REPORT SULLE ATTIVITÀ SVOLTE Corso di dottorato Fisiopatologia Clinica Cognome Del Re
Nome Marzia
Titolo della tesi
Development of a pharmacogenetic-based approach for prevention of fluoropyrimidine-related toxicities and diagnosis of resistance to targeted treatments in cancer patients.
Progetto di ricerca
The first part of the study was aimed at retrospectively evaluating the possible association of DPD polymorphisms and treatment-associated toxicities occurred in patients given fluoropyrimidines. The study included 1254 patients divided into two groups. Cohort 1 included 982 patients suffering from gastrointestinal G≥2 and hematological G≥3 ADRs that were examined for DPYD variants c.496A>G, c.1236G>A, c.1601G>A (DPYD*4), c.1627A>G (DPYD*5), c.1679T>G (DPYD*13), c.1896T>C, c. 1905+1G>A (DPYD*2A), c.2194G>A (DPYD*6), and c.2846A>T to assess their association with ADRs. Cohort 2 (control group) comprised 272 subjects not requiring dose reduction, delay or discontinuation of treatment that were screened for the same variants of cohort 1. Genetic analysis in the two cohorts were done by Real-Time PCR of DNA extracted from 3 ml of whole blood. The DPYD c.496A>G, c.1601G>A, c.1627A>G, c.1896T>C, and c.2194G>A variants were found in both cohort 1 and 2 while c.1905+1G>A and c. 2846A>T were present only in cohort 1. DPYD c.1679T>G and c.1236G>A were not found. Univariate analysis allowed the selection of c.1905+1G>A, c.2194G>A and c. 2846A>T alleles as significantly associated with gastrointestinal and hematological ADRs (p<0.05), while the c.496A>G variant showed a positive trend of association with neutropenia (p=0.06). The use of dihydropyrimidine dehydrogenase (DPYD) as a routinary test to predict fluoropyrimidines adverse drug reactions (ADRs) is still debated. The present study associates c.2194G>A to clinically relevant ADRs in addition to the already known c.1905+1G>A and c.2846A>T and suggests the analysis of these three variants to reduce the risk of fluoropyrimidine-associated ADRs.
The second part of the project was aimd at evaluating if circulating tumor nucleic acids may be a good and useful tool to monitor treatment outcome in solid tumors. Patients affected by lung cancer, prostate cancer, pancreatic cancer and melanoma have been enrolled and monitored during treatment with chemo- or target therapy by circulating tumor nucleic acids. Nucleic acids were extracted from plasma samples and analysed by digital droplet PCR for targetable drivers or for acquired mutations selected during therapy. Circulating tumor nucleic acids were find to correlate with tumor burden, disease status and rensponse to treatment, beeing a good candidate to monitor tumor response.
Attività formative previste dal corso di Dottorato
- Inglese accademico “EAP course C1” aa 2014/2015 (votazione esame finale: very good) - Inglese accademico “EAP course C1+” aa 2015/2016 (votazione esame finale:
excellent)
Attività formative inerenti al corso di Dottorato
- Vincitrice Bando Erasmus 2015/2016 per borse di studio all’estero per un periodo di 2 mesi alla Erasmus University Medical Center - Rotterdam (NL)
Durante il periodo all’estero è stata svolta una parte del progetto di dottorato,
inerente alle resistenze al trattamento nel tumore della prostata ed è stata messa a punto una metodica non invasiva per valutare biomarcatori predittivi di resistenza al trattamento su esosomi estratti dal plasma (Del Re M., et al. The Detection of Androgen Receptor Splice Variant 7 in Plasma-derived Exosomal RNA Strongly Predicts Resistance to Hormonal Therapy in Metastatic Prostate Cancer Patients. Eur Urol. 2017 Apr;71(4): 680-687).
- Vincitrice Bando Erasmus 2016/2017 per borse di studio all’estero per un periodo di 3 mesi alla Erasmus University Medical Center - Rotterdam (NL)
Durante il periodo all’estero è stata svolta una parte del progetto di dottorato,
inerente alle resistenze al trattamento nel tumore del polmone ed è stata messa a punto una metodica non invasiva per valutare biomarcatori predittivi di resistenza al trattamento su DNA tumorale circolante nel plasma (Del Re M., et al. Patients with NSCLC may display a low ratio of p.T790M vs. activating EGFR mutations in plasma at disease
progression: implications for personalised treatment. Oncotarget. 2017 Sep 15;8(49): 86056-86065)
Partecipazione come relatore a convegni di società scientifiche nazionali ed internazionali e seminari tenuti nel triennio
1) Relatore al XVII Congresso Nazionale dell'Associazione Italiana Oncologia Medica (AIOM), Roma.
Titolo della relazione: L’eterogeneità del tumore della prostata: come la fisiopatologia suggerisce l’approccio farmacologico
dal 23-10-2015 al 25-10-2015
2) Relatore al Congresso Nazionale della Fondazione Gruppo Italiano per lo Studio dei Carcinomi dell'Apparato Digerente (GISCAD), Bergamo.
Titolo della Lettura: Biomarcatori nei tumori dell’apparato gastroenterico: dal laboratorio alla clinica
dal 06-11-2015 al 07-11-2015
3) Relatore al Convegno Nazionale di Medicina di Precisione e Target in Oncologia, Milano.
Titolo della relazione: Il laboratorio nella medicina di precisione il 12-05-2016
4) Relatore al XVII Congresso INTERNAZIONALE Golden Helix - Pharmacogenomics Day - Rotterdam.
Titolo della Relazione: Cell-free DNA analysis for lung and prostate cancer Il 27-05-2016
5) Organizzazione del II Congresso "The Young Biomarkers Day", patrocinato da SIF, AIOM e GoldenHelix Foundation, che si è tenuto presso IMT Institute for advanced studies, Lucca
6) Relatore al XVIII Congresso Nazionale dell'Associazione Italiana di Oncologia Medica (AIOM), Roma.
Titolo della Relazione: The detection of AR-V7 in plasma-derived exosomal RNA strongly predicts resistance to hormonal therapy in metastatic prostate cancer patients
dal 28-10-2016 al 30-10-2016
7) Relatore al Convegno Monotematico della Società Italiana di Farmacologia (SIF), Napoli.
Titolo della relazione: Pharmacogenetic evaluation of DPYD deficient variants for pre-emptive testing in patients candidate to receive fluoropyrimidine-based chemotherapy: a comprehensive analysis in 1454 patients.
dal 15-12-2016 al 16-12-2016
8) Relatore al Congresso INTERNAZIONALE della European Society of Medical Oncology (ESMO) - Madrid.
Titolo della relazione: Selecting the optimal combination partner for today’s immunotherapeutic approaches
dal 08-09-2017 al 12-09-2017
9) Relatore alla IV Conferenza INTERNAZIONALE della European Society of Pharmacogenomics and Personalised Therapy, Catania.
Titolo della relazione: Exosomal AR-V7 for early detection of prostate cancer resistance dal 04-10-2017 al 07-10-2017
10) Relatore al 90° Congresso Nazionale della Società Italiana di Urologia (SIU), Napoli. Titolo della relazione: Advanced Prostate Cancer – heterogeneity and clinical implications: what must be known
dal 07-10-2017 al 10-10-2017
11) Relatore al 38° Congresso Nazionale della Società Italiana di Farmacologia (SIF), Rimini.
Titolo della Relazione: Il ruolo del DNA circolante e liquorale nella personalizzazione del trattamento
dal 25-10-2017 al 28-10-2017
12) Relatore per seminario presso Istituto Superiore Sanità, Roma.
Titolo del seminario: Eterogeneità clonale tumorale: implicazioni per target therapies e inibitori dei checkpoints immunitari.
il 3/11/2017
13) Relatore al Congresso Internazionale dell’American Association of Cancer Research (AACR), Chicago (IL)
Titolo della relazione: “A key role for circulating nucleic acids as predictive biomarkers of response in immunotherapy and targeted treatments”
Dal 14-04-2018 al 18-04-2018
Riconoscimenti e premi ottenuti nel triennio
2014: Vincitrice del premio della Società Italiana di Farmacologia e di Assogenerici per gli studi condotti in Farmacologia clinica e Farmacogenetica
2016: Vincitrice del premio Fondazione Berlucchi per la miglior presentazione orale tenuta al XVIII Congresso Nazionale dell'Associazione Italiana di Oncologia Medica (AIOM), Roma. Titolo della Relazione: The detection of AR-V7 in plasma-derived exosomal RNA strongly predicts resistance to hormonal therapy in metastatic prostate cancer patients.
2016: Premio SIF-Farmindustria per ricerche di Farmacologia", per la pubblicazione "Contribution of KRAS mutations and c.2369C>T (p.T790M) EGFR to acquired resistance to EGFR-TKIs in EGFR mutant NSCLC: a study on circulating tumor DNA. Oncotarget. 2017 Feb 21;8(8):13611-13619.
2016: Vincitrice del travel grant ESO per partecipare alla conferenza “Molecular Diagnostics, Genomics and Epigenetics in Clinical Oncology Conference (Rome) - 25-26 November 2016
Lavori pubblicati nel triennio
1) Santoni M, Massari F, Del Re M, Ciccarese C, Piva F, Principato G, Montironi R, Santini D, Danesi R, Tortora G, Cascinu S. Investigational therapies targeting signal transducer and activator of transcription 3 for the treatment of cancer. Expert Opin Investig Drugs. 2015 Jun;24(6):809-24
2) Aprile G, Ongaro E, Del Re M, Lutrino SE, Bonotto M, Ferrari L, Rihawi K, Cardellino GG, Pella N, Danesi R, Fasola G. Angiogenic inhibitors in gastric cancers and gastroesophageal junction carcinomas: a critical insight. Crit Rev Oncol Hematol. 2015 Mar 5. pii: S1040-8428(15)00042-6
3) Di Paolo A, Polillo M, Lastella M, Bocci G, Del Re M, Danesi R. Methods for studying pharmacogenetic profiles of combination chemotherapeutic drugs. Expert Opin Drug Metab Toxicol. 2015 Aug;11(8):1253-67
4) Fontanelli G, Baratè C, Ciabatti E, Guerrini F, Grassi S, Del Re M, Morganti R, Petrini I, Arici R, Barsotti S, Metelli MR, Danesi R, Galimberti S. Real-Time PCR and Droplet Digital PCR: two techniques for detection of the JAK2V617F mutation in Philadelphia-negative chronic myeloproliferative neoplasms. Int J Lab Hematol. 2015 Dec;37(6):766-73
5) Ulivi P, Scarpi E, Passardi A, Marisi G, Calistri D, Zoli W, Del Re M, Frassineti GL, Tassinari D, Tamberi S, Vertogen B, Amadori D. eNOS polymorphisms as predictors of efficacy of bevacizumabbased chemotherapy in metastatic colorectal cancer: data from a randomized clinical trial. J Transl Med. 2015 Aug 11;13:258
6) Del Re M, Michelucci A, Di Leo A, Cantore M, Bordonaro R, Simi P, Danesi R. Discovery of novel mutations in the dihydropyrimidine dehydrogenase gene associated with toxicity of fluoropyrimidines and viewpoint on preemptive pharmacogenetic screening in patients. EPMA J. 2015 Sep 2;6(1):17
7) Sameen S, Barbuti R, Milazzo P, Cerone A, Del Re M, Danesi R. Mathematical modeling of drug resistance due to KRAS mutation in colorectal cancer. J Theor Biol. 2015 Nov 6;389:263-273
8) Fogli S, Mogavero S, Egan CG, Del Re M, Danesi R. Pathophysiology and pharmacological targets of VEGF in diabetic macular edema. Pharmacol Res. 2015;103:149-157
9) Bordi P, Del Re M, Danesi R, Tiseo M. Circulating DNA in diagnosis and monitoring EGFR gene mutations in advanced non-small cell lung cancer. Transl Lung Cancer Res 2015;4(5):584-597
10) Del Re M, Quaquarini E, Sottotetti F, Michelucci A, Palumbo R, Simi P, Danesi R, Bernardo A. Uncommon dihydropyrimidine dehydrogenase mutations and toxicity by fluoropyrimidines: a lethal case with a new variant. Pharmacogenomics. 2016;17(1):5-9
11) Del Re M, Tiseo M, Bordi P, D'Incecco A, Camerini A, Petrini I, Lucchesi M, Inno A, Spada D, Vasile E, Citi V, Malpeli G, Testa E, Gori S, Falcone A, Amoroso D, Chella A, Cappuzzo F, Ardizzoni A, Scarpa A, Danesi R. Contribution of KRAS mutations and c. 2369C>T (p.T790M) EGFR to acquired resistance to EGFR-TKIs in EGFR mutant NSCLC: a study on circulating tumor DNA. Oncotarget. 2017 Feb;8(8):13611-13619
12) Roviello G, Sigala S, Danesi R, Del Re M, Bonetta A, Cappelletti M, Zanotti L, Bottini A, Generali D. Incidence and relative risk of adverse events of special interest in patients with castration resistant prostate cancer treated with CYP-17 inhibitors: A meta-analysis of published trials. Crit Rev Oncol Hematol. 2016 May;101:12-20
13) Del Re M, Citi V, Crucitta S, Rofi E, Belcari F, van Schaik R.H, Danesi R. Pharmacogenetics of CYP2D6 and tamoxifen therapy: light at the end of the tunnel? Pharmacol Res. 2016 Apr;107:398- 406
14) Bordi P, Del Re M, Tiseo M. Crizotinib Resensitization by Compound Mutation. N Engl J Med. 2016 May 5;374(18):1790
15) Azzariti A, Porcelli L, Brunetti O, Del Re M, Longo V, Nardulli P, Signorile M, Xu JM, Calabrese A, Quatrale AE, Maiello E, Lorusso V, Silvestris N. Total and not
bound vascular endothelial growth factor as potential predictive factors to bevacizumab-based chemotherapy in colorectal cancer. World J Gastroenterol. 2016 Jul 21;22(27): 6287-95
16) Di Paolo A, Del Re M, Petrini I, Altavilla G, Danesi R. Recent advances in epigenomics in NSCLC: real-time detection and therapeutic implications. Epigenomics. 2016 Aug;8(8): 1151-67
17) Fogli S, Saba A, Del Re M, Pistelli F, Aquilini F, Zucchi R, Palla A, Breschi MC, Carrozzi L, Danesi R. Application of a pharmacokinetic/pharmacogenetic approach to assess the nicotine metabolic profile of smokers in the real-life setting. J Pharm Biomed Anal. 2016 Aug 31;131:208-213
18) Danesi R, Del Re M, Ciccolini J, Schellens JH, Schwab M, van Schaik RH, van Kuilenburg AB. Prevention of fluoropyrimidine toxicity: do we still have to try our patient's luck? Ann Oncol. 2017 Jan 1;28(1):183
19) Del Re M, Biasco E, Crucitta S, Derosa L, Rofi E, Orlandini C, Miccoli M, Galli L, Falcone A, Jester GW, van Schaik RH, Danesi R. The detection of AR-V7 in plasma-derived exosomal RNA strongly predicts resistance to hormonal therapy in metastatic prostate cancer patients. Eur Urol. 2017 Apr;71(4):680-687
20) Guerrini F, Paolicchi M, Ghio F, Ciabatti E, Grassi S, Salehzadeh S, Ercolano G, Metelli MR, Del Re M, Iovino L, Petrini I, Carrelli G, Lecconi N, Rousseau M, Cervetti G, Galimberti S. The Droplet Digital PCR: A New Valid Molecular Approach for the Assessment of B-RAF V600E Mutation in Hairy Cell Leukemia. Front. Pharmacy. 2016 Oct 13;7:363
21) Del Re M, Rofi E, Citi V, Fidilio L, Danesi R. Should CYP2D6 be genotyped when treating with tamoxifen? Pharmacogenomics. 2016 Dec;17(18):1967-1969
22) Arrigoni E, Del Re M, Fidilio L, Fogli S, Danesi R, Di Paolo A. Pharmacogenetic Foundations of Therapeutic Efficacy and Adverse Events of Statins. Int J Mol Sci. 2017 Jan 6;18(1)
23) Del Re M, Restante G, Crucitta S, Rofi E, Danesi R. Pharmacogenetics and metabolism from science to implementation in clinical practice: the example of dihydropyrimidine dehydrogenase . Curr Pharm Des. 2017 Jan;23(14):2028-2034.
24) Di Salvatore M, Pietrantonio F, Orlandi A, Del Re M, Berenato R, Rossi E, Caporale M, Guarino D, Martinetti A, Basso M, Mennitto R, Santonocito C, Mennitto A, Schinzari G, Bossi I, Capoluongo E, Danesi R, de Braud F, Barone C. IL-8 and eNOS polymorphisms predict bevacizumab-based first line treatment outcomes in RAS mutant metastatic colorectal cancer patients. Oncotarget. 2017 Mar;8(10):16887-16898
25) Manca P, Pantano F, Iuliani M, Ribelli G, De Lisia D, Danesi R, Del Re M, Vincenzi B, Tonini G, Santini D. Determinants of bone specific metastasis in prostate cancer. Oncol Hematol. 2017 Apr;112:59-66
26) Del Re M, Latiano T, Fidilio L, Restante G, Morelli F, Maiello E, Danesi R. Unusual gastrointestinal and cutaneous toxicities by bleomycin, etoposide, and cisplatin: a case report with pharmacogenetic analysis to personalize treatment. EPMA J. 2017 Mar;8(1): 69-73
27) Del Re M, Fogli S, Derosa L, Massari F, De Souza P, Crucitta S, Bracarda S, Santini D, Danesi R. The role of drug-drug interactions in prostate cancer treatment: focus on abiraterone acetate/prednisone and enzalutamide. Cancer Treat Rev. 2017 Mar;55:71-82
28) Antonuzzo L, Del Re M, Barucca V, Spada F, Meoni G, Restante G, Danesi R, Di Costanzo F, Fazio N. Critical focus on mechanisms of resistance and toxicity of m-TOR inhibitors in pancreatic neuroendocrine tumors. Cancer Treat Rev. 2017 Jun;57:28-35
29) Del Re M, Rofi E, Citi V, Fidilio L, Danesi R. Author's reply. Should CYP2D6 be genotyped when treating with tamoxifen? Pharmacogenomics. 2017 Jun. doi: 10.2217/ pgs-2017-0065.
30) Bordi P, Tiseo M, Rofi E, Petrini I, Restante G, Danesi R, Del Re M. Detection of ALK and KRAS Mutations in Circulating Tumor DNA of Patients With Advanced ALK-Positive NSCLC With Disease Progression During Crizotinib Treatment. Clin Lung Cancer. 2017 May. doi: 10.1016/j.cllc.2017.04.013
31) Del Re M, Vivaldi C, Rofi E, Vasile E, Miccoli M, Caparello C, d'Arienzo PD, Fornaro L, Falcone A, Danesi R. Early changes in plasma DNA levels of mutant KRAS as a sensitive marker of response to chemotherapy in pancreatic cancer. Sci Rep. 2017 Aug 11;7(1): 7931
32) Matrone A, Valerio L, Pieruzzi L, Giani C, Cappagli V, Lorusso L, Agate L, Puleo L, Viola D, Bottici V, Del Re M, Molinaro E, Danesi R, Elisei R. Protein kinase inhibitors for the treatment of advanced and progressive radiorefractory thyroid tumors: From the clinical trials to the real life. Best Pract Res Clin Endocrinol Metab. 2017 Jun;31(3): 319-334
33) Del Re M, Biasco E, Crucitta S, Derosa L, Rofi E, Orlandini C, Miccoli M, Galli L, Falcone A, Jester GW, van Schaik RH, Danesi R. Author's reply. The detection of AR-V7 in plasma-derived exosomal RNA strongly predicts resistance to hormonal therapy in metastatic prostate cancer patients. Eur. Urol. 2017. DOI:10.1016/j.eururo.2017.07.034
34) Del Re M, Bordi P, Petrini I, Rofi E, Mazzoni F, Belluomini L, Vasile E, Restante G, Di Costanzo F, Falcone A, Frassoldati A, van Schaik R, Steendam CMJ, Chella A, Tiseo M, Morganti R, Danesi R. p.T790M positive patients with advanced NSCLC resistant to first-line EGFR-tyrosine kinase inhibitors may display a low ratio of resistance vs. activating EGFR mutations. Oncotarget. 2017 Sep 15;8(49):86056-86065.
35) Di Paolo A, Del Re M, Arrigoni E, Di Desidero T, Rofi E, Danesi R, Bocci G. Pharmacokinetic Markers of 5-Fluorouracil Toxicity in Clinical Trials and Real World. Clin Canc Drugs. 2017. DOI:10.2174/2212697X04666170817124625
36) Minari R, Bordi P, Del Re M, Facchinetti F, Mazzoni F, Barbieri F, Camerini A, Comin CE, Gnetti L, Azzoni C, Nizzoli R, Bortesi B, Rofi E, Petreni P, Campanini N, Rossi G, Danesi R, Tiseo M. Primary resistance to osimertinib due to SCLC transformation: issue of T790M determination on liquid rebiopsy. Lung Cancer 2017(115)21-27.
37) Del Re M, Rofi E, Restante G, Crucitta S, Arrigoni E, Fogli S, Di Maio M, Petrini I, Danesi R. Implications of KRAS mutations in acquired resistance to treatment in NSCLC. Oncotarget. 2017;9(5):6630-6643
38) Cremolini C, Del Re M, Antoniotti C, Lonardi S, Bergamo F, Loupakis F, Borelli B, Marmorino F, Citi V, Cortesi E, Moretto R, Ronzoni M, Tomasello G, Zaniboni A, Racca P, Buonadonna A, Allegrini G, Ricci V, Di Donato S, Zagonel V, Boni L, Falcone A, Danesi R. DPYD and UGT1A1 genotyping to predict adverse events during first-line FOLFIRI or FOLFOXIRI plus bevacizumab in metastatic colorectal cancer. Oncotarget 2017. doi: 10.18632/oncotarget.23559
39) Fogli S, Del Re M, Rofi E, Posarelli C, Figus M, Danesi R. Clinical pharmacology of intravitreal anti-VEGF drugs. Eye 2018 in press
40) Del Re M, Arrigoni E, Restante G, Passaro A, Rofi E, Crucitta S, De Marinis F, Di Paolo A, Danesi R. Resistance to Tyrosine Kinase Inhibitors in Non-Small Cell Lung Cancer: The Role of Cancer Stem Cells. Stem Cells. 2018 Jan. doi: 10.1002/stem.2787
41) Arrigoni E, Del Re M, Galimberti S, Restante G, Rofi E, Crucitta S, Baratè C, Petrini M, Danesi R, Di Paolo A. Chronic myeloid leukemia: stem cell niche and response to pharmacologic treatment. Stem Cells Transl Med. 2018 Mar;7(3):305-314
42) Citi V, Del Re M, Martelli A, Calderone V, Breschi MC, Danesi R. Phosphorylation of AKT and ERK1/2 and mutations of PIK3CA and PTEN are predictive of breast cancer cell
sensitivity to everolimus in vitro. Cancer Chemother Pharmacol. 2018. doi: 10.1007/ s00280-018-3543-6
43) Del Re M, Marconcini R, Pasquini G, Rofi E, Vivaldi C, Bloise F, Restante G, Arrigoni E, Caparello C, Bianco MG, Crucitta S, Petrini I, Vasile E, Falcone A, Danesi R. PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC. BJC 2018. doi:10.1038/bjc.2018.9
44) Del Re M, Crucitta S, Restante G, Rofi E, Arrigoni E, Biasco E, Sbrana A, Coppi E, Galli L, Bracarda S, Santini D, Danesi R. Pharmacogenetics of androgen signaling in prostate cancer: focus on castration resistance and predictive biomarkers of response to treatment. Crit Rev Oncol Hematol. 2018 https://doi.org/10.1016/j.critrevonc.2018.03.002
Attività di tutoraggio
- Tutoraggio a studenti per tesi di laurea in Medicina e Chirurgia (2), Farmacia (2), Tecniche di laboratorio (1), per la realizzazione della parte sperimentale e scrittura della tesi
- Tutoraggio ad allievi del Corso di Dottorato in Scienze Cliniche e Traslazionali (3) per la realizzazione della parte sperimentale e scrittura della tesi
