cicero, A, Consoli, A, Corsini, A, Desideri, G, Di Giacinto, B, Fernando, F, Ferri, C, Galiuto, L, Grassi, D, Grassi, G, Icardi, G, Indolfi, C, Lodi, E, Modena, M, Muiesan, M, Nati, G, Orsi, A, Palermi, S, Parati, G, Passantino, A, Patelli, A, Pelliccia, A, Pengo, M, Filardi, P, Perseghin, G, Pirro, M, Pontremoli, R, Rengo, G, Ricotti, R, Rizzoni, D, Rocca, B, Rotella, C, Rubattu, S, Salvetti, G, Sciacqua, A, Serdoz, A, Sirico, F, Squeo, M, Tocci, G, Trimarco, B, Vigili de Kreutzenberg, S, Volpe, R, Volpe, M, Battistoni, Allegra, Gallo, Giovanna, Aragona, Caterina Oriana, Barchiesi, Fabio, Basolo, Alessio, Bellone, Simonetta, Bellotti, Paolo, Bertolotti, Marco, Bianco, Andrea, Biffi, Alessandro, Borghi, Claudio, Cicero, Arrigo Francesco Giuseppe, Consoli, Agostino, Corsini, Alberto, Desideri, Giovambattista, Di Giacinto, Barbara, Fernando, Fredrik, Ferri, Claudio, Galiuto, Leonarda, Grassi, Davide, Grassi, Guido, Icardi, Giancarlo, Indolfi, Ciro, Lodi, Elisa, Modena, Maria Grazia, Muiesan, Maria Lorenza, Nati, Giulio, Orsi, Andrea, Palermi, Stefano, Parati, Gianfranco, Passantino, Andrea, Patelli, Alessandra, Pelliccia, Antonio, Pengo, Martino, Filardi, Pasquale Perrone, Perseghin, Gianluca, Pirro, Matteo, Pontremoli, Roberto, Rengo, Giuseppe, Ricotti, Roberta, Rizzoni, Damiano, Rocca, Bianca, Rotella, Carlo, Rubattu, Speranza, Salvetti, Guido, Sciacqua, Angela, Serdoz, Andrea, Sirico, Felice, Squeo, Maria Rosaria, Tocci, Giuliano, Trimarco, Bruno, Vigili de Kreutzenberg, Saula, Volpe, Roberto, Volpe, Massimo, Battistoni, A, Gallo, G, Aragona, C, Barchiesi, F, Basolo, A, Bellone, S, Bellotti, P, Bertolotti, M, Bianco, A, Biffi, A, Borghi, C, Cicero, A, Consoli, A, Corsini, A, Desideri, G, Di Giacinto, B, Fernando, F, Ferri, C, Galiuto, L, Grassi, D, Grassi, G, Icardi, G, Indolfi, C, Lodi, E, Modena, M, Muiesan, M, Nati, G, Orsi, A, Palermi, S, Parati, G, Passantino, A, Patelli, A, Pelliccia, A, Pengo, M, Filardi, P, Perseghin, G, Pirro, M, Pontremoli, R, Rengo, G, Ricotti, R, Rizzoni, D, Rocca, B, Rotella, C, Rubattu, S, Salvetti, G, Sciacqua, A, Serdoz, A, Sirico, F, Squeo, M, Tocci, G, Trimarco, B, Vigili de Kreutzenberg, S, Volpe, R, Volpe, M, Battistoni, Allegra, Gallo, Giovanna, Aragona, Caterina Oriana, Barchiesi, Fabio, Basolo, Alessio, Bellone, Simonetta, Bellotti, Paolo, Bertolotti, Marco, Bianco, Andrea, Biffi, Alessandro, Borghi, Claudio, Cicero, Arrigo Francesco Giuseppe, Consoli, Agostino, Corsini, Alberto, Desideri, Giovambattista, Di Giacinto, Barbara, Fernando, Fredrik, Ferri, Claudio, Galiuto, Leonarda, Grassi, Davide, Grassi, Guido, Icardi, Giancarlo, Indolfi, Ciro, Lodi, Elisa, Modena, Maria Grazia, Muiesan, Maria Lorenza, Nati, Giulio, Orsi, Andrea, Palermi, Stefano, Parati, Gianfranco, Passantino, Andrea, Patelli, Alessandra, Pelliccia, Antonio, Pengo, Martino, Filardi, Pasquale Perrone, Perseghin, Gianluca, Pirro, Matteo, Pontremoli, Roberto, Rengo, Giuseppe, Ricotti, Roberta, Rizzoni, Damiano, Rocca, Bianca, Rotella, Carlo, Rubattu, Speranza, Salvetti, Guido, Sciacqua, Angela, Serdoz, Andrea, Sirico, Felice, Squeo, Maria Rosaria, Tocci, Giuliano, Trimarco, Bruno, Vigili de Kreutzenberg, Saula, Volpe, Roberto, and Volpe, Massimo

Published
2021

35. The PARP inhibitor niraparib demonstrates preclinical activity against HRD-deficient carcinosarcomas

Author

Tymon-Rosario, J.R., primary, Manara, P., additional, Manzano, A., additional, Zammataro, L., additional, Bonazzoli, E., additional, Perrone, E., additional, Bellone, S., additional, Alexandrov, L.B., additional, Zeybek, B., additional, Han, C., additional, Altwerger, G., additional, Menderes, G., additional, Ratner, E.S., additional, Silasi, D.A., additional, Huang, G.S., additional, Azodi, M., additional, Schwartz, P.E., additional, and Santin, A.D., additional

Published
2020
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36. Randomized phase II trial of carboplatin-paclitaxel compared to carboplatin-paclitaxel-trastuzumab in advanced or recurrent uterine serous carcinomas that overexpress HER2/Neu (NCT01367002): Updated survival analysis

Author

Fader, A.N., primary, Roque, D.M., additional, Siegel, E.R., additional, Buza, N., additional, Hui, P., additional, Havrilesky, L.J., additional, Secord, A.A., additional, O'Malley, D.M., additional, Backes, F.J., additional, Nevadunsky, N.S., additional, Chambers, S.K., additional, Edraki, B., additional, Celano, P., additional, Bellone, S., additional, Azodi, M., additional, Ratner, E.S., additional, Litkouhi, B., additional, Silasi, D.A., additional, Schwartz, P.E., additional, and Santin, A.D., additional

Published
2020
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37. Cervical carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab-govitecan

Author

Zeybek, B., primary, Manzano, A., additional, Bianchi, A., additional, Bonazzoli, E., additional, Bellone, S., additional, Buza, N., additional, Hui, P., additional, Lopez, S., additional, Perrone, E., additional, Manara, P., additional, Zammataro, L., additional, Altwerger, G., additional, Han, C., additional, Tymon-Rosario, J.R., additional, Menderes, G., additional, Ratner, E.S., additional, Silasi, D.A., additional, Huang, G.S., additional, Azodi, M., additional, Schwartz, P.E., additional, and Santin, A.D., additional

Published
2020
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38. Final height in GH-deficient paediatric patients: a nationwide experience

Author

Zucchini, S, Lonero, A, Bellone, S, Bozzola, M, Cassio, A, Faienza, Mf, Giacomozzi, C, Grandone, A, Guzzetti, C, Iughetti, L, Parpagnoli, M, Salerno, M, Street, Me, Tornese, G, Wasniewska, M, Delvecchio, M., Zucchini, S, Lonero, A, Bellone, S, Bozzola, M, Cassio, A, Faienza, Mf, Giacomozzi, C, Grandone, A, Guzzetti, C, Iughetti, L, Parpagnoli, M, Salerno, M, Street, Me, Tornese, G, Wasniewska, M, and Delvecchio, M.

Subjects
growth hormone deficiency, GH, final height, GHD, growth hormone deficiency, final height
Abstract

N/A

Published
2019

39. Consensus document and recommendations for the prevention of cardiovascular disease in Italy - 2018 [Consensus document and recommendations for the prevention of cardiovascular disease in Italy - 2018]

Author

Volpe, M, Tocci, G, Accettura, D, Battistoni, A, Costanzo, G, Rubattu, S, Volpe, R, Bellone, S, Ricotti, R, Bellotti, P, Bertolotti, M, Modena, M, Borghi, C, Casasco, M, Rizzoni, D, Consoli, A, Coppini, R, Galanti, G, Lombardi, N, Modesti, P, Mugelli, A, Rotella, C, Corsini, A, Parati, G, Perseghin, G, Desideri, G, Ferri, C, Giada, F, Icardi, G, Orsi, A, Monti, G, Pedretti, R, Pirro, M, Salvetti, G, Sarto, P, Tassinari, F, Trimarco, B, de Kreutzenberg, S, Volpe M., Tocci G., Accettura D., Battistoni A., Costanzo G., Rubattu S., Volpe R., Bellone S., Ricotti R., Bellotti P., Bertolotti M., Modena M. G., Borghi C., Casasco M., Rizzoni D., Consoli A., Coppini R., Galanti G., Lombardi N., Modesti P. A., Mugelli A., Rotella C., Corsini A., Parati G., Perseghin G., Desideri G., Ferri C., Giada F., Icardi G., Orsi A., Monti G., Pedretti R. F. E., Pirro M., Salvetti G., Sarto P., Tassinari F., Trimarco B., de Kreutzenberg S. V., Volpe, M, Tocci, G, Accettura, D, Battistoni, A, Costanzo, G, Rubattu, S, Volpe, R, Bellone, S, Ricotti, R, Bellotti, P, Bertolotti, M, Modena, M, Borghi, C, Casasco, M, Rizzoni, D, Consoli, A, Coppini, R, Galanti, G, Lombardi, N, Modesti, P, Mugelli, A, Rotella, C, Corsini, A, Parati, G, Perseghin, G, Desideri, G, Ferri, C, Giada, F, Icardi, G, Orsi, A, Monti, G, Pedretti, R, Pirro, M, Salvetti, G, Sarto, P, Tassinari, F, Trimarco, B, de Kreutzenberg, S, Volpe M., Tocci G., Accettura D., Battistoni A., Costanzo G., Rubattu S., Volpe R., Bellone S., Ricotti R., Bellotti P., Bertolotti M., Modena M. G., Borghi C., Casasco M., Rizzoni D., Consoli A., Coppini R., Galanti G., Lombardi N., Modesti P. A., Mugelli A., Rotella C., Corsini A., Parati G., Perseghin G., Desideri G., Ferri C., Giada F., Icardi G., Orsi A., Monti G., Pedretti R. F. E., Pirro M., Salvetti G., Sarto P., Tassinari F., Trimarco B., and de Kreutzenberg S. V.

Abstract

Cardiovascular prevention represents a cornerstone of modern strategies to reduce the burden of cardiovascular disease. It is of key importance to prevent cardiovascular diseases and associated events, not only to reduce morbidity and mortality, but also to increase the years of wellness in the aging population and to make the growing socio-economic burden imposed by cardiovascular events more sustainable. The current approach to prevention is based on an integrated use of effective lifestyle measures and, whenever appropriate, of antihypertensive and antidiabetic drugs, lipid-lowering agents and antiplatelet drugs. Given that population characteristics, in terms of ethnicity, demography and lifestyle habits, and healthcare system organizations differ among countries, international guidelines are not always applicable to specific countries and, often, are difficult to translate into daily clinical practice. In order to afford the specific features of Italy, 10 Scientific Societies and Research Institutions, mostly involved in preventive strategies, contributed to the present Italian consensus document, which includes brief, practical recommendations to support the preventive actions within the physician community and the general practice setting.

Published
2018

47. Sacituzumab govitecan, an antibody-drug conjugate targeting trophoblast cell-surface antigen 2, shows cytotoxic activity against poorly differentiated endometrial adenocarcinomas in vitro and in vivo

Author

Perrone, Elisabetta, Manara, P., Lopez, S., Bellone, S., Bonazzoli, E., Manzano, A., Zammataro, L., Bianchi, A., Zeybek, B., Buza, N., Tymon-Rosario, J., Altwerger, G., Han, C., Menderes, G., Huang, G. S., Ratner, E., Silasi, D. -A., Azodi, M., Hui, P., Schwartz, P. E., Scambia, Giovanni, Santin, A. D., Perrone E., Scambia G. (ORCID:0000-0003-2758-1063), Perrone, Elisabetta, Manara, P., Lopez, S., Bellone, S., Bonazzoli, E., Manzano, A., Zammataro, L., Bianchi, A., Zeybek, B., Buza, N., Tymon-Rosario, J., Altwerger, G., Han, C., Menderes, G., Huang, G. S., Ratner, E., Silasi, D. -A., Azodi, M., Hui, P., Schwartz, P. E., Scambia, Giovanni, Santin, A. D., Perrone E., and Scambia G. (ORCID:0000-0003-2758-1063)

Abstract

Endometrial cancer is the most common gynecologic malignancy in developed countries. The antibody–drug conjugate (ADC) sacituzumab govitecan (SG) targets trophoblast cell-surface antigen-2 (Trop-2) – a cell-surface glycoprotein highly expressed in many epithelial tumors – and delivers the active metabolite of irinotecan SN-38 to Trop-2-positive tumor cells. We evaluated Trop-2 expression in endometrial endometrioid carcinoma (EC) tissues and the activity of SG against primary poorly differentiated EC cell lines and xenografts. Trop-2 expression was assessed in 143 formalin-fixed–paraffin-embedded tumors and seven primary tumor cell lines by immunohistochemistry and flow cytometry, respectively. Cell viability of primary tumor cell lines was assessed following exposure to SG, or control antibodies. Antibody-dependent cell cytotoxicity (ADCC) against Trop-2-positive and Trop-2-negative EC cell lines was measured in vitro using 4-h chromium release assays. A Trop-2-positive EC xenograft model was used to determine the in vivo activity of SG. Moderate-to-strong staining was detected in 84% (120/143) of EC samples, whereas 43% (3/7) of the primary EC cell lines tested overexpressed Trop-2. EC cell lines overexpressing Trop-2 were significantly more sensitive to SG compared to control ADC (P = 0.014 and P = 0.005). Both SG and the unconjugated parental antibody hRS7 mediated high ADCC against Trop-2-positive cell lines. Moreover, SG induced significant bystander killing of Trop-2-negative tumors cocultured with Trop-2-positive tumors. In the xenograft model, intravenous administration of SG twice weekly for three weeks was well tolerated and demonstrated impressive tumor growth inhibition against poorly differentiated, chemotherapy-resistant EC xenografts (P = 0.011). In summary, SG is a novel ADC with remarkable preclinical activity against poorly differentiated EC cell lines overexpressing Trop-2. These findings warrant future cli

Published
2020

48. Preclinical Activity of Sacituzumab Govitecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2 (Trop-2) Linked to the Active Metabolite of Irinotecan (SN-38), in Ovarian Cancer

Author

Perrone, Elisabetta, Lopez, S., Zeybek, B., Bellone, S., Bonazzoli, E., Pelligra, Silvia, Zammataro, L., Manzano, A., Manara, P., Bianchi, A., Buza, N., Tymon-Rosario, J., Altwerger, G., Han, C., Menderes, G., Ratner, E., Silasi, D. -A., Azodi, M., Hui, P., Schwartz, P. E., Scambia, Giovanni, Santin, A. D., Perrone E., Pelligra S., Scambia G. (ORCID:0000-0003-2758-1063), Perrone, Elisabetta, Lopez, S., Zeybek, B., Bellone, S., Bonazzoli, E., Pelligra, Silvia, Zammataro, L., Manzano, A., Manara, P., Bianchi, A., Buza, N., Tymon-Rosario, J., Altwerger, G., Han, C., Menderes, G., Ratner, E., Silasi, D. -A., Azodi, M., Hui, P., Schwartz, P. E., Scambia, Giovanni, Santin, A. D., Perrone E., Pelligra S., and Scambia G. (ORCID:0000-0003-2758-1063)

Abstract

Background: Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. Sacituzumab govitecan (SG) is a novel antibody-drug-conjugate (ADC) targeting trophoblast-antigen-2 (Trop-2), a cell surface glycoprotein highly expressed in many epithelial tumors, to deliver SN-38, the active metabolite of irinotecan. This study aimed to evaluate Trop-2 expression in EOC tissues and the preclinical activity of SG against primary EOC cell lines and xenografts. Methods: Trop-2 expression was assessed in 90 formalin-fixed-paraffin-embedded tumors and nine primary tumor cell lines by immunohistochemistry (IHC) and flow cytometry, respectively. Trop-2 expression and cell viability after exposure to SG in primary tumor cell lines, non-targeting control ADC, and SG-parental antibody hRS7 were evaluated using flow-cytometry-based-assays. Antibody-dependent-cell-cytotoxicity (ADCC) against Trop-2+ and Trop-2– EOC cell lines was tested in vitro using 4 h Chromium-release-assays. In vivo activity of SG was evaluated against Trop-2+ EOC xenografts. Results: Moderate-to-strong staining was seen in 47% (42/90) of ovarian tumors by IHC while 89% (8/9) of the primary EOC cell lines overexpressed Trop-2 by flow cytometry. EOC Trop-2+ were significantly more sensitive to SG compared to control ADC (p < 0.05). Both SG and hRS7 mediated high ADCC activity against Trop-2+ cell lines. SG also induced significant bystander killing of Trop-2– tumor cells admixed with Trop-2+ EOC cells. In in vivo experiments SG treatment demonstrated impressive anti-tumor activity against chemotherapy-resistant EOC xenografts. Conclusion: SG demonstrates remarkable preclinical activity against biologically aggressive and chemotherapy-resistant EOC cell lines and a significant bystander effect against EOC cell lines with heterogenous Trop-2 expression. Clinical trials are warranted.

Published
2020

49. Selection of HER2/NEU negative tumor cells as a mechanism of resistance to trastuzumab in uterine serous carcinoma

Author

Pelligra, Silvia, Buza, N., Hui, P., Bellone, S., Zeybek, B., Ratner, E., Schwartz, P. E., Scambia, Giovanni, Santin, A. D., Pelligra S., Scambia G. (ORCID:0000-0003-2758-1063), Pelligra, Silvia, Buza, N., Hui, P., Bellone, S., Zeybek, B., Ratner, E., Schwartz, P. E., Scambia, Giovanni, Santin, A. D., Pelligra S., and Scambia G. (ORCID:0000-0003-2758-1063)

Abstract

Background: Uterine serous carcinoma (USC) is an aggressive variant of endometrial cancer overexpressing HER2/neu in about 30% of cases. Trastuzumab, a humanized monoclonal antibody targeting Her2/Neu, in combination with carboplatin/paclitaxel, is considered the preferred regimen for the treatment of advanced or recurrent HER2/Neu+ USC per NCCN guidelines. Case: We describe two USC patients with overexpression of HER2/neu at 2+/3+ level by immunohistochemistry and c-erbB2 gene amplification by fluorescence in situ hybridization (FISH) assay that, after an initial clinical response to trastuzumab, developed resistance/progression. Post-treatment biopsy (collected at the time of clinical progression on trastuzumab) demonstrated loss of HER2/neu overexpression in the recurrent/progressing tumor cells in both patients. Conclusion: Selection of HER2/NEU negative tumor cells may represent a major mechanism of resistance to trastuzumab in USC patients.

Published
2020

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