14 results on '"Ghelli A."'
Search Results
2. Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies
- Author
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Antonella Padella, Andrea Ghelli Luserna Di Rorà, Giovanni Marconi, Martina Ghetti, Giovanni Martinelli, and Giorgia Simonetti
- Subjects
PARP ,Acute myeloid leukemia ,Acute lymphoblastic leukemia ,Synthetic lethality ,Biomarkers ,DNA damage response ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract The members of the Poly(ADP‐ribose) polymerase (PARP) superfamily are involved in several biological processes and, in particular, in the DNA damage response (DDR). The most studied members, PARP1, PARP2 and PARP3, act as sensors of DNA damages, in order to activate different intracellular repair pathways, including single-strand repair, homologous recombination, conventional and alternative non-homologous end joining. This review recapitulates the functional role of PARPs in the DDR pathways, also in relationship with the cell cycle phases, which drives our knowledge of the mechanisms of action of PARP inhibitors (PARPi), encompassing inhibition of single-strand breaks and base excision repair, PARP trapping and sensitization to antileukemia immune responses. Several studies have demonstrated a preclinical activity of the current available PARPi, olaparib, rucaparib, niraparib, veliparib and talazoparib, as single agent and/or in combination with cytotoxic, hypomethylating or targeted drugs in acute leukemia, thus encouraging the development of clinical trials. We here summarize the most recent preclinical and clinical findings and discuss the synthetic lethal interactions of PARPi in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL). Despite the low frequency of genomic alterations of PARP and other DDR-related genes in acute leukemia, selective vulnerabilities have been reported in several disease subgroups, along with a “BRCAness phenotype.” AML carrying the RUNX1-RUNX1T1 or PML-RARA fusion genes or mutations in signaling genes (FLT3-ITD in combination with TET2 or TET2 and DNMT3A deficiency), cohesin complex members (STAG2), TP53 and BCOR as co-occurring lesions, IDH1/2 and ALL cases expressing the TCF3-HLF chimera or TET1 was highly sensitive to PARPi in preclinical studies. These data, along with the warning coming from the observation of cases of therapy-related myeloid malignancies among patients receiving PARPi for solid tumors treatment, indicate that PARPi represents a promising strategy in a personalized medicine setting. The characterization of the clonal and subclonal genetic background and of the DDR functionality is crucial to select acute leukemia patients that will likely benefit of PARPi-based therapeutic regimens.
- Published
- 2022
- Full Text
- View/download PDF
3. A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target
- Author
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Andrea Ghelli Luserna di Rorà, Claudio Cerchione, Giovanni Martinelli, and Giorgia Simonetti
- Subjects
WEE1 family kinases ,WEE1 ,PKMYT1 ,Cell cycle ,DNA repair ,Pseudo-oncogene ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract The inhibition of the DNA damage response (DDR) pathway in the treatment of cancer has recently gained interest, and different DDR inhibitors have been developed. Among them, the most promising ones target the WEE1 kinase family, which has a crucial role in cell cycle regulation and DNA damage identification and repair in both nonmalignant and cancer cells. This review recapitulates and discusses the most recent findings on the biological function of WEE1/PKMYT1 during the cell cycle and in the DNA damage repair, with a focus on their dual role as tumor suppressors in nonmalignant cells and pseudo-oncogenes in cancer cells. We here report the available data on the molecular and functional alterations of WEE1/PKMYT1 kinases in both hematological and solid tumors. Moreover, we summarize the preclinical information on 36 chemo/radiotherapy agents, and in particular their effect on cell cycle checkpoints and on the cellular WEE1/PKMYT1-dependent response. Finally, this review outlines the most important pre-clinical and clinical data available on the efficacy of WEE1/PKMYT1 inhibitors in monotherapy and in combination with chemo/radiotherapy agents or with other selective inhibitors currently used or under evaluation for the treatment of cancer patients.
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- 2020
- Full Text
- View/download PDF
4. The balance between mitotic death and mitotic slippage in acute leukemia: a new therapeutic window?
- Author
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Andrea Ghelli Luserna di Rorà, Giovanni Martinelli, and Giorgia Simonetti
- Subjects
Acute leukemia ,Mitotic death ,Mitotic slippage ,Mitotic inhibitors ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Mitosis is the process whereby an eukaryotic cell divides into two identical copies. Different multiprotein complexes are involved in the fine regulation of cell division, including the mitotic promoting factor and the anaphase promoting complex. Prolonged mitosis can result in cellular division, cell death, or mitotic slippage, the latter leading to a new interphase without cellular division. Mitotic slippage is one of the causes of genomic instability and has an important therapeutic and clinical impact. It has been widely studied in solid tumors but not in hematological malignancies, in particular, in acute leukemia. We review the literature data available on mitotic regulation, alterations in mitotic proteins occurring in acute leukemia, induction of prolonged mitosis and its consequences, focusing in particular on the balance between cell death and mitotic slippage and on its therapeutic potentials. We also present the most recent preclinical and clinical data on the efficacy of second-generation mitotic drugs (CDK1-Cyclin B1, APC/CCDC20, PLK, Aurora kinase inhibitors). Despite the poor clinical activity showed by these drugs as single agents, they offer a potential therapeutic window for synthetic lethal combinations aimed to selectively target leukemic cells at the right time, thus decreasing the risk of mitotic slippage events.
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- 2019
- Full Text
- View/download PDF
5. Targeting WEE1 to enhance conventional therapies for acute lymphoblastic leukemia
- Author
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Andrea Ghelli Luserna Di Rorà, Neil Beeharry, Enrica Imbrogno, Anna Ferrari, Valentina Robustelli, Simona Righi, Elena Sabattini, Maria Vittoria Verga Falzacappa, Chiara Ronchini, Nicoletta Testoni, Carmen Baldazzi, Cristina Papayannidis, Maria Chiara Abbenante, Giovanni Marconi, Stefania Paolini, Sarah Parisi, Chiara Sartor, Maria Chiara Fontana, Serena De Matteis, Ilaria Iacobucci, Pier Giuseppe Pelicci, Michele Cavo, Timothy J. Yen, and Giovanni Martinelli
- Subjects
Acute lymphoblastic leukemia ,WEE1 inhibitor ,Chemo-sensitizer agent ,G2/M checkpoint ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Despite the recent progress that has been made in the understanding and treatment of acute lymphoblastic leukemia (ALL), the outcome is still dismal in adult ALL cases. Several studies in solid tumors identified high expression of WEE1 kinase as a poor prognostic factor and reported its role as a cancer-conserving oncogene that protects cancer cells from DNA damage. Therefore, the targeted inhibition of WEE1 kinase has emerged as a rational strategy to sensitize cancer cells to antineoplastic compounds, which we evaluate in this study. Methods The effectiveness of the selective WEE1 inhibitor AZD-1775 as a single agent and in combination with different antineoplastic agents in B and T cell precursor ALL (B/T-ALL) was evaluated in vitro and ex vivo studies. The efficacy of the compound in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed using different B/T-ALL cell lines and confirmed in primary ALL blasts. Results We showed that WEE1 was highly expressed in adult primary ALL bone marrow and peripheral blood blasts (n = 58) compared to normal mononuclear cells isolated from the peripheral blood of healthy donors (p = 0.004). Thus, we hypothesized that WEE1 could be a rational target in ALL, and its inhibition could enhance the cytotoxicity of conventional therapies used for ALL. We evaluated the efficacy of AZD-1775 as a single agent and in combination with several antineoplastic agents, and we elucidated its mechanisms of action. AZD-1775 reduced cell viability in B/T-ALL cell lines by disrupting the G2/M checkpoint and inducing apoptosis. These findings were confirmed in human primary ALL bone marrow and peripheral blood blasts (n = 15). In both cell lines and primary leukemic cells, AZD-1775 significantly enhanced the efficacy of several tyrosine kinase inhibitors (TKIs) such as bosutinib, imatinib, and ponatinib, and of chemotherapeutic agents (clofarabine and doxorubicin) in terms of the reduction of cell viability, apoptosis induction, and inhibition of proliferation. Conclusions Our data suggest that WEE1 plays a role in ALL blast’s survival and is a bona fide target for therapeutic intervention. These data support the evaluation of the therapeutic potential of AZD-1775 as chemo-sensitizer agent for the treatment of B/T-ALL.
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- 2018
- Full Text
- View/download PDF
6. A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target
- Author
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Ghelli Luserna di Rorà, Andrea, Cerchione, Claudio, Martinelli, Giovanni, and Simonetti, Giorgia
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- 2020
- Full Text
- View/download PDF
7. The balance between mitotic death and mitotic slippage in acute leukemia: a new therapeutic window?
- Author
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Ghelli Luserna di Rorà, Andrea, Martinelli, Giovanni, and Simonetti, Giorgia
- Published
- 2019
- Full Text
- View/download PDF
8. The cell cycle checkpoint inhibitors in the treatment of leukemias
- Author
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A. Ghelli Luserna di Rora’, I. Iacobucci, and G. Martinelli
- Subjects
DNA damage response ,Checkpoint kinase inhibitor ,Acute lymphoblastic leukemia ,Acute myeloid leukemia ,Chronic myeloid leukemia ,Chronic lymphocytic leukemia ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract The inhibition of the DNA damage response (DDR) pathway in the treatment of cancers has recently reached an exciting stage with several cell cycle checkpoint inhibitors that are now being tested in several clinical trials in cancer patients. Although the great amount of pre-clinical and clinical data are from the solid tumor experience, only few studies have been done on leukemias using specific cell cycle checkpoint inhibitors. This review aims to summarize the most recent data found on the biological mechanisms of the response to DNA damages highlighting the role of the different elements of the DDR pathway in normal and cancer cells and focusing on the main genetic alteration or aberrant gene expression that has been found on acute and chronic leukemias. This review, for the first time, outlines the most important pre-clinical and clinical data available on the efficacy of cell cycle checkpoint inhibitors in single agent and in combination with different agents normally used for the treatment of acute and chronic leukemias.
- Published
- 2017
- Full Text
- View/download PDF
9. Targeting WEE1 to enhance conventional therapies for acute lymphoblastic leukemia
- Author
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Ghelli Luserna Di Rorà, Andrea, Beeharry, Neil, Imbrogno, Enrica, Ferrari, Anna, Robustelli, Valentina, Righi, Simona, Sabattini, Elena, Verga Falzacappa, Maria Vittoria, Ronchini, Chiara, Testoni, Nicoletta, Baldazzi, Carmen, Papayannidis, Cristina, Abbenante, Maria Chiara, Marconi, Giovanni, Paolini, Stefania, Parisi, Sarah, Sartor, Chiara, Fontana, Maria Chiara, De Matteis, Serena, Iacobucci, Ilaria, Pelicci, Pier Giuseppe, Cavo, Michele, Yen, Timothy J., and Martinelli, Giovanni
- Published
- 2018
- Full Text
- View/download PDF
10. The balance between mitotic death and mitotic slippage in acute leukemia: a new therapeutic window?
- Author
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Giovanni Martinelli, Giorgia Simonetti, and Andrea Ghelli Luserna di Rorà
- Subjects
Genome instability ,Cancer Research ,Programmed cell death ,Cell division ,Mitosis ,Antineoplastic Agents ,Apoptosis ,Cell Cycle Proteins ,Mitotic inhibitors ,Review ,Biology ,Mitotic death ,lcsh:RC254-282 ,Genomic Instability ,Aurora kinase ,Humans ,Molecular Biology ,Acute leukemia ,Leukemia ,lcsh:RC633-647.5 ,Hematology ,lcsh:Diseases of the blood and blood-forming organs ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,Neoplasm Proteins ,Oncology ,Acute Disease ,Cancer research ,Interphase ,Mitotic slippage ,Anaphase-promoting complex - Abstract
Mitosis is the process whereby an eukaryotic cell divides into two identical copies. Different multiprotein complexes are involved in the fine regulation of cell division, including the mitotic promoting factor and the anaphase promoting complex. Prolonged mitosis can result in cellular division, cell death, or mitotic slippage, the latter leading to a new interphase without cellular division. Mitotic slippage is one of the causes of genomic instability and has an important therapeutic and clinical impact. It has been widely studied in solid tumors but not in hematological malignancies, in particular, in acute leukemia. We review the literature data available on mitotic regulation, alterations in mitotic proteins occurring in acute leukemia, induction of prolonged mitosis and its consequences, focusing in particular on the balance between cell death and mitotic slippage and on its therapeutic potentials. We also present the most recent preclinical and clinical data on the efficacy of second-generation mitotic drugs (CDK1-Cyclin B1, APC/CCDC20, PLK, Aurora kinase inhibitors). Despite the poor clinical activity showed by these drugs as single agents, they offer a potential therapeutic window for synthetic lethal combinations aimed to selectively target leukemic cells at the right time, thus decreasing the risk of mitotic slippage events.
- Published
- 2019
11. Targeting WEE1 to enhance conventional therapies for acute lymphoblastic leukemia
- Author
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Simona Righi, Valentina Robustelli, Sarah Parisi, Nicoletta Testoni, Maria Vittoria Verga Falzacappa, Chiara Sartor, Cristina Papayannidis, Maria Chiara Abbenante, Timothy J. Yen, Michele Cavo, Andrea Ghelli Luserna di Rorà, Chiara Ronchini, Serena De Matteis, Pier Giuseppe Pelicci, Enrica Imbrogno, Anna Maria Ferrari, Neil Beeharry, Giovanni Marconi, Maria Chiara Fontana, Giovanni Martinelli, Ilaria Iacobucci, Carmen Baldazzi, Elena Sabattini, Stefania Paolini, Ghelli Luserna Di Rorà, Andrea, Beeharry, Neil, Imbrogno, Enrica, Ferrari, Anna, Robustelli, Valentina, Righi, Simona, Sabattini, Elena, Verga Falzacappa, Maria Vittoria, Ronchini, Chiara, Testoni, Nicoletta, Baldazzi, Carmen, Papayannidis, Cristina, Abbenante, Maria Chiara, Marconi, Giovanni, Paolini, Stefania, Parisi, Sarah, Sartor, Chiara, Fontana, Maria Chiara, De Matteis, Serena, Iacobucci, Ilaria, Pelicci, Pier Giuseppe, Cavo, Michele, Yen, Timothy J, and Martinelli, Giovanni
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0301 basic medicine ,Cancer Research ,medicine.medical_specialty ,T cell ,Cell Cycle Proteins ,Acute lymphoblastic leukemia ,Peripheral blood mononuclear cell ,lcsh:RC254-282 ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Cell Line, Tumor ,Internal medicine ,medicine ,Humans ,Clofarabine ,Molecular Biology ,G2/M checkpoint ,Hematology ,business.industry ,lcsh:RC633-647.5 ,Research ,Ponatinib ,Nuclear Proteins ,lcsh:Diseases of the blood and blood-forming organs ,Precursor Cell Lymphoblastic Leukemia-Lymphoma ,Protein-Tyrosine Kinases ,Chemo-sensitizer agent ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,3. Good health ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer cell ,Cancer research ,WEE1 inhibitor ,business ,Bosutinib ,Tyrosine kinase ,medicine.drug - Abstract
Background Despite the recent progress that has been made in the understanding and treatment of acute lymphoblastic leukemia (ALL), the outcome is still dismal in adult ALL cases. Several studies in solid tumors identified high expression of WEE1 kinase as a poor prognostic factor and reported its role as a cancer-conserving oncogene that protects cancer cells from DNA damage. Therefore, the targeted inhibition of WEE1 kinase has emerged as a rational strategy to sensitize cancer cells to antineoplastic compounds, which we evaluate in this study. Methods The effectiveness of the selective WEE1 inhibitor AZD-1775 as a single agent and in combination with different antineoplastic agents in B and T cell precursor ALL (B/T-ALL) was evaluated in vitro and ex vivo studies. The efficacy of the compound in terms of cytotoxicity, induction of apoptosis, and changes in gene and protein expression was assessed using different B/T-ALL cell lines and confirmed in primary ALL blasts. Results We showed that WEE1 was highly expressed in adult primary ALL bone marrow and peripheral blood blasts (n = 58) compared to normal mononuclear cells isolated from the peripheral blood of healthy donors (p = 0.004). Thus, we hypothesized that WEE1 could be a rational target in ALL, and its inhibition could enhance the cytotoxicity of conventional therapies used for ALL. We evaluated the efficacy of AZD-1775 as a single agent and in combination with several antineoplastic agents, and we elucidated its mechanisms of action. AZD-1775 reduced cell viability in B/T-ALL cell lines by disrupting the G2/M checkpoint and inducing apoptosis. These findings were confirmed in human primary ALL bone marrow and peripheral blood blasts (n = 15). In both cell lines and primary leukemic cells, AZD-1775 significantly enhanced the efficacy of several tyrosine kinase inhibitors (TKIs) such as bosutinib, imatinib, and ponatinib, and of chemotherapeutic agents (clofarabine and doxorubicin) in terms of the reduction of cell viability, apoptosis induction, and inhibition of proliferation. Conclusions Our data suggest that WEE1 plays a role in ALL blast’s survival and is a bona fide target for therapeutic intervention. These data support the evaluation of the therapeutic potential of AZD-1775 as chemo-sensitizer agent for the treatment of B/T-ALL. Electronic supplementary material The online version of this article (10.1186/s13045-018-0641-1) contains supplementary material, which is available to authorized users.
- Published
- 2018
12. The cell cycle checkpoint inhibitors in the treatment of leukemias
- Author
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Ghelli Luserna di Rora’, A., primary, Iacobucci, I., additional, and Martinelli, G., additional
- Published
- 2017
- Full Text
- View/download PDF
13. In vitro and in vivo single-agent efficacy of checkpoint kinase inhibition in acute lymphoblastic leukemia
- Author
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Iacobucci, Ilaria, primary, Di Rorà, Andrea Ghelli Luserna, additional, Falzacappa, Maria Vittoria Verga, additional, Agostinelli, Claudio, additional, Derenzini, Enrico, additional, Ferrari, Anna, additional, Papayannidis, Cristina, additional, Lonetti, Annalisa, additional, Righi, Simona, additional, Imbrogno, Enrica, additional, Pomella, Silvia, additional, Venturi, Claudia, additional, Guadagnuolo, Viviana, additional, Cattina, Federica, additional, Ottaviani, Emanuela, additional, Abbenante, Maria Chiara, additional, Vitale, Antonella, additional, Elia, Loredana, additional, Russo, Domenico, additional, Zinzani, Pier Luigi, additional, Pileri, Stefano, additional, Pelicci, Pier Giuseppe, additional, and Martinelli, Giovanni, additional
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- 2015
- Full Text
- View/download PDF
14. The cell cycle checkpoint inhibitors in the treatment of leukemias.
- Author
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di Rora, A. Ghelli Luserna, Iacobucci, I., and Martinelli, G.
- Subjects
- *
LEUKEMIA treatment , *DNA damage , *CELL cycle , *GENE expression , *CANCER cells - Abstract
The inhibition of the DNA damage response (DDR) pathway in the treatment of cancers has recently reached an exciting stage with several cell cycle checkpoint inhibitors that are now being tested in several clinical trials in cancer patients. Although the great amount of pre-clinical and clinical data are from the solid tumor experience, only few studies have been done on leukemias using specific cell cycle checkpoint inhibitors. This review aims to summarize the most recent data found on the biological mechanisms of the response to DNA damages highlighting the role of the different elements of the DDR pathway in normal and cancer cells and focusing on the main genetic alteration or aberrant gene expression that has been found on acute and chronic leukemias. This review, for the first time, outlines the most important pre-clinical and clinical data available on the efficacy of cell cycle checkpoint inhibitors in single agent and in combination with different agents normally used for the treatment of acute and chronic leukemias. [ABSTRACT FROM AUTHOR]
- Published
- 2017
- Full Text
- View/download PDF
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