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5. BET bromodomain inhibitor birabresib in mantle cell lymphoma: in vivo activity and identification of novel combinations to overcome adaptive resistance

Author

Tarantelli, Chiara, Bernasconi, Elena, Gaudio, Eugenio, Cascione, Luciano, Restelli, Valentina, Arribas, Alberto Jesus, Spriano, Filippo, Rinaldi, Andrea, Mensah, Afua Adjeiwaa, Kwee, Ivo, Ponzoni, Maurilio, Zucca, Emanuele, Carrassa, Laura, Riveiro, Maria E., Rezai, Keyvan, Stathis, Anastasios, Cvitkovic, Esteban, and Bertoni, Francesco

Published
2018
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6. Molecular mechanisms regulating the G2 checkpoint induced after DNA damage

Author

Carrassa, Laura

Subjects
616.994
Abstract

The checkpoint kinase (chk) 1 is an essential component of the DNA damage checkpoint acting as the effector of the DNA damage to block the cell cycle at the G2-M transition. The studies reported here were aimed at elucidating the molecular mechanisms regulating the G2 checkpoint after DNA damage and at investigating Chk1 as a potential therapeutic target for new cancer treatments. The promoter region of the human Chk1 gene was at first isolated and characterized. It was possible to show a p53 dependent downregulation of the Chk1 gene. The transcriptional factor E2F1 was also found to have a role in modulating Chk1 promoter activity. To further understand the interplay between p53 and Chk1 in the G2 checkpoint, the cellular response to anticancer treatments in isogenic cellular systems differing in the expression of Chk1 and p53 was studied. The expression of Chk1 was downregulated by siRNA, in the HCT-116 colon carcinoma cell line and in its isogenic systems lacking either p53 or p21. The inhibition of Chk1 in p21-/- and p53-/- cell lines caused a greater abrogation of the G2 block and a greater sensitization to anticancer treatments than in the parental cells with an intact G1 checkpoint. Tetracycline-inducible expressing Chk1 siRNA clones have been obtained in HCT-116 wt and p53 deficient cells and have been transplanted in nude mice. Experiments are undergoing to verify the downregulation of Chk1 upon addition of tetracycline in mice drinking water. The last part of my thesis focused on the investigation of the physiological role of Chk1 in cancer somatic cell lines. The understanding of this aspect appears particularly important as Chk1 has been proposed to be a potential drug target for anticancer therapy. The effects of the lack of Chk1 by siRNA transfection were studied in different human somatic cell lines. The downregulation of Chk1 by siRNA in the HCT-116 isogenic cellular systems did not alter cell growth or compromise survival of these cells independently from the status of p53 and p21. On the other hand, in different cell lines, like U20S and HeLa, an effect in cell growth, and in the cell phenotype was observed. These data suggest that the lack of Chk1 may have different consequences depending on the intrinsic genetic background of the cell line studied.

Published
2006
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9. Combined Inhibition of Smoothened and the DNA Damage Checkpoint WEE1 Exerts Antitumor Activity in Cholangiocarcinoma

Author

Anichini, Giulia, Raggi, Chiara, Pastore, Mirella, Carrassa, Laura, Maresca, Luisa, Crivaro, Enrica, Lottini, Tiziano, Duwe, Lea, Andersen, Jesper B., Tofani, Lorenzo, Di Tommaso, Luca, Banales, Jesus M., Arcangeli, Annarosa, Marra, Fabio, Stecca, Barbara, Anichini, Giulia, Raggi, Chiara, Pastore, Mirella, Carrassa, Laura, Maresca, Luisa, Crivaro, Enrica, Lottini, Tiziano, Duwe, Lea, Andersen, Jesper B., Tofani, Lorenzo, Di Tommaso, Luca, Banales, Jesus M., Arcangeli, Annarosa, Marra, Fabio, and Stecca, Barbara

Abstract

Cholangiocarcinoma (CCA) is characterized by resistance to chemotherapy and a poor prognosis. Therefore, treatments that can effectively suppress tumor growth are urgently needed. Aberrant activation of hedgehog (HH) signaling has been implicated in several cancers, including those of the hepatobiliary tract. However, the role of HH signaling in intrahepatic CCA (iCCA) has not been completely elucidated. In this study, we addressed the function of the main transducer Smoothened (SMO) and the transcription factors (TFs) GLI1 and GLI2 in iCCA. In addition, we evaluated the potential benefits of the combined inhibition of SMO and the DNA damage kinase WEE1. Transcriptomic analysis of 152 human iCCA samples showed increased expression of GLI1, GLI2, and Patched 1 (PTCH1) in tumor tissues compared with nontumor tissues. Genetic silencing of SMO, GLI1, and GLI2 inhibited the growth, survival, invasiveness, and self-renewal of iCCA cells. Pharmacologic inhibition of SMO reduced iCCA growth and viability in vitro, by inducing double-strand break DNA damage, leading to mitotic arrest and apoptotic cell death. Importantly, SMO inhibition resulted in the activation of the G2–M checkpoint and DNA damage kinase WEE1, increasing the vulnerability to WEE1 inhibition. Hence, the combination of MRT-92 with the WEE1 inhibitor AZD-1775 showed increased antitumor activity in vitro and in iCCA xenografts compared with single treatments. These data indicate that combined inhibition of SMO and WEE1 reduces tumor burden and may represent a strategy for the clinical development of novel therapeutic approaches in iCCA., Cholangiocarcinoma (CCA) is characterized by resistance to chemotherapy and a poor prognosis. Therefore, treatments that can effectively suppress tumor growth are urgently needed. Aberrant activation of hedgehog (HH) signaling has been implicated in several cancers, including those of the hepatobiliary tract. However, the role of HH signaling in intrahepatic CCA (iCCA) has not been completely elucidated. In this study, we addressed the function of the main transducer Smoothened (SMO) and the transcription factors (TFs) GLI1 and GLI2 in iCCA. In addition, we evaluated the potential benefits of the combined inhibition of SMO and the DNA damage kinase WEE1. Transcriptomic analysis of 152 human iCCA samples showed increased expression of GLI1, GLI2, and Patched 1 (PTCH1) in tumor tissues compared with nontumor tissues. Genetic silencing of SMO, GLI1, and GLI2 inhibited the growth, survival, invasiveness, and self-renewal of iCCA cells. Pharmacologic inhibition of SMO reduced iCCA growth and viability in vitro, by inducing double-strand break DNA damage, leading to mitotic arrest and apoptotic cell death. Importantly, SMO inhibition resulted in the activation of the G2-M checkpoint and DNA damage kinase WEE1, increasing the vulnerability to WEE1 inhibition. Hence, the combination of MRT-92 with the WEE1 inhibitor AZD-1775 showed increased antitumor activity in vitro and in iCCA xenografts compared with single treatments. These data indicate that combined inhibition of SMO and WEE1 reduces tumor burden and may represent a strategy for the clinical development of novel therapeutic approaches in iCCA.

Published
2023

11. Supplementary Data from Combined Inhibition of Smoothened and the DNA Damage Checkpoint WEE1 Exerts Antitumor Activity in Cholangiocarcinoma

Author

Anichini, Giulia, primary, Raggi, Chiara, primary, Pastore, Mirella, primary, Carrassa, Laura, primary, Maresca, Luisa, primary, Crivaro, Enrica, primary, Lottini, Tiziano, primary, Duwe, Lea, primary, Andersen, Jesper B., primary, Tofani, Lorenzo, primary, Di Tommaso, Luca, primary, Banales, Jesus M., primary, Arcangeli, Annarosa, primary, Marra, Fabio, primary, and Stecca, Barbara, primary

Published
2023
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16. Data from Combined Inhibition of Smoothened and the DNA Damage Checkpoint WEE1 Exerts Antitumor Activity in Cholangiocarcinoma

Author

Anichini, Giulia, primary, Raggi, Chiara, primary, Pastore, Mirella, primary, Carrassa, Laura, primary, Maresca, Luisa, primary, Crivaro, Enrica, primary, Lottini, Tiziano, primary, Duwe, Lea, primary, Andersen, Jesper B., primary, Tofani, Lorenzo, primary, Di Tommaso, Luca, primary, Banales, Jesus M., primary, Arcangeli, Annarosa, primary, Marra, Fabio, primary, and Stecca, Barbara, primary

Published
2023
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18. Table S5 from The ETS Inhibitors YK-4-279 and TK-216 Are Novel Antilymphoma Agents

Author

Spriano, Filippo, primary, Chung, Elaine Yee Lin, primary, Gaudio, Eugenio, primary, Tarantelli, Chiara, primary, Cascione, Luciano, primary, Napoli, Sara, primary, Jessen, Katti, primary, Carrassa, Laura, primary, Priebe, Valdemar, primary, Sartori, Giulio, primary, Graham, Garrett, primary, Selvanathan, Saravana P., primary, Cavalli, Andrea, primary, Rinaldi, Andrea, primary, Kwee, Ivo, primary, Testoni, Monica, primary, Genini, Davide, primary, Ye, B. Hilda, primary, Zucca, Emanuele, primary, Stathis, Anastasios, primary, Lannutti, Brian, primary, Toretsky, Jeffrey A., primary, and Bertoni, Francesco, primary

Published
2023
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19. Table S2 from PQR309 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in Lymphomas as a Single Agent and in Combination Therapy

Author

Tarantelli, Chiara, primary, Gaudio, Eugenio, primary, Arribas, Alberto J., primary, Kwee, Ivo, primary, Hillmann, Petra, primary, Rinaldi, Andrea, primary, Cascione, Luciano, primary, Spriano, Filippo, primary, Bernasconi, Elena, primary, Guidetti, Francesca, primary, Carrassa, Laura, primary, Pittau, Roberta Bordone, primary, Beaufils, Florent, primary, Ritschard, Reto, primary, Rageot, Denise, primary, Sele, Alexander, primary, Dossena, Barbara, primary, Rossi, Francesca Maria, primary, Zucchetto, Antonella, primary, Taborelli, Monica, primary, Gattei, Valter, primary, Rossi, Davide, primary, Stathis, Anastasios, primary, Stussi, Georg, primary, Broggini, Massimo, primary, Wymann, Matthias P., primary, Wicki, Andreas, primary, Zucca, Emanuele, primary, Cmiljanovic, Vladimir, primary, Fabbro, Doriano, primary, and Bertoni, Francesco, primary

Published
2023
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20. Figure S3 from Combination of PPARγ Agonist Pioglitazone and Trabectedin Induce Adipocyte Differentiation to Overcome Trabectedin Resistance in Myxoid Liposarcomas

Author

Frapolli, Roberta, primary, Bello, Ezia, primary, Ponzo, Marianna, primary, Craparotta, Ilaria, primary, Mannarino, Laura, primary, Ballabio, Sara, primary, Marchini, Sergio, primary, Carrassa, Laura, primary, Ubezio, Paolo, primary, Porcu, Luca, primary, Brich, Silvia, primary, Sanfilippo, Roberta, primary, Casali, Paolo Giovanni, primary, Gronchi, Alessandro, primary, Pilotti, Silvana, primary, and D'Incalci, Maurizio, primary

Published
2023
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21. Supplementary figures, table legends, Table S1, S9 from PQR309 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in Lymphomas as a Single Agent and in Combination Therapy

Author

Tarantelli, Chiara, primary, Gaudio, Eugenio, primary, Arribas, Alberto J., primary, Kwee, Ivo, primary, Hillmann, Petra, primary, Rinaldi, Andrea, primary, Cascione, Luciano, primary, Spriano, Filippo, primary, Bernasconi, Elena, primary, Guidetti, Francesca, primary, Carrassa, Laura, primary, Pittau, Roberta Bordone, primary, Beaufils, Florent, primary, Ritschard, Reto, primary, Rageot, Denise, primary, Sele, Alexander, primary, Dossena, Barbara, primary, Rossi, Francesca Maria, primary, Zucchetto, Antonella, primary, Taborelli, Monica, primary, Gattei, Valter, primary, Rossi, Davide, primary, Stathis, Anastasios, primary, Stussi, Georg, primary, Broggini, Massimo, primary, Wymann, Matthias P., primary, Wicki, Andreas, primary, Zucca, Emanuele, primary, Cmiljanovic, Vladimir, primary, Fabbro, Doriano, primary, and Bertoni, Francesco, primary

Published
2023
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23. Combined Inhibition of Smoothened and the DNA Damage Checkpoint WEE1 Exerts Antitumor Activity in Cholangiocarcinoma

Author

Anichini, Giulia, primary, Raggi, Chiara, additional, Pastore, Mirella, additional, Carrassa, Laura, additional, Maresca, Luisa, additional, Crivaro, Enrica, additional, Lottini, Tiziano, additional, Duwe, Lea, additional, Andersen, Jesper B., additional, Tofani, Lorenzo, additional, Di Tommaso, Luca, additional, Banales, Jesus M., additional, Arcangeli, Annarosa, additional, Marra, Fabio, additional, and Stecca, Barbara, additional

Published
2023
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24. Targeting the DNA damage response for patients with lymphoma: preclinical and clinical evidences

Author

Carrassa, Laura, Colombo, Ilaria, Damia, Giovanna, Bertoni, Francesco, Carrassa, Laura, Colombo, Ilaria, Damia, Giovanna, and Bertoni, Francesco

Abstract

The DNA damage response (DDR) is a well-coordinated cellular network activated by DNA damage. The unravelling of the key players in DDR, their specific inactivation in different tumor types and the synthesis of specific chemical inhibitors of DDR represent a new hot topic in cancer therapy. In this article, we will review the importance of DDR in lymphoma development and how this can be exploited therapeutically. Specifically, we will focus on CHK1, WEE1, ATR, DNA-PK and PARP inhibitors, for which preclinical data as single agents or in combination has been accumulating, fostering their clinical development. The few available clinical data on these inhibitors will also be discussed.

Published
2022

29. Correction: Combination of PPARγ Agonist Pioglitazone and Trabectedin Induce Adipocyte Differentiation to Overcome Trabectedin Resistance in Myxoid Liposarcomas

Author

Frapolli, Roberta, primary, Bello, Ezia, additional, Ponzo, Marianna, additional, Craparotta, Ilaria, additional, Mannarino, Laura, additional, Ballabio, Sara, additional, Marchini, Sergio, additional, Carrassa, Laura, additional, Ubezio, Paolo, additional, Porcu, Luca, additional, Brich, Silvia, additional, Sanfilippo, Roberta, additional, Casali, Paolo Giovanni, additional, Gronchi, Alessandro, additional, Pilotti, Silvana, additional, and D'Incalci, Maurizio, additional

Published
2020
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31. Combination of PPARγ Agonist Pioglitazone and Trabectedin Induce Adipocyte Differentiation to Overcome Trabectedin Resistance in Myxoid Liposarcomas

Author

Frapolli, Roberta, primary, Bello, Ezia, additional, Ponzo, Marianna, additional, Craparotta, Ilaria, additional, Mannarino, Laura, additional, Ballabio, Sara, additional, Marchini, Sergio, additional, Carrassa, Laura, additional, Ubezio, Paolo, additional, Porcu, Luca, additional, Brich, Silvia, additional, Sanfilippo, Roberta, additional, Casali, Paolo Giovanni, additional, Gronchi, Alessandro, additional, Pilotti, Silvana, additional, and D'Incalci, Maurizio, additional

Published
2019
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32. The ETS Inhibitors YK-4-279 and TK-216 Are Novel Antilymphoma Agents

Author

Spriano, Filippo, primary, Chung, Elaine Yee Lin, additional, Gaudio, Eugenio, additional, Tarantelli, Chiara, additional, Cascione, Luciano, additional, Napoli, Sara, additional, Jessen, Katti, additional, Carrassa, Laura, additional, Priebe, Valdemar, additional, Sartori, Giulio, additional, Graham, Garrett, additional, Selvanathan, Saravana P., additional, Cavalli, Andrea, additional, Rinaldi, Andrea, additional, Kwee, Ivo, additional, Testoni, Monica, additional, Genini, Davide, additional, Ye, B. Hilda, additional, Zucca, Emanuele, additional, Stathis, Anastasios, additional, Lannutti, Brian, additional, Toretsky, Jeffrey A., additional, and Bertoni, Francesco, additional

Published
2019
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35. Combination of PPARg agonist pioglitazone and trabectedin induce adipocyte differentiation to overcome trabectedin resistance in myxoid liposarcomas

Author

Frapolli, R, Bello, E, Ponzo, M, Craparotta, I, Mannarino, L, Ballabio, S, Marchini, S, Carrassa, L, Ubezio, P, Porcu, L, Brich, S, Sanfilippo, R, Casali, P, Gronchi, A, Pilotti, S, D'Incalci, M, Frapolli, Roberta, Bello, Ezia, Ponzo, Marianna, Craparotta, Ilaria, Mannarino, Laura, Ballabio, Sara, Marchini, Sergio, Carrassa, Laura, Ubezio, Paolo, Porcu, Luca, Brich, Silvia, Sanfilippo, Roberta, Casali, Paolo Giovanni, Gronchi, Alessandro, Pilotti, Silvana, D'Incalci, Maurizio, Frapolli, R, Bello, E, Ponzo, M, Craparotta, I, Mannarino, L, Ballabio, S, Marchini, S, Carrassa, L, Ubezio, P, Porcu, L, Brich, S, Sanfilippo, R, Casali, P, Gronchi, A, Pilotti, S, D'Incalci, M, Frapolli, Roberta, Bello, Ezia, Ponzo, Marianna, Craparotta, Ilaria, Mannarino, Laura, Ballabio, Sara, Marchini, Sergio, Carrassa, Laura, Ubezio, Paolo, Porcu, Luca, Brich, Silvia, Sanfilippo, Roberta, Casali, Paolo Giovanni, Gronchi, Alessandro, Pilotti, Silvana, and D'Incalci, Maurizio

Abstract

Purpose: This study was aimed at investigating whether the PPARg agonist pioglitazone—given in combination with trabectedin—is able to reactivate adipocytic differentiation in myxoid liposarcoma (MLS) patient-derived xenografts, overcoming resistance to trabectedin. Experimental Design: The antitumor and biological effects of trabectedin, pioglitazone, and the combination of the two drugs were investigated in nude mice bearing well-characterized MLS xenografts representative of innate or acquired resistance against trabectedin. Pioglitazone and trabectedin were given by daily oral and weekly i.v. administrations, respectively. Molecular studies were performed by using microarrays approach, real-time PCR, and Western blotting. Results: We found that the resistance of MLS against trabectedin is associated with the lack of activation of adipogenesis. The PPARg agonist pioglitazone reactivated adipogenesis, assessed by histologic and gene pathway analyses. Pioglitazone was well tolerated and did not increase the toxicity of trabectedin. The ability of pioglitazone to reactivate adipocytic differentiation was observed by morphologic examination, and it is consistent with the increased expression of genes such as ADIPOQ implicated in the adipogenesis process. The determination of adiponectin by Western blotting constitutes a good and reliable biomarker related to MLS adipocytic differentiation. Conclusions: The finding that the combination of pioglitazone and trabectedin induces terminal adipocytic differentiation of some MLSs with the complete pathologic response and cure of tumor-bearing mice provides a strong rationale to test the combination of trabectedin and pioglitazone in patients with MLS.

Published
2019

38. PQR309 Is a Novel Dual PI3K/mTOR Inhibitor with Preclinical Antitumor Activity in Lymphomas as a Single Agent and in Combination Therapy

Author

Tarantelli, Chiara, primary, Gaudio, Eugenio, additional, Arribas, Alberto J., additional, Kwee, Ivo, additional, Hillmann, Petra, additional, Rinaldi, Andrea, additional, Cascione, Luciano, additional, Spriano, Filippo, additional, Bernasconi, Elena, additional, Guidetti, Francesca, additional, Carrassa, Laura, additional, Pittau, Roberta Bordone, additional, Beaufils, Florent, additional, Ritschard, Reto, additional, Rageot, Denise, additional, Sele, Alexander, additional, Dossena, Barbara, additional, Rossi, Francesca Maria, additional, Zucchetto, Antonella, additional, Taborelli, Monica, additional, Gattei, Valter, additional, Rossi, Davide, additional, Stathis, Anastasios, additional, Stussi, Georg, additional, Broggini, Massimo, additional, Wymann, Matthias P., additional, Wicki, Andreas, additional, Zucca, Emanuele, additional, Cmiljanovic, Vladimir, additional, Fabbro, Doriano, additional, and Bertoni, Francesco, additional

Published
2018
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42. Abstract 380: The dual PI3K/MTOR inhibitor PQR309 is active in mature B cell lymphoma cell lines bearing resistance to the PI3K-delta inhibitor idelalisib and specific gene expression features

Author

Chiara, Tarantelli, primary, Gaudio, Eugenio, additional, Kwee, Ivo, additional, Arribas, Alberto, additional, Rinaldi, Andrea, additional, Bernasconi, Elena, additional, Cascione, Luciano, additional, Hillmann, Petra, additional, Stathis, Anastasios, additional, Carrassa, Laura, additional, Broggini, Massimo, additional, Stussi, Georg, additional, Fabbro, Doriano, additional, Zucca, Emanuele, additional, Cmiljanovic, Vladimir, additional, and Bertoni, Francesco, additional

Published
2016
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47. Abstract 1654: The small molecule YK-4-279 shows anti-lymphoma activity in pre-clinical models

Author

Chung, Elain YL, primary, Priebe, Valdemar, additional, Gaudio, Eugenio, additional, Kwee, Ivo, additional, Tarantelli, Chiara, additional, Rinaldi, Andrea, additional, Carrassa, Laura, additional, Testoni, Monica, additional, Cascione, Luciano, additional, Broggini, Massimo, additional, Toretsky, Jeffrey A., additional, Zucca, Emanuele, additional, and Bertoni, Francesco, additional

Published
2015
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48. Abstract 2652: Pre-clinical activity and mechanism of action of the novel dual PI3K/mTOR inhibitor PQR309 in B-cell lymphomas

Author

Tarantelli, Chiara, primary, Gaudio, Eugenio, additional, Kwee, Ivo, additional, Rinaldi, Andrea, additional, Bernasconi, Elena, additional, Cascione, Luciano, additional, Hillmann, Petra, additional, Stathis, Anastasios, additional, Carrassa, Laura, additional, Broggini, Massimo, additional, Stussi, Georg, additional, Fabbro, Doriano, additional, Beaufils, Florent, additional, Melone, Anna, additional, Bohnacker, Thomas, additional, Wymann, Matthias P., additional, Wicki, Andreas, additional, Zucca, Emanuele, additional, Cmiljanovic, Vladimir, additional, and Bertoni, Francesco, additional

Published
2015
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49. The Novel PI3K/mTOR Dual Inhibitor PQR309 in Pre-Clinical Lymphoma Models: Demonstration of Anti-Tumor Activity As Single Agent and in Combination and Identification of Gene Expression Signatures Associated with Response

Author

Tarantelli, Chiara, primary, Gaudio, Eugenio, additional, Kwee, Ivo, additional, Rinaldi, Andrea, additional, Stifanelli, Matteo, additional, Bernasconi, Elena, additional, Barassi, Chiara, additional, Hillmann, Petra, additional, Stathis, Anastasios, additional, Carrassa, Laura, additional, Broggini, Massimo, additional, Stussi, Georg, additional, Fabbro, Doriano, additional, Hebeisen, Paul, additional, Betts, Frances, additional, Wicki, Andreas, additional, Zucca, Emanuele, additional, Cmiljanovic, Vladimir, additional, and Bertoni, Francesco, additional

Published
2014
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50. Combined inhibition of Chk1 and Wee1 as a new therapeutic strategy for mantle cell lymphoma

Author

Chilà, Rosaria, primary, Basana, Alessandra, additional, Lupi, Monica, additional, Guffanti, Federica, additional, Gaudio, Eugenio, additional, Rinaldi, Andrea, additional, Cascione, Luciano, additional, Restelli, Valentina, additional, Tarantelli, Chiara, additional, Bertoni, Francesco, additional, Damia, Giovanna, additional, and Carrassa, Laura, additional

Published
2014
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