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Role of Akt signaling in resistance to DNA-targeted therapy

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World Journal of Clinical Oncology 2016年第5期7卷 352-369页

作者： Abolfazl Avan Ravi Narayan elisa giovannetti Godefridus J Peters Department of Medical Oncology VU University Medical Center Department of Radiation Oncology VU University Medical Center

The Akt signal transduction pathway controls most hallmarks of cancer. Activation of the Akt cascade promotes a malignant phenotype and is also widely implicated in drug resistance. Therefore, the modulation of Akt activity is regarded as an attractive strategy to enhance the efficacy of cancer therapy and irradiation. This pathway consists of phosphatidylinositol 3 kinase(PI3K), mammalian target of rapamycin, and the transforming serine-threonine kinase Akt protein isoforms, also known as protein kinase B. DNA-targeted agents, such as platinum agents, taxanes, and antimetabolites, as well as radiation have had a significant impact on cancer treatment by affecting DNA replication, which is aberrantly activated in malignancies. However, the caveat is that they may also trigger the activation of repairing mechanisms, such as upstream and downstream cascade of Akt survival pathway. Thus, each target can theoretically be inhibited in view of improving the potency of conventional treatment. Akt inhibitors, e.g., MK-2206 and perifosine, or PI3K modulators, e.g., LY294002 and Wortmannin, have shown some promising results in favor of sensitizing the cancer cells to the therapy in vitro and in vivo, which have provided the rationale for incorporation of these novel agents into multimodality treatment of different malignancies. Nevertheless, despite the acceptable safety profile of some of these agents in the clinical studies, with regard to the efficacy, the results are still too preliminary. Hence, we need to wait for the upcoming data from the ongoing trials before utilizing them into the standard care of cancer patients.

关键词： Phosphatidylinositol 3 kinase/Akt Platinum Taxane Antimetabolite Radiation

Fungal mycobiome-mediated immune response:a non-negligible promoter in pancreatic oncogenesis and chemoresistance

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Cancer Drug Resistance 2023年第2期6卷 284-290页

作者： Yaling Jiang Valentina Donati Godefridus J.Peters elisa giovannetti Dong Mei Deng Department of Preventive Dentistry Academic Center for Dentistry Amsterdam(ACTA)University of Amsterdam and Vrije Universiteit AmsterdamAmsterdam 1081 LANetherlands Department of Medical Oncology Amsterdam University Medical Centerslocation VUMCVrije Universiteit AmsterdamAmsterdam 1081 HVNetherlands Unit of Pathological Anatomy 2 Azienda Ospedaliero-Universitaria PisanaPisa 56100Italy Department of Biochemistry Medical University of GdanskGdansk 80-210Poland Fondazione Pisana per la Scienza ONLUS San Giuliano TermePisa 56017Italy

Pancreatic ductal adenocarcinoma(PDAC)is one of the most lethal cancers in humans due to late diagnosis and poor response to *** tumor microenvironment(TME)of PDAC is characterized by a distinctive,suppressive immune profile,which inhibits the protective functions of anti-tumor immunity and thereby contributes to PDAC ***,the study of Alam et *** for the first time that the intratumoral fungal mycobiome could contribute to the recruitment and activation of type 2 immune cells in the TME of PDAC via enhancing the secretion of a chemoattractant,interleukin(IL-)*** this article,we reviewed the important findings of this *** with our findings,we synthetically discussed the role of the fungal mycobiome in orchestrating the immune response and thereby modulating tumor progression.

关键词： Mycobiome pancreatic cancer chemoresistance interleukin 33 type 2 immune cells

Tyrosine kinase inhibitors:Multi-targeted or single-targeted?

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World Journal of Clinical Oncology 2011年第2期2卷 80-93页

作者： Fleur Broekman elisa giovannetti Godefridus J Peters Department of Medical Oncology VU University Medical Center1007 MB AmsterdamThe Netherlands

Since in most tumors multiple signaling pathways are involved,many of the inhibitors in clinical development are designed to affect a wide range of targeted *** most important tyrosine kinase families in the development of tyrosine kinase inhibitors are the ABL,SCR,platelet derived growth factor,vascular endothelial growth factor receptor and epidermal growth factor receptor *** multi-kinase inhibitors and singlekinase inhibitors have advantages and disadvantages,which are related to potential resistance mechanisms,pharmacokinetics,selectivity and tumor *** different malignancies various tyrosine kinases are mutated or overexpressed and several resistance mechanisms *** is influenced by interindividual differences and differs for two single targeted inhibitors or between patients treated by the same tyrosine kinase *** tyrosine kinase inhibitors have various mechanisms to achieve selectivity,while differences in gene expression exist between tumor and stromal *** these aspects,one type of inhibitor can generally not be preferred above the other,but will depend on the specific genetic constitution of the patient and the tumor,allowing personalized *** most effective way of cancer treatment by using tyrosine kinase inhibitors is to consider each patient/tumor individually and to determine the strategy that specifically targets the consequences of altered(epi)genetics of the *** strategy might result in treatment by a single multi kinase inhibitor for one patient,but in treatment by a couple of single kinase inhibitors for other patients.

关键词： Tyrosine kinase inhibitors Targeted therapy Epidermal growth factor receptor Vascular endothelial growth factor receptor Platelet derived growth factor Breakpoint cluster region-Abelson murine leukemia oncogene homolog 1 Janus kinase

FOLFIRINOX and translational studies: Towards personalized therapy in pancreatic cancer

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World Journal of Gastroenterology 2016年第31期22卷 6987-7005页

作者： Chiara Caparello Laura L Meijer Ingrid Garajova Alfredo Falcone Tessa Y Le Large Niccola Funel Geert Kazemier Godefridus J Peters Enrico Vasile elisa giovannetti University Hospital of Pisa 56124 Pisa Italy Department of Medical Oncology VU University Medical Center 1081 HV Amsterdam The Netherlands Department of Surgery VU University Medical Center 1081 HV Amsterdam The Netherlands Department of Experimental Diagnostic and Speciality Medicine University of Bologna Sant'Orsola-Malpighi Hospital Via Massarenti 9 40138 Bologna Italy Cancer Pharmacology Lab AIRC Start-Up Unit University of Pisa 56124 Pisa Italy CNR-Nano Institute of Nanoscience and Nanotechnology University of Pisa 56124 Pisa Italy

Pancreatic cancer is an extremely aggressive disease; although progress has been made in the last few years, the prognosis of these patients remains dismal. FOLFIRINOX is now considered a standard treatment in first-line setting, since it demonstrated an improved overall and progression-free survival vs gemcitabine alone. However, the enthusiasm over the benefit of this three-drug regimen is tempered by the associated increased toxicity profile, and many efforts have been made to improve the feasibility of this schedule. After a more recent phase Ⅲ trial showing an improved outcome over gemcitabine, the combination of gemcitabine/nab-paclitaxel emerged as another standard first-line treatment. However, this treatment is also associated with more side effects. In addition, despite initial promising data on the predictive role of SPARClevels, recent studies showed that these levels are not associated with nab-paclitaxel efficacy. The choice to use this treatment over FOLFIRINOX is therefore a topic of debate, also because no validated biomarkers to guide FOLFIRINOX treatment are available. In the era of actionable mutations and target agents it would be desirable to identify molecular factors or biomarkers to predict response to therapy in order to maximize the efficacy of treatment and avoid useless toxic effects for non-responding patients. However, until today the milestone of treatment for pancreatic cancer remains chemotherapy combinations, without predictive or monitoring tools existing to optimize therapy. This review analyzes the state-of-the-art treatments, promises and limitations of targeted therapies, ongoing trials and future perspectives, including potential role of microR NAs as predictive biomarkers.

关键词： FOLFIRINOX Personalized therapy New treatments MicroR NA Pancreatic cancer

Resistance to epidermal growth factor receptor inhibition in non-small cell lung cancer

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Cancer Drug Resistance 2018年第4期1卷 230-249页

作者： Nele Van Der Steen elisa giovannetti Daniela Carbone Alessandro Leonetti Christian D.Rolfo Godefridus J.Peters Department of Medical Oncology VU University Medical CenterAmsterdam 1081 HVthe Netherlands Department of Pathology Antwerp University HospitalAntwerp 2650Belgium Center for Oncological Research University of AntwerpAntwerp 2610Belgium Cancer Pharmacology Lab AIRC Start-Up UnitUniversity of PisaPisa 56124Italy Medical Oncology Unit University Hospital of ParmaParma 43126Italy University of Maryland Greenebaum Comprehensive Cancer Center Baltimore21220 MDUSA

Aberrant activation of the epidermal growth factor receptor(EGFR)is a driving force for cancer growth in a subgroup of non-small cell lung cancer *** patients can be identified by the presence of activating EGFR *** three generations of EGFR-tyrosine kinase inhibitors(TKIs)have been approved by the Food and Drug Administration and European Medicine *** paper reviews the structure of EGFR and the downstream signaling pathways of EGFR and describes the mechanisms of intrinsic and acquired resistance against *** mechanisms include secondary or tertiary mutations in EGFR,the activation of bypassing signaling pathways or a histological transformation to small cell lung ***,drug efflux transporters will affect the cellular accumulation of EGFR-TKIs and penetration of the first generation of EGFR-TKI into the *** sequestration of some EGFR-TKIs may also prevent the drugs to reach their *** conclusion,resistance to EGFR-TKIs is multifactorial,including primary and acquired mutations in the EGFR gene,activation of bypassing pathways and limited uptake of drugs in the cells or target *** pharmacological studies are needed in order to develop new specific compounds targeted to overcome new resistance mechanisms in order to enable a personalized treatment approach.

关键词： Epidermal growth factor receptor non-small cell lung cancer resistance EGFR-tyrosine kinase inhibitors erlotinib gefitinib afatinib osimertinib rociletinib

Better to be alone than in bad company:The antagonistic effect of cisplatin and crizotinib combination therapy in non-small cell lung cancer

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World Journal of Clinical Oncology 2016年第6期7卷 425-432页

作者： Nele Van Der Steen Christophe Deben Vanessa Deschoolmeester An Wouters Filip Lardon Christian Rolfo Paul Germonpré elisa giovannetti Godefridus J Peters Patrick Pauwels Center for Oncological Research University of Antwerp Department of Pathology Antwerp University Hospital Department of Medical Oncology VU University Medical Center Department of Oncology Antwerp University Hospital Department of Pneumology Cancer Pharmacology Lab AIRC Start-Up UnitUniversity of Pisa

AIM To investigate the potential benefit of combining the cMET inhibitor crizotinib and cisplatin we performed in vitro combination *** We tested three different treatment schemes in four non-small cell lung cancer(NSCLC) cell lines with a different cMET/epidermal growth factor receptor genetic background by means of the sulforhodamine B assay and performed analysis with *** All treatment schemes showed an antagonistic effect in all cell lines,independent of the cMET *** their different genetic backgrounds,all cell lines(EBC-1,HCC827,H1975 and LUDLU-1) showed antagonistic combination indexes ranging from *** results were independent of the treatment *** These results discourage further efforts to combine cMET inhibition with cisplatin chemotherapy in NSCLC.

关键词： Non-small cell lung cancer Combination therapy Cisplatin Crizotinib cMET

SF3B1 modulators affect key genes in metastasis and drug influx: a new approach to fight pancreatic cancer chemoresistance

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Cancer Drug Resistance 2021年第4期4卷 904-922页

作者： Ornella Randazzo Stella M.Cascioferro Camilla Pecoraro Widad Ait Iddouch Amir Avan Barbara Parrino Daniela Carbone Ugo Perricone Godefridus J.Peters Patrizia Diana elisa giovannetti Department of Medical Oncology Cancer Center AmsterdamAmsterdam UMCVU University Medical CenterAmsterdam 1081 HVThe Netherlands Dipartimento di Scienze e Tecnologie Biologiche Chimiche e Farmaceutiche(STEBICEF) Universitàdegli Studi di PalermoPalermo 90133Italy Metabolic Syndrome Research Center Mashhad University of Medical SciencesMashhad 91886-17871Iran Cancer Research Center Mashhad University of Medical SciencesMashhad 91886-17871Iran Student Research Committee School of MedicineMashhad University of Medical SciencesMashhad 91886-17871Iran Drug Discovery Unit Fondazione Ri.MEDPalermo 90128Italy Department of Biochemistry Medical University of GdanskGdansk 80-210Poland Cancer Pharmacology Lab AIRC Start Up UnitFondazione Pisana per la ScienzaPisa 56124Italy.

Aim:Because mutations of splicing factor 3B subunit-1(SF3B1)have been identified in 4%of pancreatic ductal adenocarcinoma(PDAC)patients,we investigated the activity of new potential inhibitors of SF3B1 in combination with gemcitabine,one of the standard drugs,in PDAC cell ***:One imidazo[2,1-b][1,3,4]thiadiazole derivative(IS1)and three indole derivatives(IS2,IS3 and IS4),selected by virtual screening from an in-house library,were evaluated by the sulforhodamine-B and wound healing assay for their cytotoxic and antimigratory activity in the PDAC cells SUIT-2,Hs766t and Panc05.04,the latter harbouring the SF3B1 *** effects on the splicing pattern of proto-oncogene recepteur d’origine nantais(RON)and the gemcitabine transporter human equilibrative nucleoside transporter-1(hENT1)were assessed by PCR,while the ability to reduce tumour volume was tested in spheroids of primary PDAC ***:The potential SF3B1 modulators inhibited PDAC cell proliferation and prompted induction of cell *** compounds showed an interesting anti-migratory ability,associated with splicing RON/ΔRON shift in SUIT-2 cells after 24 h ***,IS1 and IS4 potentiated the sensitivity to gemcitabine in both conventional 2D monolayer and 3D spheroid cultures,and these results might be explained by the statistically significant increase in hENT1 expression(P<0.05 *** control cells),potentially reversing PDAC ***:These results support further studies on new SF3B1 inhibitors and the role of RON/hENT1 modulation to develop effective drug combinations against PDAC.

关键词： Pancreatic ductal adenocarcinoma gemcitabine indole derivatives anti-proliferative activity anti-migratory activity SF3B1 RON hENT1

Five Stylized Facts on Belt and Road Countries and Their Trade Patterns

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China & World Economy 2023年第1期31卷 149-181页

作者： Kaku Attah Damoah Giorgia giovannetti Enrico Marvasi Department of Economics and Management University of FlorenceItaly Department of Economics and Management University of FlorenceItalyand European University InstituteItaly Department of Economics Roma Tre UniversityItaly

The Belt and Road Initiative(BRI)offers investment opportunities for several Eurasian countries but not all of them attract investments in the same *** paper investigates the geographical distribution of BRI projects completed between 2013 and *** analysis shows that pre-existing trade patterns are related to the likelihood of a country receiving completed BRI *** single out and provide evidence in support of five stylized ***,BRI countries with completed projects tend to be poorer and ***,projects are more likely to occur in countries with intense intermediate trade with ***,the countries that received projects have more diversified export structures and their sectoral specialization overlaps with that of ***,among middle-high-income countries,the allocation ofprojects tends to favor those with high levels of intra-industry ***,among BRI countries with projects,the complexity or sophistication of the goods traded increases faster with *** findings suggest that fostering trade integration has direct benefits and may also contribute to further BRI investments.

关键词： Belt and Road Initiative China global value chains network trade in intermediates

The management of the long head of the biceps in rotator cuff repair:A comparative study of high *** tenodesis

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Journal of Sport and Health Science 2023年第5期12卷 613-618页

作者： Edoardo Franceschetti Edoardo giovannetti de Sanctis Alessio Palumbo Michele Paciotti Luca La Verde Nicola Maffulli Francesco Franceschi Department of Orthopaedic and Trauma Surgery Campus Biomedico University of RomeVia Alvaro del Portillo 20000100 RomeItaly Department of Orthopaedics and Traumatology Catholic UniversityAgostino Gemelli Hospital00100 RomeItaly Anca Surgical Center Via Francesco Maidalchini 20Roma00152RomeItaly Department of Musculoskeletal Disorders Via Salvador Allende4384081 BaronissiSalernoItaly Centre for Sports and Exercise Medicine Barts and The London School of Medicine and DentistryMile End Hospital275 Bancroft RoadLondon E14DGEnglandUK School of Pharmacy and Bioengineering Keele University School of MedicineThornburrow DriveStoke on Trent ST4EnglandUK

Background:Tenodesis of the long head of the biceps(LHB)is commonly undertaken during arthroscopic rotator cuff *** assessed the clinical and structural outcomes after high arthroscopic tenodesis(HAT)or mini-open subpectoral tenodesis(ST).We hypothesized that the clinical and structural results after HAT and ST are ***:We included 40 patients with rotator cuff tear and LHB *** patients(7 women and 13 men;mean age:57.9 years;range:56-63 years)were treated using HAT,and 20 patients(8 women and 12 men;mean age:58.5 years;range:55-64 years)were treated using *** evaluation was performed preoperatively and at 6 weeks,6 months,and 1 year after surgery,using the Constant Murley Score and Simple Shoulder Test scores;the LHB was evaluated using the LHB score.A Visual Analogue Scale was administered to all patients preoperatively and 2 days after ***:The postoperative total and pain subscale’s Constant scores were significantly higher in the ST ***,2 LHB score values were significantly different between the *** postoperative LHB total score in the ST and HAT groups averaged 86.9±4.1(mean±SD)points and 73.3±6.4 points,*** Pain/Cramps subscale in the ST and HAT groups averaged 47.1±5.9 and 33.2±4.6 points,*** 2 groups showed no difference in Visual Analogue Scale values(5.5 in the HAT group;5.8 in the ST group)*** patient in the HAT group reported a secondary onset of Popeye ***:Both high arthroscopic and mini-open ST of the LHB tendon produced reliably good functional results,but the ST group was associated with better postoperative clinical outcomes.

关键词： Long head of the biceps Shoulder Shoulder arthroscopy Subpectoral TenodesisTagedEnd