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Article: Incorporating Immunotherapy in the Management of Gastric Cancer: Molecular and Clinical Implications.

Agnarelli, Alessandro / Vella, Viviana / Samuels, Mark / Papanastasopoulos, Panagiotis / Giamas, Georgios

2022 Volume 14, Issue 18

Abstract: Gastric cancer has a median survival of 11 months, and this poor prognosis has not improved over the last 30 years. Recent pre-clinical data suggest that there is high tumour-related neoantigen expression in gastric cancer cells, suggesting that a ... ...

Abstract	Gastric cancer has a median survival of 11 months, and this poor prognosis has not improved over the last 30 years. Recent pre-clinical data suggest that there is high tumour-related neoantigen expression in gastric cancer cells, suggesting that a clinical strategy that enhances the host's immune system against cancer cells may be a successful approach to improve clinical outcomes. Additionally, there has been an increasing amount of translational evidence highlighting the relevance of PD-L1 expression in gastric cancer cells, indicating that PD-1/PD-L1 inhibitors may be useful. Several molecular subgroups of gastric cancer have been identified to respond with excellent outcomes to immunotherapy, including microsatellite instable tumours, tumours bearing a high tumour mutational burden, and tumours related to a chronic EBV infection. In gastric cancer, immunotherapy has produced durable responses in chemo-refractory patients; however, most recently there has been a lot of enthusiasm as several large-scale clinical trials highlight the improved survival noted from the incorporation of immunotherapy in the first line setting for advanced gastric cancer. Our review aims to discuss current pre-clinical and clinical data supporting the innovative role of immunotherapy in gastric cancer.
Language	English
Publishing date	2022-09-08
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers14184378
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Article ; Online: Loss of POLE3-POLE4 unleashes replicative gap accumulation upon treatment with PARP inhibitors.

Hill, Bethany Rebekah / Ozgencil, Meryem / Buckley-Benbow, Lauryn / Skingsley, Sophie Louise Pamela / Tomlinson, Danielle / Eizmendi, Carmen Ortueta / Agnarelli, Alessandro / Bellelli, Roberto

Cell reports

2024 Volume 43, Issue 5, Page(s) 114205

Abstract: The advent of PARP inhibitors (PARPis) has profoundly changed the treatment landscape of BRCA1/BRCA2-mutated cancers. Despite this, the development of resistance to these compounds has become a major challenge. Hence, a detailed understanding of the ... ...

Abstract	The advent of PARP inhibitors (PARPis) has profoundly changed the treatment landscape of BRCA1/BRCA2-mutated cancers. Despite this, the development of resistance to these compounds has become a major challenge. Hence, a detailed understanding of the mechanisms underlying PARPi sensitivity is crucially needed. Here, we show that loss of the POLE3-POLE4 subunits of DNA polymerase epsilon (Polε) strongly sensitizes cancer cells to PARPis in a Polε level-independent manner. Loss of POLE3-POLE4 is not associated with defective RAD51 foci formation, excluding a major defect in homologous recombination. On the contrary, treatment with PARPis triggers replicative gap accumulation in POLE3-POLE4 knockout (KO) cells in a PRIMPOL-dependent manner. In addition to this, the loss of POLE3-POLE4 further sensitizes BRCA1-silenced cells to PARPis. Importantly, the knockdown of 53BP1 does not rescue PARPi sensitivity in POLE3-POLE4 KO cells, bypassing a common PARPi resistance mechanism and outlining a potential strategy to sensitize cancer cells to PARPis.
MeSH term(s)	Poly(ADP-ribose) Polymerase Inhibitors/pharmacology ; Humans ; DNA Replication/drug effects ; Cell Line, Tumor ; BRCA1 Protein/metabolism ; BRCA1 Protein/genetics ; DNA Polymerase II/metabolism ; Tumor Suppressor p53-Binding Protein 1/metabolism ; Rad51 Recombinase/metabolism
Chemical Substances	Poly(ADP-ribose) Polymerase Inhibitors ; BRCA1 Protein ; DNA Polymerase II (EC 2.7.7.7) ; Tumor Suppressor p53-Binding Protein 1 ; Rad51 Recombinase (EC 2.7.7.-)
Language	English
Publishing date	2024-05-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2024.114205
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Article ; Online: Phosphorus and sulfur SAD phasing of the nucleic acid-bound DNA-binding domain of interferon regulatory factor 4.

Agnarelli, Alessandro / El Omari, Kamel / Duman, Ramona / Wagner, Armin / Mancini, Erika J

Acta crystallographica. Section F, Structural biology communications

2021 Volume 77, Issue Pt 7, Page(s) 202–207

Abstract: Pivotal to the regulation of key cellular processes such as the transcription, replication and repair of DNA, DNA-binding proteins play vital roles in all aspects of genetic activity. The determination of high-quality structures of DNA-binding proteins, ... ...

Abstract	Pivotal to the regulation of key cellular processes such as the transcription, replication and repair of DNA, DNA-binding proteins play vital roles in all aspects of genetic activity. The determination of high-quality structures of DNA-binding proteins, particularly those in complexes with DNA, provides crucial insights into the understanding of these processes. The presence in such complexes of phosphate-rich oligonucleotides offers the choice of a rapid method for the routine solution of DNA-binding proteins through the use of long-wavelength beamlines such as I23 at Diamond Light Source. This article reports the use of native intrinsic phosphorus and sulfur single-wavelength anomalous dispersion methods to solve the complex of the DNA-binding domain (DBD) of interferon regulatory factor 4 (IRF4) bound to its interferon-stimulated response element (ISRE). The structure unexpectedly shows three molecules of the IRF4 DBD bound to one ISRE. The sole reliance on native intrinsic anomalous scattering elements that belong to DNA-protein complexes renders the method of general applicability to a large number of such protein complexes that cannot be solved by molecular replacement or by other phasing methods.
MeSH term(s)	Binding Sites/physiology ; Crystallography, X-Ray/methods ; DNA-Binding Proteins/chemistry ; DNA-Binding Proteins/metabolism ; Humans ; Interferon Regulatory Factors/chemistry ; Interferon Regulatory Factors/metabolism ; Nucleic Acids/chemistry ; Nucleic Acids/metabolism ; Phosphorus/chemistry ; Phosphorus/metabolism ; Protein Domains/physiology ; Protein Structure, Secondary ; Protein Structure, Tertiary ; Sulfur/chemistry ; Sulfur/metabolism
Chemical Substances	DNA-Binding Proteins ; Interferon Regulatory Factors ; Nucleic Acids ; interferon regulatory factor-4 ; Phosphorus (27YLU75U4W) ; Sulfur (70FD1KFU70)
Language	English
Publishing date	2021-06-29
Publishing country	United States
Document type	Journal Article
ISSN	2053-230X
ISSN (online)	2053-230X
DOI	10.1107/S2053230X21006506
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Article ; Online: IRF4 in multiple myeloma-Biology, disease and therapeutic target.

Agnarelli, Alessandro / Chevassut, Tim / Mancini, Erika J

Leukemia research

2018 Volume 72, Page(s) 52–58

Abstract: Multiple Myeloma (MM) is an incurable hematologic malignancy characterized by abnormal proliferation of plasma cells. Interferon Regulatory Factor 4 (IRF4), a member of the interferon regulatory family of transcription factors, is central to the genesis ... ...

Abstract	Multiple Myeloma (MM) is an incurable hematologic malignancy characterized by abnormal proliferation of plasma cells. Interferon Regulatory Factor 4 (IRF4), a member of the interferon regulatory family of transcription factors, is central to the genesis of MM. IRF4 is highly expressed in B cells and plasma cells where it plays essential roles in controlling B cell to plasma cell differentiation and immunoglobulin class switching. Overexpression of IRF4 is found in MM patients' derived cells, often as a result of activating mutations or translocations, where it is required for their survival. In this review, we first describe the roles of IRF4 in B cells and plasma cells and then analyse the subversion of the IRF4 transcriptional network in MM. Moreover, we discuss current therapies for MM as well as direct targeting of IRF4 as a potential new therapeutic strategy.
MeSH term(s)	Animals ; Disease-Free Survival ; Gene Expression Regulation, Neoplastic ; Humans ; Interferon Regulatory Factors/genetics ; Interferon Regulatory Factors/metabolism ; Multiple Myeloma/genetics ; Multiple Myeloma/metabolism ; Multiple Myeloma/mortality ; Multiple Myeloma/pathology ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Plasma Cells/metabolism ; Plasma Cells/pathology ; Survival Rate
Chemical Substances	Interferon Regulatory Factors ; Neoplasm Proteins ; interferon regulatory factor-4
Language	English
Publishing date	2018-08-03
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	752396-8
ISSN	1873-5835 ; 0145-2126
ISSN (online)	1873-5835
ISSN	0145-2126
DOI	10.1016/j.leukres.2018.07.025
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Zs.A 1321: Show issues

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Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Dissecting the impact of bromodomain inhibitors on the Interferon Regulatory Factor 4-MYC oncogenic axis in multiple myeloma.

Agnarelli, Alessandro / Mitchell, Simon / Caalim, Gillian / Wood, C David / Milton-Harris, Leanne / Chevassut, Timothy / West, Michelle J / Mancini, Erika J

Hematological oncology

2022 Volume 40, Issue 3, Page(s) 417–429

Abstract: B-cell progenitor fate determinant interferon regulatory factor 4 (IRF4) exerts key roles in the pathogenesis and progression of multiple myeloma (MM), a currently incurable plasma cell malignancy. Aberrant expression of IRF4 and the establishment of a ... ...

Abstract	B-cell progenitor fate determinant interferon regulatory factor 4 (IRF4) exerts key roles in the pathogenesis and progression of multiple myeloma (MM), a currently incurable plasma cell malignancy. Aberrant expression of IRF4 and the establishment of a positive auto-regulatory loop with oncogene MYC, drives a MM specific gene-expression program leading to the abnormal expansion of malignant immature plasma cells. Targeting the IRF4-MYC oncogenic loop has the potential to provide a selective and effective therapy for MM. Here we evaluate the use of bromodomain inhibitors to target the IRF4-MYC axis through combined inhibition of their known epigenetic regulators, BRD4 and CBP/EP300. Although all inhibitors induced cell death, we found no synergistic effect of targeting both of these regulators on the viability of MM cell-lines. Importantly, for all inhibitors over a time period up to 72 h, we detected reduced IRF4 mRNA, but a limited decrease in IRF4 protein expression or mRNA levels of downstream target genes. This indicates that inhibitor-induced loss of cell viability is not mediated through reduced IRF4 protein expression, as previously proposed. Further analysis revealed a long half-life of IRF4 protein in MM cells. In support of our experimental observations, gene network modeling of MM suggests that bromodomain inhibition is exerted primarily through MYC and not IRF4. These findings suggest that despite the autofeedback positive regulatory loop between IRF4 and MYC, bromodomain inhibitors are not effective at targeting IRF4 in MM and that novel therapeutic strategies should focus on the direct inhibition or degradation of IRF4.
MeSH term(s)	Cell Cycle Proteins/metabolism ; Cell Cycle Proteins/pharmacology ; Cell Cycle Proteins/therapeutic use ; Cell Line, Tumor ; Cell Proliferation ; Humans ; Interferon Regulatory Factors/genetics ; Interferon Regulatory Factors/metabolism ; Multiple Myeloma/drug therapy ; Multiple Myeloma/genetics ; Multiple Myeloma/metabolism ; Nuclear Proteins/genetics ; Nuclear Proteins/metabolism ; Proto-Oncogene Proteins c-myc/genetics ; Proto-Oncogene Proteins c-myc/metabolism ; RNA, Messenger ; Transcription Factors/genetics ; Transcription Factors/metabolism
Chemical Substances	BRD4 protein, human ; Cell Cycle Proteins ; Interferon Regulatory Factors ; Nuclear Proteins ; Proto-Oncogene Proteins c-myc ; RNA, Messenger ; Transcription Factors ; interferon regulatory factor-4
Language	English
Publishing date	2022-05-18
Publishing country	England
Document type	Journal Article
ZDB-ID	604884-5
ISSN	1099-1069 ; 0278-0232
ISSN (online)	1099-1069
ISSN	0278-0232
DOI	10.1002/hon.3016
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Zs.A 1816: Show issues

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bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: The Inhibitory Properties of a Novel, Selective LMTK3 Kinase Inhibitor.

Agnarelli, Alessandro / Lauer Betrán, Andrea / Papakyriakou, Athanasios / Vella, Viviana / Samuels, Mark / Papanastasopoulos, Panagiotis / Giamas, Christina / Mancini, Erika J / Stebbing, Justin / Spencer, John / Cilibrasi, Chiara / Ditsiou, Angeliki / Giamas, Georgios

International journal of molecular sciences

2023 Volume 24, Issue 1

Abstract: Recently, the oncogenic role of lemur tyrosine kinase 3 (LMTK3) has been well established in different tumor types, highlighting it as a viable therapeutic target. In the present study, using in vitro and cell-based assays coupled with biophysical ... ...

Abstract	Recently, the oncogenic role of lemur tyrosine kinase 3 (LMTK3) has been well established in different tumor types, highlighting it as a viable therapeutic target. In the present study, using in vitro and cell-based assays coupled with biophysical analyses, we identify a highly selective small molecule LMTK3 inhibitor, namely C36. Biochemical/biophysical and cellular studies revealed that C36 displays a high in vitro selectivity profile and provides notable therapeutic effect when tested in the National Cancer Institute (NCI)-60 cancer cell line panel. We also report the binding affinity between LMTK3 and C36 as demonstrated via microscale thermophoresis (MST). In addition, C36 exhibits a mixed-type inhibition against LMTK3, consistent with the inhibitor overlapping with both the adenosine 5'-triphosphate (ATP)- and substrate-binding sites. Treatment of different breast cancer cell lines with C36 led to decreased proliferation and increased apoptosis, further reinforcing the prospective value of LMTK3 inhibitors for cancer therapy.
MeSH term(s)	Cell Line, Tumor ; Prospective Studies ; Protein Kinase Inhibitors/pharmacology ; Protein Serine-Threonine Kinases/antagonists & inhibitors ; Humans
Chemical Substances	Protein Kinase Inhibitors ; Protein Serine-Threonine Kinases (EC 2.7.11.1) ; LMTK3 protein, human (EC 2.7.11.1)
Language	English
Publishing date	2023-01-03
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24010865
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Article: Protopine/Gemcitabine Combination Induces Cytotoxic or Cytoprotective Effects in Cell Type-Specific and Dose-Dependent Manner on Human Cancer and Normal Cells.

Garcia-Gil, Mercedes / Turri, Benedetta / Gabriele, Morena / Pucci, Laura / Agnarelli, Alessandro / Lai, Michele / Freer, Giulia / Pistello, Mauro / Vignali, Robert / Batistoni, Renata / Marracci, Silvia

Pharmaceuticals (Basel, Switzerland)

2021 Volume 14, Issue 2

Abstract: The natural alkaloid protopine (PRO) exhibits pharmacological properties including anticancer activity. We investigated the effects of PRO, alone and in combination with the chemotherapeutic gemcitabine (GEM), on human tumor cell lines and non-tumor ... ...

Abstract	The natural alkaloid protopine (PRO) exhibits pharmacological properties including anticancer activity. We investigated the effects of PRO, alone and in combination with the chemotherapeutic gemcitabine (GEM), on human tumor cell lines and non-tumor human dermal fibroblasts (HDFs). We found that treatments with different PRO/GEM combinations were cytotoxic or cytoprotective, depending on concentration and cell type. PRO/GEM decreased viability in pancreatic cancer MIA PaCa-2 and PANC-1 cells, while it rescued the GEM-induced viability decline in HDFs and in tumor MCF-7 cells. Moreover, PRO/GEM decreased G1, S and G2/M phases, concomitantly with an increase of subG1 phase in MIA PaCa-2 and PANC-1 cells. Differently, PRO/GEM restored the normal progression of the cell cycle, altered by GEM, and decreased cell death in HDFs. PRO alone increased mitochondrial reactive oxygen species (ROS) in MIA PaCa-2, PANC-1 cells and HDFs, while PRO/GEM increased both intracellular and mitochondrial ROS in the three cell lines. These results indicate that specific combinations of PRO/GEM may be used to induce cytotoxic effects in pancreatic tumor MIA PaCa-2 and PANC-1 cells, but have cytoprotective or no effects in HDFs.
Language	English
Publishing date	2021-01-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2193542-7
ISSN	1424-8247
ISSN	1424-8247
DOI	10.3390/ph14020090
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Article ; Online: Cell-specific pattern of berberine pleiotropic effects on different human cell lines.

Agnarelli, Alessandro / Natali, Marco / Garcia-Gil, Mercedes / Pesi, Rossana / Tozzi, Maria Grazia / Ippolito, Chiara / Bernardini, Nunzia / Vignali, Robert / Batistoni, Renata / Bianucci, Anna Maria / Marracci, Silvia

Scientific reports

2018 Volume 8, Issue 1, Page(s) 10599

Abstract: The natural alkaloid berberine has several pharmacological properties and recently received attention as a potential anticancer agent. In this work, we investigated the molecular mechanisms underlying the anti-tumor effect of berberine on glioblastoma ... ...

Abstract	The natural alkaloid berberine has several pharmacological properties and recently received attention as a potential anticancer agent. In this work, we investigated the molecular mechanisms underlying the anti-tumor effect of berberine on glioblastoma U343 and pancreatic carcinoma MIA PaCa-2 cells. Human dermal fibroblasts (HDF) were used as non-cancer cells. We show that berberine differentially affects cell viability, displaying a higher cytotoxicity on the two cancer cell lines than on HDF. Berberine also affects cell cycle progression, senescence, caspase-3 activity, autophagy and migration in a cell-specific manner. In particular, in HDF it induces cell cycle arrest in G2 and senescence, but not autophagy; in the U343 cells, berberine leads to cell cycle arrest in G2 and induces both senescence and autophagy; in MIA PaCa-2 cells, the alkaloid induces arrest in G1, senescence, autophagy, it increases caspase-3 activity and impairs migration/invasion. As demonstrated by decreased citrate synthase activity, the three cell lines show mitochondrial dysfunction following berberine exposure. Finally, we observed that berberine modulates the expression profile of genes involved in different pathways of tumorigenesis in a cell line-specific manner. These findings have valuable implications for understanding the complex functional interactions between berberine and specific cell types.
MeSH term(s)	Apoptosis/drug effects ; Autophagy/drug effects ; Berberine/pharmacology ; Berberine/therapeutic use ; Carcinogenesis/drug effects ; Carcinogenesis/pathology ; Caspase 3/metabolism ; Cell Line, Tumor ; Cell Movement/drug effects ; Cell Proliferation/drug effects ; Cell Survival/drug effects ; Cellular Senescence/drug effects ; Citrate (si)-Synthase/metabolism ; Drug Screening Assays, Antitumor ; Fibroblasts ; G2 Phase Cell Cycle Checkpoints/drug effects ; Humans ; Mitochondria/drug effects ; Mitochondria/metabolism ; Neoplasms/drug therapy ; Neoplasms/pathology
Chemical Substances	Berberine (0I8Y3P32UF) ; Citrate (si)-Synthase (EC 2.3.3.1) ; CASP3 protein, human (EC 3.4.22.-) ; Caspase 3 (EC 3.4.22.-)
Language	English
Publishing date	2018-07-13
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-28952-3
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Article: Incorporating Immunotherapy in the Management of Gastric Cancer: Molecular and Clinical Implications.

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Article ; Online: Loss of POLE3-POLE4 unleashes replicative gap accumulation upon treatment with PARP inhibitors.

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Article ; Online: Phosphorus and sulfur SAD phasing of the nucleic acid-bound DNA-binding domain of interferon regulatory factor 4.

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Article ; Online: IRF4 in multiple myeloma-Biology, disease and therapeutic target.

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Article ; Online: Dissecting the impact of bromodomain inhibitors on the Interferon Regulatory Factor 4-MYC oncogenic axis in multiple myeloma.

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Article ; Online: The Inhibitory Properties of a Novel, Selective LMTK3 Kinase Inhibitor.

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Article: Protopine/Gemcitabine Combination Induces Cytotoxic or Cytoprotective Effects in Cell Type-Specific and Dose-Dependent Manner on Human Cancer and Normal Cells.

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Article ; Online: Cell-specific pattern of berberine pleiotropic effects on different human cell lines.

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