A5003221695- Lymphoma Diagnosis and Treatment
- DNA Repair Mechanisms
- PI3K/AKT/mTOR signaling in cancer
- Protein Degradation and Inhibitors
- Radiopharmaceutical Chemistry and Applications
- Cancer-related Molecular Pathways
- Monoclonal and Polyclonal Antibodies Research
- Microtubule and mitosis dynamics
- Cancer therapeutics and mechanisms
- Peroxisome Proliferator-Activated Receptors
- Cancer-related gene regulation
- Acute Lymphoblastic Leukemia research
- Chronic Lymphocytic Leukemia Research
- RNA modifications and cancer
- Sarcoma Diagnosis and Treatment
- Lung Cancer Treatments and Mutations
- Synthesis and Biological Evaluation
- CAR-T cell therapy research
- Peptidase Inhibition and Analysis
- DNA and Nucleic Acid Chemistry
- Ubiquitin and proteasome pathways
- Ovarian cancer diagnosis and treatment
- Synthesis and biological activity
- Cancer Mechanisms and Therapy
- Epigenetics and DNA Methylation
Ospedale San Donato
2024
Mario Negri Institute for Pharmacological Research
2012-2023
Piedmont Reference Center for Epidemiology and Cancer Prevention
2021-2022
Azienda Usl 8 Arezzo
2022
Istituti di Ricovero e Cura a Carattere Scientifico
2013-2019
Laboratory of Molecular Genetics
2012-2013
Molecular Oncology (United States)
2008
Targeting Chk1 protein kinase can enhance the antitumor effects of radio- and chemotherapy. Recent evidence disclosed a role in unperturbed cell proliferation survival, implying that inhibitors could also be effective as single agents tumors with specific genetic background. To identify genes synthetic lethality Chk1, we did high-throughput screening using siRNA library directed against 719 human kinases ovarian cancer line OVCAR-5, resistant to inhibitors. Wee1 tyrosine was most significant...
Abstract Purpose: Activation of the PI3K/mTOR signaling pathway is recurrent in different lymphoma types, and pharmacologic inhibition has shown activity patients. Here, we extensively characterized vitro vivo mechanism action PQR309 (bimiralisib), a novel oral selective dual inhibitor under clinical evaluation, preclinical models. Experimental Design: This study included screening on large panel cell lines, both as single agent combination, validation experiments models primary cells,...
The cytotoxic activity of ecteinascidin 743 (ET-743), a natural product derived from the marine tunicate Ecteinascidia turbinata that exhibits potent anti-tumor in pre-clinical systems and promising phase I II clinical trials, was investigated number cell with well-defined deficiencies DNA-repair mechanisms. ET-743 binds to N2 guanine minor groove, but its does not appear be related DNA-topoisomerase poisoning as drug is equally active wild-type yeast deletion gene. Defects mismatch repair...
// Rosaria Chilà 1 , Alessandra Basana Monica Lupi Federica Guffanti Eugenio Gaudio 2 Andrea Rinaldi Luciano Cascione 2, 3 Valentina Restelli Chiara Tarantelli Francesco Bertoni Giovanna Damia Laura Carrassa Laboratory of Molecular Pharmacology and Cancer Pharmacology, Department Oncology, IRCCS- Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy Lymphoma Genomics Research Program, IOR Institute Oncology Research, Bellinzona, Switzerland Unit, IOSI Southern Switzerland,...
Transcription factors are commonly deregulated in cancer, and they have been widely considered as difficult to target due their nonenzymatic mechanism of action. Altered expression levels members the ETS-transcription often observed many different tumors, including lymphomas. Here, we characterized two small molecules, YK-4-279 its clinical derivative, TK-216, targeting ETS via blocking protein-protein interaction with RNA helicases, for antilymphoma activity.The study included preclinical...
Abstract Despite the development of new targeted and immune therapies, prognosis metastatic melanoma remains bleak. Therefore, it is critical to better understand mechanisms controlling advanced develop more effective treatment regimens. Hedgehog/GLI (HH/GLI) signaling inhibitors targeting central pathway transducer Smoothened (SMO) have shown be clinical efficacious in skin cancer; however, several non-canonical HH/GLI activation limit their efficacy. Here, we identify a novel SOX2-BRD4...
Posttranslational modifications of p53 induced by two widely used anticancer agents, cisplatinum (DDP) and taxol were investigated in human cancer cell lines. Although both drugs able to induce phosphorylation at serine 20 (Ser20), only DDP treatment 15 (Ser15). Moreover, drug treatments increase levels consequently the transcription waf1 mdm-2 genes, although resulted a stronger inducer genes. Using ataxia telangiectasia mutated (ATM) lines, role ATM druginduced phosphorylations was...
Mammalian Chk1 and Chk2 protein kinases are two important components of the G(2) DNA damage checkpoint. They activated by upstream (ataxia telangectasia mutated gene ATM Rad 3 related gene) interfere with activity cdc2/cyclinB1 complex, necessary for G(2)-M transition, through inactivation cdc25 phosphatases (cdc25A cdc25C). To understand role in cellular response to different anticancer agents, we knocked down expression each or simultaneously both proteins using small interfering RNA...
Allosteric targeting of protein kinases via displacement the structural αC helix with type III allosteric inhibitors is currently gaining a foothold in drug discovery. Recently, first crystal structure CDK2 an open pocket adjacent to has been described, prospecting new opportunities design more selective inhibitors, but not yet exploited for structure-based inhibitors. In this work we report results virtual screening campaign that resulted discovery first-in-class ligands CDK2. Using...
Mucinous epithelial ovarian cancer (mEOC) is a rare subset of cancer. When diagnosed at late stage, its prognosis very poor, as it quite chemo-resistant. To find new therapeutic options for mEOC, we performed high-throughput screening using siRNA library directed against human protein kinases in mEOC cell line, and polo-like kinase1 (PLK1) was identified the kinase whose downregulation interfered with proliferation. Both PLK1 two specific inhibitors (onvansertib volasertib) were able to...
The DNA damage response (DDR) kinases ATR, Chk1, and Wee1 play vital roles in the to replication stress maintaining cancer genomic stability. Inhibitors of these are currently under clinical investigation. Mantle cell lymphoma (MCL) diffuse large B-cell (DLBCL) aggressive lymphomas whose outcome is still largely unsatisfactory. These subtypes highly dependent on both Chk1 for survival. We investigated activity ATR inhibitor AZD6738 as single agent combination with either (AZD6738) or...
Abstract Chk1 is a conserved protein kinase originally identified in fission yeast, required to delay entry of cells with damaged or unreplicated DNA into mitosis. The requirement for both S and G2/M checkpoints has been elucidated while only few studies have connected the mitotic spindle checkpoint. We used small interference RNA strategy investigate role unstressed conditions. depletion U2OS human osteosarcoma inhibited cell proliferation raised percentage 4N content, which correlated...
Abstract Purpose: After DNA damage, checkpoints pathways are activated in the cells to halt cell cycle, thus ensuring repair or inducing death. To better investigate role of checkpoint kinase 1 (Chk1) cellular response different anticancer agents, Chk1 was knocked down HCT-116 line and its p53-deficient subline by using small interfering RNAs (siRNA). Experimental Design: abrogated transient transfection specific siRNA against it, stable tetracycline-inducible clones were obtained...
Chk1 kinase is a key signal transducer in the checkpoint pathways responding to DNA damage. has been shown be transcriptionally down-regulated response cis-dichloro-diamino platinum treatment p53-dependent manner. Now we isolated and characterised 5' flanking region of gene. We demonstrated that promoter activity when cloned upstream reporter luciferase gene could define minimal region. The modulation transcriptional by different transcription factors was investigated co-transfection...
Chk1 is implicated in several checkpoints of the cell cycle acting as a key player signal transduction pathway activated response to DNA damage and crucial for maintenance genomic stability. also plays role mitotic spindle checkpoint, which ensures fidelity segregation during mitosis, preventing chromosomal instability aneuploidy. Mad2 one main checkpoint components exerts cellular damage. To investigate possible crosslink existing between Mad2, we studied protein levels after inhibition...
// Valentina Restelli 1 , Rosaria Chilà Monica Lupi Andrea Rinaldi 2 Ivo Kwee 2,3,4 Francesco Bertoni 2,5 Giovanna Damia and Laura Carrassa Laboratory of Molecular Pharmacology Cancer Pharmacology, Department Oncology, IRCCS- Istituto di Ricerche Farmacologiche "Mario Negri", Milan, Italy Lymphoma Genomics Research Program, IOR Institute Oncology Research, Bellinzona, Switzerland 3 Dalle Molle for Artificial Intelligence (IDSIA), Manno, 4 Swiss Bioinformatics (SIB), Lausanne, 5 Unit, IOSI...
BackgroundThe outcome of patients affected by mantle cell lymphoma (MCL) has improved in recent years, but there is still a need for novel treatment strategies these patients. Human cancers, including MCL, present recurrent alterations genes that encode transcription machinery proteins and involved regulating chromatin structure, providing the rationale to pharmacologically target epigenetic proteins. The Bromodomain Extra Terminal domain (BET) family act as transcriptional regulators key...
Abstract Purpose: This study was aimed at investigating whether the PPARγ agonist pioglitazone—given in combination with trabectedin—is able to reactivate adipocytic differentiation myxoid liposarcoma (MLS) patient-derived xenografts, overcoming resistance trabectedin. Experimental Design: The antitumor and biological effects of trabectedin, pioglitazone, two drugs were investigated nude mice bearing well-characterized MLS xenografts representative innate or acquired against Pioglitazone...
In vitro and in vivo studies have demonstrated that UCB (unconjugated bilirubin) is neurotoxic. Although previous suggested both MRP1 (multidrug resistance-associated protein 1) MDR1 resistance may protect cells against accumulation of UCB, direct comparison their role transport was never performed. To this end, we used an inducible siRNA (small interfering RNA) expression system to silence the human neuroblastoma SH-SY5Y cells. The effects exposure clinically-relevant levels unbound were...