Imperial College London

DrRaffaellaGadaleta

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Honorary Research Associate
 
 
 
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Contact

 

+44 (0)20 7594 2805r.gadaleta

 
 
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Location

 

140ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

12 results found

Magnani L, Frige G, Gadaleta RM, Corleone G, Fabris S, Kempe MH, Vershure PJ, Barozzi I, Vircillo V, Hong S, Perone Y, Saini M, Trumpp A, Viale G, Neri A, Simak A, Colleoni MA, Pruneri G, Minucci Set al., 2017, Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer, Nature Genetics, Vol: 49, Pages: 444-450, ISSN: 1546-1718

Tumor evolution is shaped by many variables, potentially involving external selective pressures induced by therapies1. After surgery, patients with estrogen receptor (ERα)-positive breast cancer are treated with adjuvant endocrine therapy2, including selective estrogen receptor modulators (SERMs) and/or aromatase inhibitors (AIs)3. However, more than 20% of patients relapse within 10 years and eventually progress to incurable metastatic disease4. Here we demonstrate that the choice of therapy has a fundamental influence on the genetic landscape of relapsed diseases. We found that 21.5% of AI-treated, relapsed patients had acquired CYP19A1 (encoding aromatase) amplification (CYP19A1amp). Relapsed patients also developed numerous mutations targeting key breast cancer–associated genes, including ESR1 and CYP19A1. Notably, CYP19A1amp cells also emerged in vitro, but only in AI-resistant models. CYP19A1 amplification caused increased aromatase activity and estrogen-independent ERα binding to target genes, resulting in CYP19A1amp cells showing decreased sensitivity to AI treatment. These data suggest that AI treatment itself selects for acquired CYP19A1amp and promotes local autocrine estrogen signaling in AI-resistant metastatic patients.

Journal article

Pellicciari R, Passeri D, De Franco F, Mostarda S, Filipponi P, Colliva C, Gadaleta RM, Franco P, Carotti A, Macchiarulo A, Roda A, Moschetta A, Gioiello Aet al., 2016, Discovery of 3<i>α</i>,7<i>α</i>,11<i>β</i>-Trihydroxy-6<i>α</i>-ethyl-5<i>β</i>-cholan-24-oic Acid (TC-100), a Novel Bile Acid as Potent and Highly Selective FXR Agonist for Enterohepatic Disorders, JOURNAL OF MEDICINAL CHEMISTRY, Vol: 59, Pages: 9201-9214, ISSN: 0022-2623

Journal article

Gadaleta RM, Cariello M, Sabba C, Moschetta Aet al., 2015, Tissue-specific actions of FXR in metabolism and cancer, BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, Vol: 1851, Pages: 30-39, ISSN: 1388-1981

Journal article

Gadaleta RM, Magnani L, 2014, Nuclear receptors and chromatin: an inducible couple, JOURNAL OF MOLECULAR ENDOCRINOLOGY, Vol: 52, Pages: R137-R149, ISSN: 0952-5041

Journal article

van Schaik FDM, Gadaleta RM, Schaap FG, van Mil SWC, Siersema PD, Oldenburg B, van Erpecum KJet al., 2012, Pharmacological Activation of the Bile Acid Nuclear Farnesoid X Receptor Is Feasible in Patients with Quiescent Crohn's Colitis, PLOS ONE, Vol: 7, ISSN: 1932-6203

Journal article

Gadaleta RM, Moschetta A, 2012, Nuclear bile acid receptor FXR and hepatobiliary transport systems, Hepatobiliary Transport in Health and Disease, Editors: Häussinger, Keitel, Kubitz, ISBN: 978-3-11-027934-4

Book chapter

Nijmeijer RM, Gadaleta RM, van Mil SWC, van Bodegraven AA, Crusius JBA, Dijkstra G, Hommes DW, de Jong DJ, Stokkers PCF, Verspaget HW, Weersma RK, van der Woude CJ, Stapelbroek JM, Schipper MEI, Wijmenga C, van Erpecum KJ, Oldenburg Bet al., 2011, Farnesoid X Receptor (FXR) Activation and FXR Genetic Variation in Inflammatory Bowel Disease, PLOS ONE, Vol: 6, ISSN: 1932-6203

Journal article

Gadaleta RM, Oldenburg B, Willemsen ECL, Spit M, Murzilli S, Salvatore L, Klomp LWJ, Siersema PD, van Erpecum KJ, van Mil SWCet al., 2011, Activation of bile salt nuclear receptor FXR is repressed by pro-inflammatory cytokines activating NF-κB signaling in the intestine, BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE, Vol: 1812, Pages: 851-858, ISSN: 0925-4439

Journal article

Gadaleta RM, 2011, Farnesoid X Receptor activation protects against intestinal inflammation: potential mechanisms and therapeutic implications, ISBN: 978-90-8891-272-6

Book

Gadaleta RM, van Erpecum KJ, Oldenburg B, Willemsen ECL, Renooij W, Murzilli S, Klomp LWJ, Siersema PD, Schipper MEI, Danese S, Penna G, Laverny G, Adorini L, Moschetta A, van Mil SWCet al., 2011, Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease, GUT, Vol: 60, Pages: 463-472, ISSN: 0017-5749

Journal article

Modica S, Gadaleta RM, Moschetta A, 2010, Deciphering the nuclear bile acid receptor FXR paradigm., Nucl Recept Signal, Vol: 8

Originally called retinoid X receptor interacting protein 14 (RIP14), the farnesoid X receptor (FXR) was renamed after the ability of its rat form to bind supra-physiological concentrations of farnesol. In 1999 FXR was de-orphanized since primary bile acids were identified as natural ligands. Strongly expressed in the liver and intestine, FXR has been shown to be the master transcriptional regulator of several entero-hepatic metabolic pathways with relevance to the pathophysiology of conditions such as cholestasis, fatty liver disease, cholesterol gallstone disease, intestinal inflammation and tumors. Furthermore, given the importance of FXR in the gut-liver axis feedbacks regulating lipid and glucose homeostasis, FXR modulation appears to have great input in diseases such as metabolic syndrome and diabetes. Exciting results from several cellular and animal models have provided the impetus to develop synthetic FXR ligands as novel pharmacological agents. Fourteen years from its discovery, FXR has gone from bench to bedside; a novel nuclear receptor ligand is going into clinical use.

Journal article

Gadaleta RM, van Mil SWC, Oldenburg B, Siersema PD, Klomp LWJ, van Erpecum KJet al., 2010, Bile acids and their nuclear receptor FXR: Relevance for hepatobiliary and gastrointestinal disease, BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS, Vol: 1801, Pages: 683-692, ISSN: 1388-1981

Journal article

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