8 results on '"Valentino Clemente"'
Search Results
2. Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries
- Author
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Xiaonan Zhang, Mihir Shetty, Valentino Clemente, Stig Linder, and Martina Bazzaro
- Subjects
ARID1A ,OCCC ,mitochondria ,ovarian cancer ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Ovarian clear cell carcinoma (OCCC) is a rare but chemorefractory tumor. About 50% of all OCCC patients have inactivating mutations of ARID1A, a member of the SWI/SNF chromatin-remodeling complex. Members of the SWI/SNF remodeling have emerged as regulators of the energetic metabolism of mammalian cells; however, the role of ARID1A as a modulator of the mitochondrial metabolism in OCCCs is yet to be defined. Here, we show that ARID1A loss results in increased mitochondrial metabolism and renders ARID1A-mutated cells increasingly and selectively dependent on it. The increase in mitochondrial activity following ARID1A loss is associated with increase in c-Myc expression and increased mitochondrial number and reduction of their size consistent with a higher mitochondrial cristae/outer membrane ratio. Significantly, preclinical testing of the complex I mitochondrial inhibitor IACS-010759 showed it extends overall survival in a preclinical model of ARID1A-mutated OCCC. These findings provide for the targeting mitochondrial activity in ARID1A-mutated OCCCs.
- Published
- 2021
- Full Text
- View/download PDF
3. Deubiquitinating Enzymes in Coronaviruses and Possible Therapeutic Opportunities for COVID-19
- Author
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Valentino Clemente, Padraig D’Arcy, and Martina Bazzaro
- Subjects
DUBs ,coronavirus ,SARS ,SARS-CoV2 ,papain-like protease ,PLP inhibitors ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Following the outbreak of novel severe acute respiratory syndrome (SARS)-coronavirus (CoV)2, the majority of nations are struggling with countermeasures to fight infection, prevent spread and improve patient survival. Considering that the pandemic is a recent event, no large clinical trials have been possible and since coronavirus specific drug are not yet available, there is no strong consensus on how to treat the coronavirus disease 2019 (COVID-19) associated viral pneumonia. Coronaviruses code for an important multifunctional enzyme named papain-like protease (PLP), that has many roles in pathogenesis. First, PLP is one of the two viral cysteine proteases, along with 3-chymotripsin-like protease, that is responsible for the production of the replicase proteins required for viral replication. Second, its intrinsic deubiquitinating and deISGylating activities serve to antagonize the host’s immune response that would otherwise hinder infection. Both deubiquitinating and deISGylating functions involve the removal of the small regulatory polypeptides, ubiquitin and ISG15, respectively, from target proteins. Ubiquitin modifications can regulate the innate immune response by affecting regulatory proteins, either by altering their stability via the ubiquitin proteasome pathway or by directly regulating their activity. ISG15 is a ubiquitin-like modifier with pleiotropic effects, typically expressed during the host cell immune response. PLP inhibitors have been evaluated during past coronavirus epidemics, and have showed promising results as an antiviral therapy in vitro. In this review, we recapitulate the roles of PLPs in coronavirus infections, report a list of PLP inhibitors and suggest possible therapeutic strategies for COVID-19 treatment, using both clinical and preclinical drugs.
- Published
- 2020
- Full Text
- View/download PDF
4. Data from GLS1 is a Protective Factor in Patients with Ovarian Clear Cell Carcinoma and its Expression Does Not Correlate with ARID1A-mutated Tumors
- Author
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Martina Bazzaro, Emil Lou, S. John Weroha, Mahmoud Khalifa, Nathan Rubin, Ruth Baker, Britt K. Erickson, Andrew Nelson, Mihir Shetty, Asumi Hoshino, and Valentino Clemente
- Abstract
Targeting glutamine metabolism has emerged as a novel therapeutic strategy for several human cancers, including ovarian cancer. The primary target of this approach is the kidney isoform of glutaminase, glutaminase 1 (GLS1), a key enzyme in glutamine metabolism that is overexpressed in several human cancers. A first-in-class inhibitor of GLS1, called CB839 (Telaglenastat), has been investigated in several clinical trials, with promising results. The first clinical trial of CB839 in platinum-resistant patients with ovarian cancer is forthcoming. ARID1A-mutated ovarian clear cell carcinoma (OCCC) is a relatively indolent and chemoresistant ovarian cancer histotype. In OCCC-derived cells ARID1A simultaneously drives GLS1 expression and metabolism reprograming. In ARID1A-mutated OCCC-derived mouse models, loss of ARID1A corresponds to GLS1 upregulation and increases sensitivity to GLS1 inhibition. Thus, targeting of GLS1 with CB839 has been suggested as a targeted approach for patients with OCCC with tumors harboring ARID1A mutations. Here, we investigated whether GLS1 is differentially expressed between patients with OCCC whose tumors are ARID1A positive and patients whose tumors are ARID1A negative. In clinical specimens of OCCC, we found that GLS1 overexpression was not correlated with ARID1A loss. In addition, GLS1 overexpression was associated with better clinical outcomes. Our findings have implications for human trials using experimental therapeutics targeting GLS1.Significance:GLS1 differential expression in patients with OCCC with or without ARID1A mutations is significant because a clinical trial with a GLS1 inhibitor is forthcoming. Tumors without ARID1A have low levels of GLS1 and GLS1 expression is associated to better outcome. Thus, blockade of GLS1 could be counterproductive for patients with OCCC.
- Published
- 2023
5. Supplementary Figures S1, Tables S1-S2 from GLS1 is a Protective Factor in Patients with Ovarian Clear Cell Carcinoma and its Expression Does Not Correlate with ARID1A-mutated Tumors
- Author
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Martina Bazzaro, Emil Lou, S. John Weroha, Mahmoud Khalifa, Nathan Rubin, Ruth Baker, Britt K. Erickson, Andrew Nelson, Mihir Shetty, Asumi Hoshino, and Valentino Clemente
- Abstract
Figure S1, Table S1, Table S2
- Published
- 2023
6. GLS1 is a protective factor in patients with ovarian clear cell carcinoma and its expression does not correlate with ARID1A-mutated tumors
- Author
-
Valentino Clemente, Asumi Hoshino, Mihir Shetty, Andrew Nelson, Britt K. Erickson, Ruth Baker, Nathan Rubin, Mahmoud Khalifa, S. John Weroha, Emil Lou, and Martina Bazzaro
- Subjects
Article - Abstract
Targeting glutamine metabolism has emerged as a novel therapeutic strategy for several human cancers, including ovarian cancer. The primary target of this approach is the kidney isoform of glutaminase, glutaminase 1 (GLS1), a key enzyme in glutamine metabolism that is overexpressed in several human cancers. A first-in-class inhibitor of GLS1, called CB839 (Telaglenastat), has been investigated in several clinical trials, with promising results. The first clinical trial of CB839 in platinum-resistant patients with ovarian cancer is forthcoming. ARID1A-mutated ovarian clear cell carcinoma (OCCC) is a relatively indolent and chemoresistant ovarian cancer histotype. In OCCC-derived cells ARID1A simultaneously drives GLS1 expression and metabolism reprograming. In ARID1A-mutated OCCC-derived mouse models, loss of ARID1A corresponds to GLS1 upregulation and increases sensitivity to GLS1 inhibition. Thus, targeting of GLS1 with CB839 has been suggested as a targeted approach for patients with OCCC with tumors harboring ARID1A mutations. Here, we investigated whether GLS1 is differentially expressed between patients with OCCC whose tumors are ARID1A positive and patients whose tumors are ARID1A negative. In clinical specimens of OCCC, we found that GLS1 overexpression was not correlated with ARID1A loss. In addition, GLS1 overexpression was associated with better clinical outcomes. Our findings have implications for human trials using experimental therapeutics targeting GLS1. Significance: GLS1 differential expression in patients with OCCC with or without ARID1A mutations is significant because a clinical trial with a GLS1 inhibitor is forthcoming. Tumors without ARID1A have low levels of GLS1 and GLS1 expression is associated to better outcome. Thus, blockade of GLS1 could be counterproductive for patients with OCCC.
- Published
- 2022
7. GLS1 is a protective factor rather than a molecular target in ARID1A-mutated ovarian clear cell carcinoma
- Author
-
Mihir Shetty, Ruth E. Baker, Asumi Hoshino, Emil Lou, Mahmoud A. Khalifa, Nathan Rubin, Britt K. Erickson, Andrew C. Nelson, Valentino Clemente, and Martina Bazzaro
- Subjects
Kidney ,ARID1A ,Glutaminase ,business.industry ,medicine.disease ,In vitro ,Clinical trial ,medicine.anatomical_structure ,Downregulation and upregulation ,Clear cell carcinoma ,medicine ,Cancer research ,Ovarian cancer ,business - Abstract
Targeting glutamine metabolism has emerged as a novel therapeutic strategy for several human cancers, including ovarian cancer. The primary target of this approach is the kidney isoform of glutaminase, glutaminase 1 (GLS1), a key enzyme in glutamine metabolism that is overexpressed in several human cancers. A first-in-class inhibitor of GLS1, called CB839 (Telaglenastat), has been investigated in several clinical trials, with promising results. The first clinical trial of CB839 in platinum-resistant ovarian cancer patients is forthcoming. ARID1A-mutated ovarian clear cell carcinoma (OCCC) is a relatively indolent and chemoresistant ovarian cancer histotype. In OCCC-derived cells in vitro and mouse models, loss of ARID1A leads to upregulation of GLS1. Thus, targeting of GLS1 with CB839 has been suggested as a targeted approach for OCCC patients with tumors harboring ARID1A-mutations. Here, we investigated whether GLS1 is differentially expressed between OCCC patients whose tumors are ARID1A positive and patients whose tumors are ARID1A negative. In clinical specimens of OCCC, we found that GLS1 overexpression was not correlated with ARID1A loss. In addition, GLS1 overexpression was associated with better clinical outcomes. Our findings suggest that GLS1 expression in OCCC may be a protective factor and that caution should be taken when considering the use of CB839 to treat OCCC patients.
- Published
- 2021
8. Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries
- Author
-
Mihir Shetty, Valentino Clemente, Martina Bazzaro, Stig Linder, and Xiaonan Zhang
- Subjects
ARID1A ,cells ,genetic processes ,Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy) ,OCCC ,Mitochondrion ,mitochondria ,ovarian cancer ,Oxidative Phosphorylation ,Mice ,Random Allocation ,Piperidines ,Increased mitochondrial number ,Biology (General) ,RNA, Small Interfering ,Spectroscopy ,Membrane Potential, Mitochondrial ,Ovarian Neoplasms ,Oxadiazoles ,Chemistry ,Biochemistry and Molecular Biology ,General Medicine ,Neoplasm Proteins ,Computer Science Applications ,Cell biology ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Gene Knockdown Techniques ,Clear cell carcinoma ,Mitochondrial cristae ,Female ,RNA Interference ,biological phenomena, cell phenomena, and immunity ,Bacterial outer membrane ,QH301-705.5 ,Mice, Nude ,Antineoplastic Agents ,macromolecular substances ,Biology ,Article ,Chromatin remodeling ,Catalysis ,Inorganic Chemistry ,Oxygen Consumption ,Cell Line, Tumor ,Spheroids, Cellular ,Overall survival ,medicine ,Animals ,Humans ,Physical and Theoretical Chemistry ,QD1-999 ,Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci) ,Molecular Biology ,Electron Transport Complex I ,Organic Chemistry ,Metabolism ,medicine.disease ,Xenograft Model Antitumor Assays ,enzymes and coenzymes (carbohydrates) ,Ovarian cancer ,Biokemi och molekylärbiologi ,Adenocarcinoma, Clear Cell ,Transcription Factors - Abstract
Ovarian clear cell carcinoma (OCCC) is a rare but chemorefractory tumor. About 50% of all OCCC patients have inactivating mutations of ARID1A, a member of the SWI/SNF chromatin-remodeling complex. Members of the SWI/SNF remodeling have emerged as regulators of the energetic metabolism of mammalian cells, however, the role of ARID1A as a modulator of the mitochondrial metabolism in OCCCs is yet to be defined. Here, we show that ARID1A loss results in increased mitochondrial metabolism and renders ARID1A-mutated cells increasingly and selectively dependent on it. The increase in mitochondrial activity following ARID1A loss is associated with increase in c-Myc expression and increased mitochondrial number and reduction of their size consistent with a higher mitochondrial cristae/outer membrane ratio. Significantly, preclinical testing of the complex I mitochondrial inhibitor IACS-010759 showed it extends overall survival in a preclinical model of ARID1A-mutated OCCC. These findings provide for the targeting mitochondrial activity in ARID1A-mutated OCCCs.
- Published
- 2021
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