Chemochine

Le chemochine nel sistema immunitario

Il sistema immunitario è costituito da una complessa rete di cellule e molecole e ha la funzione di difendere il nostro organismo da agenti patogeni esterni – virus, batteri, parassiti e funghi – nonché dalla crescita di cellule tumorali. Quando un pericolo viene rilevato, all’interno di uno dei distretti dell’organismo, le cellule del sistema immunitario lasciano il circolo sanguigno e si dirigono verso il sito richiesto, “guidate” da alcune molecole chiamate chemochine. Tali molecole vengono prodotte e rilasciate dalle cellule presenti nel sito compromesso e funzionano come vere e proprio calamite che richiamano le cellule del sistema immunitario nel punto esatto dove queste dovranno poi agire. Di solito questo meccanismo viene finemente regolato in modo che il sistema immunitario si “attivi” solo quando è necessario. Per ragioni ancora non del tutto comprese, in alcuni soggetti può succedere che il sistema immunitario si attivi anche senza una minaccia specifica, andando a riconoscere e attaccare sostanze estranee ma innocue o addirittura interne al proprio stesso organismo. Da questo malfunzionamento delle cellule immunitarie hanno origine rispettivamente le allergie e le malattie autoimmuni, le quali sono caratterizzate da una spiccata componente infiammatoria.

La ricerca Dompé sulle chemochine

Dompè è impegnata attivamente nello sviluppo di terapie innovative per diverse malattie autoimmuni come il diabete, la vasculite, l’artrite reumatoide e il pemfigoide oculare (disturbo caratterizzato dall’ispessimento della congiuntiva che può portare a completa cecità) e per malattie con un forte carattere a base immunitaria, come i tumori.

Nel corso degli anni l’Azienda ha sviluppato inibitori potenti e selettivi in grado di bloccare l’azione di particolari chemochine e quindi i processi infiammatori. Alcune di queste molecole sono ad oggi impegnate in trial clinici in diverse aree terapeutiche.

Un campo di ricerca promettente: la NETosi

Un altro settore di ricerca che punta ad un nuovo approccio terapeutico è quello della NETosi. Un processo messo in atto da una particolare popolazione del sistema immunitario: i neutrofili. Queste cellule sono la prima barriera contro infezioni batteriche e fungine. Quando un patogeno riesce ad entrare nel nostro organismo, i neutrofili circolanti vengono reclutati dalle chemochine nel sito dell’infiammazione, dove si attivano e formano delle strutture particolari, simili a trappole, chiamate NET, capaci di inglobare i patogeni eliminandone quindi la minaccia. Sebbene in tale contesto i NET abbiano un ruolo positivo, un crescente numero di studi sta mettendo in evidenza come il processo di formazione dei NET, se non finemente controllato, rappresenti un fattore aggravante in un numero elevato di patologie. Per tale ragione vari programmi di ricerca hanno indirizzato i loro sforzi allo sviluppo di molecole capaci di bloccare la NETosi. Dompé crede molto in questo approccio, tanto da aver avviato una serie di collaborazioni nazionali e internazionali con l’obiettivo di costituire un network multidisciplinare di esperti di tutto il mondo e accelerare così lo sviluppo di nuovi composti che inibiscano efficacemente la NETosi, tramite la selettiva inibizione dell’effetto di alcune chemochine sui neutrofili.

Il diabete

Il diabete è una malattia cronica autoimmune caratterizzata da un eccesso di glucosio nel sangue, nota come iperglicemia. Nel diabete tipo 1 il pancreas non è in grado di produrre insulina a causa della distruzione, da parte del sistema immunitario, delle beta-cellule, delle isole pancreatiche, che sono atte alla produzione di questo ormone. Riguarda circa il 3-5% delle persone affette da diabete e in genere insorge nell’infanzia o nell’adolescenza, ma può manifestarsi anche negli adulti.

Tutt'oggi la causa del diabete tipo 1 è sconosciuta, ma è ormai noto che alla base della malattia ci sia un "sabotaggio" da parte del sistema immunitario nei confronti delle cellule che producono insulina: la patologia si manifesta infatti con la presenza nel sangue di anticorpi diretti contro antigeni presenti a livello delle cellule che producono l'insulina. È per questo motivo che il diabete di tipo 1 viene classificato tra le malattie cosiddette “autoimmuni”, caratterizzate cioè da una reazione del sistema immunitario contro l’organismo stesso. Il danno che il sistema immunitario induce nei confronti delle cellule che producono l'insulina si ritiene possa essere legato a fattori ereditari e/o a fattori ambientali.

Negli ultimi anni si sono via via accumulate diverse evidenze scientifiche sul ruolo della NETosi nel diabete, la quale sembra essere soprattutto coinvolta nello sviluppo delle varie complicanze del diabete. Per questo motivo e considerando che il centro dell’impegno della ricerca Dompé è cercare una possibile soluzione terapeutica per i tanti pazienti colpiti dal diabete di tipo 1, uno degli obiettivi è proprio quello di capire come viene attivato il processo di NETosi nel diabetico e quindi bloccarlo in maniera specifica.

Fatigue e infiammazione: compagne di strada del paziente oncologico

Un’area di grande interesse per la ricerca Dompé è anche quella della fatigue, un termine inglese usato internazionalmente con cui si indica uno stato di affaticamento o di spossatezza. Si tratta di una condizione lamentata da gran parte dei soggetti affetti da patologie con una importante componente infiammatoria, quali i pazienti oncologici, che tuttavia non ha mai ricevuto l’attenzione che merita da parte dei clinici. Fortunatamente negli ultimi anni si è capito che il miglioramento della qualità della vita dei pazienti oncologici è una chiave importante per aumentare le chance di sopravvivenza.

Dompé è impegnata da anni nella ricerca di un farmaco in grado di bloccare o ridurre questo particolare tipo di infiammazione. Una molecola promettente in questa direzione è il Reparixin, che è attualmente in sperimentazione clinica per valutarne le potenzialità nel ridurre l’infiammazione.

Pipeline Chemochine

Ladarixin

INN (International Non-proprietary Name): Ladarixin
phase III

Ladarixin is a non-competitive allosteric inhibitor of CXCL8 receptors, CXCR1 and CXCR2, able to inhibit the intracellular signal transduction events activated by CXCL8 without affecting binding of CXCL8 to CXCR1 and CXCR2. Chemical computational studies and alanine-replacement mutagenesis studies have identified the binding site of Ladarixin on CXCR1/2 in the transmembrane domain of the receptors.

On going Clinical studies
LDX0219

A Single Dose Study About the Influence of Food on the Oral Bioavailability of Ladarixin Capsule in Healthy Volunteers

LDX0119

Ladarixin in obese pre-diabetic patients eligible to bariatric surgery

LDX0419

A Study to Assess Efficacy/Safety of Ladarixin in Type 1 Diabetes Patients With Preserved ß-cell Function at Baseline

LDX0319

A Study of Oral Ladarixin in New-onset Type 1 Diabetes and a Low Residual β-cell Function

Completed Clinical studies
MEX0114

A Phase 2, Multicentre, Randomized, Double-blind, Placebo-controlled Study in Patients With New-onset Type 1 Diabetes

Reparixin L-lysine salt

INN (International Non-proprietary Name): Reparixin L-lysine salt
phase II

Reparixin is a non-competitive allosteric inhibitor of CXCL8 receptors, CXCR1 and CXCR2, able to inhibit the intracellular signal transduction events activated by the binding of CXCL8 to CXCR1 and CXCR2. The binding site hypothesis derived through computational studies was confirmed by alanine scanning mutagenesis, and a region in the transmembrane of CXCR1 and CXCR2 was identified.

On going Clinical studies
REP0220

Study on Efficacy and Safety of Reparixin in the Treatment of Hospitalized Patients With Severe COVID-19 Pneumonia

Completed Clinical studies
REP0114

A Double-blind Study of Paclitaxel in Combination With Reparixin or Placebo for Metastatic Triple-Negative Breast Cancer (FRIDA)

REP0210

Pilot Study to Evaluate Safety & Biological Effects of Orally Administered Reparixin in Early Breast Cancer

REP0111

Pilot Study to Evaluate Reparixin With Weekly Paclitaxel in Patients With HER 2 Negative Metastatic Breast Cancer (MBC)

Pubblicazioni su Chemochine

Breast Cancer Research and Treatment settembre 2021

A randomized, placebo-controlled phase 2 study of paclitaxel in combination with reparixin compared to paclitaxel alone as front-line therapy for metastatic triple-negative breast cancer (fRida)

Lori J. Goldstein, Mauro Mansutti, Christelle Levy, Jenny C. Chang, Stephanie Henry, Isaura Fernandez-Perez, Jana Prausovà, Elzbieta Staroslawska, Giuseppe Viale, Beth Butler, Susan McCanna, Pier Adelchi Ruffini, Max S. Wicha & Anne F. Schott for the fRida Trial Investigators

Pharmaceuticals giugno 2021

Unexpected Salt/Cocrystal Polymorphism of the Ketoprofen-Lysine System: Discovery of a New Ketoprofen-l-Lysine Salt Polymorph with Different Physicochemical and Pharmacokinetic Properties

Andrea Aramini, Gianluca Bianchini, Samuele Lillini, Simone Bordignon, Mara Tomassetti, Rubina Novelli, Simone Mattioli, Larisa Lvova, Roberto Paolesse, Michele Remo Chierotti, Marcello Allegretti

Frontiers in Immunology ottobre 2020

CXCR1 and CXCR2 Inhibition by Ladarixin Improves Neutrophil-Dependent Airway Inflammation in Mice

Matheus Silverio Mattos et al.

Immunity maggio 2020

CXCR1 and CXCR2 Chemokine Receptor Agonists Produced by Tumors Induce Neutrophil Extracellular Traps That Interfere With Immune Cytotoxicity

Á. Teijeira et al.

Aging gennaio 2020

Autocrine CXCL8-dependent invasiveness triggers modulation of actin cytoskeletal network and cell dynamics

A Antonosante et al.

Diabetes Care gennaio 2020

Targeting CXCR1/2 does not improve insulin secretion after pancreatic islet transplantation: A phase 3, double-blind, randomized, placebo-controlled trial in type 1 diabetes

Paola Maffi et al.

Breast Cancer Research gennaio 2020

A window-of-opportunity trial of the CXCR1/2 inhibitor reparixin in operable HER-2-negative breast cancer

Lori J. Goldstein et al.

Molecules ottobre 2019

Catalyst-Free Synthesis of Polysubstituted 5-Acylamino-1,3-Thiazoles via Hantzsch Cyclization of α-Chloroglycinates

M Tomassetti et al.

Nature agosto 2019

DF2726A, a new IL-8 signalling inhibitor, is able to counteract chemotherapy-induced neuropathic pain

L Brandolini et al.

Adv Ther. agosto 2019

Towards an Effective and Safe Treatment of Inflammatory Pain: A Delphi-Guided Expert Consensus

G. Varrassi, E. Alon, M. Bagnasco, L. Lanata, V. Mayoral-Rojals, A. Paladini, J. V. Pergolizzi, S. Perrot, C. Scarpignato, T. To¨lle

International journal of molecular sciences giugno 2019

Chemokine Signaling in Chemotherapy-Induced Neuropathic Pain

L Brandolini et al.

Frontiers in oncology febbraio 2019

The CXCL8-CXCR1/2 Axis as a Therapeutic Target in Breast Cancer Stem-Like Cells

PA Ruffini

The American journal of pathology febbraio 2019

Inflammatory Stress Causes N-Glycan Processing Deficiency in Ocular Autoimmune Disease

AM Woodward et al.

ACS Omega novembre 2018

1,3-Dibromo-1,1-difluoro-2-propanone as a Useful Synthon for a Chemoselective Preparation of 4-Bromodifluoromethyl Thiazoles

M Colella et al.

Int J Paediatr Dent ottobre 2018

Efficacy of ketoprofen lysine salt and paracetamol/acetaminophen to reduce pain during rapid maxillary expansion: A randomized controlled clinical trial

G. Cossellu, V. Lanteri, R. Lione, A. Ugolini, F. Gaffuri, P. Cozza, M. Farronato

JCI Insight agosto 2018

IL-6 and CXCL8 Mediate Osteosarcoma-Lung Interactions Critical to Metastasis

AC Gross et al.

Cancer Research luglio 2018

IL6 and CXCL8 mediate redundant, targetable tumor-host interactions that drive osteosarcoma lung metastasis

Ryan D. Roberts. Hakan Cam, Laura Brandolini, John M. Hinckley, Amy C. Gross

British Journal of Pharmacology giugno 2018

Therapeutic inhibition of CXCR2 by Reparixin attenuates acute lung injury in mice

A Zarbock, M Allegretti, K Ley

British journal of pharmacology maggio 2018

Antinociceptive effect of two novel transient receptor potential melastatin 8 antagonists in acute and chronic pain models in rat

De Caro C et al.

European journal of medicinal chemistry aprile 2018

Challenging clinically unresponsive medullary thyroid cancer: Discovery and pharmacological activity of novel RET inhibitors

La Pietra V et al.

Molecular Cancer Therapeutics aprile 2018

Differential alteration of IL-8 in liver cancer stem cell enrichment in response to PI3K/Akt/mTOR inhibitors and sorafenib

Kahraman DC et al.

European Journal of immunology marzo 2018

CXCR2 Is Critical for Bacterial Control and Development of Joint Damage and Pain in Staphylococcus Aureus-Induced Septic Arthritis in Mouse

D Boff et al. Eur J Immunol

Frontiers in immunology gennaio 2018

Intravital Microscopic Evaluation of the Effects of a CXCR2 Antagonist in a Model of Liver Ischemia Reperfusion Injury in Mice

THC de Oliveira et al.

Frontiers in immunology dicembre 2017

CXCR1/2 Antagonism Is Protective During Influenza and Post-Influenza Pneumococcal Infection

LP Tavares et al.

Italian Journal of Pediatrics ottobre 2017

Management of acute respiratory diseases in the pediatric population: the role of oral corticosteroids

R. Cutrera, E. Baraldi, L. Indinnimeo, M. Miraglia Del Giudice, G. Piacentini, F. Scaglione, N. Ullmann, L. Moschino, F. Galdo, M. Duse

Clinical Cancer Research settembre 2017

Phase Ib Pilot Study to Evaluate Reparixin in Combination with Weekly Paclitaxel in Patients with HER-2-Negative Metastatic Breast Cancer

A. F. Schott, L. J. Goldstein, M. Cristofanilli, P. A. Ruffini, S. McCanna, J. M. Reuben, R. P. Perez, G. Kato, M. Wicha

Journal of Cellular Physiology luglio 2017

Differential protein modulation by ketoprofen and ibuprofen underlines different cellular response by gastric epithelium

L. Brandolini, M. d’Angelo, A. Antonosante, S. Villa, L. Cristiano, V. Castelli, E. Benedetti, M. Catanesi, A. Aramini, A. Luini, S. Parashuraman, E. Mayo, A. Giordano, A. Cimini, M. Allegretti

Oncotarget maggio 2017

Multiple Anti-Tumor Effects of Reparixin on Thyroid Cancer

F Liotti et al.

Oncotarget. aprile 2017

CXCR1/2 pathways in paclitaxel-induced neuropathic pain

Brandolini L, Benedetti E, Ruffini PA, Russo R, Cristiano L, Antonosante A, d'Angelo M, Castelli V, Giordano A, Allegretti M, Cimini A.

Oncotarget febbraio 2017

Ladarixin, a Dual CXCR1/2 Inhibitor, Attenuates Experimental Melanomas Harboring Different Molecular Defects by Affecting Malignant Cells and Tumor Microenvironment

DM Kemp et al.

Central nervous system agents in medicinal chemistry gennaio 2017

Synthesis and Antioxidant Properties of Novel Memantine Derivatives

Fornasari E et al.

Clin Cancer Res. agosto 2016

Tumor-Produced Interleukin-8 Attracts Human Myeloid-Derived Suppressor Cells and Elicits Extrusion of Neutrophil Extracellular Traps (NETs)

Alfaro C., Teijeira A., Oñate C., Pérez G1, Sanmamed M.F., Andueza M.P., Alignani D., Labiano S., Azpilikueta A., Rodriguez-Paulete A., Garasa S., Fusco J.P., Aznar A., Inogés S., De Pizzol M., Allegretti M., Medina-Echeverz J., Berraondo P., Perez-Gracia J.L., Melero I.

Cancer Research luglio 2016

A single arm, preoperative, pilot study to evaluate the safety and biological effects of orally administered reparixin in early breast cancer patients who are candidates for surgery

Lori J. Goldstein, Raymond P. Perez, Denise A. Yardley, Linda K Han, James M. Reuben, Susan McCanna, Beth Butler, Pier Adelchi Ruffini, Jenny C. Chang

Multidiscip Respir Med giugno 2016

Prospective study of the efficacy of antibiotics versus antitussive drugs for the management of URTI-related acute cough in children

A. Zanasi, L. Lanata, F. Saibene, G. Fontana, P. Dicpinigaitis, V. Venier, F. De Blasio

Frontiers in Immunology maggio 2016

Allosteric Modulation of Chemoattractant Receptors

Marcello Allegretti, Maria Candida Cesta and Massimo Locati

Cancer Research febbraio 2016

A randomized, placebo-controlled phase 2 study of paclitaxel in combination with reparixin compared to paclitaxel alone as front-line therapy for triple-negative breast cancer (fRida)

JC Chang, AF Schott, MS Wicha, M Cristofanilli, PA Ruffini, S McCanna, LJ Goldstein

Pharmacological research gennaio 2016

DF2755A, a Novel Non-Competitive Allosteric Inhibitor of CXCR1/2, Reduces Inflammatory and Post-Operative Pain

AH Lopes et al.

The journal of pharmacology & experimental therapeutics gennaio 2016

DFL23448, A Novel Transient Receptor Potential Melastin 8-Selective Ion Channel Antagonist, Modifies Bladder Function and Reduces Bladder Overactivity in Awake Rats

FA Mistretta et al.

Oncotarget. dicembre 2015

Targeting CXCR1 on breast cancer stem cells: signaling pathways and clinical application modelling

Brandolini L, Cristiano L, Fidoamore A, De Pizzol M, Di Giacomo E, Florio TM, Confalone G, Galante A, Cinque B, Benedetti E, Ruffini PA, Cifone MG, Giordano A, Alecci M, Allegretti M, Cimini A.

Annual of the rheumatic diseases dicembre 2015

A Homeostatic Function of CXCR2 Signalling in Articular Cartilage

J Sherwood et al.

Pharmacological research agosto 2015

Novel Immunological Strategies for Islet Transplantation

S Tezza et al.

American Diabetes Association aprile 2015

CXCR1/2 Inhibition Blocks and Reverses Type 1 Diabetes in Mice

Antonio Citro, Andrea Valle, Elisa Cantarelli, Alessia Mercalli, Silvia Pellegrini, Daniela Liberati, Luisa Daffonchio, Olga Kastsiuchenka, Pier Adelchi Ruffini, Manuela Battaglia, Marcello Allegretti and Lorenzo Piemonti

J Cell Physiol aprile 2015

Gastroprotective Effects of L-Lysine Salification of Ketoprofen in Ethanol-Injured Gastric Mucosa

A. Cimini, L. Brandolini, R. Gentile, L. Cristiano, P. Menghini, A. Fidoamore, A. Antonosante, E. Benedetti, A. Giordano, M. Allegretti

Curr Med Chem. marzo 2015

P2X receptors and diabetes

Carmen Fotino, Andrea Vergani, Paolo Fiorina and Antonello Pileggi

World Journal of Pharmacology marzo 2015

Improving cancer therapy by targeting cancer stem cells: Directions, challenges, and clinical results Improving cancer therapy by targeting cancer stem cells: Directions, challenges, and clinical results

Pier Adelchi Ruffini, Valentina Vaja and Marcello Allegretti

Transplantation dicembre 2014

Islet allotransplantation in type 1 diabetes: Phase 2 pilot study with CXCL8 inhibitor (reparixin)

Maffi P, Daffonchio L, Ruffini PA, Allegretti M, Citro A, Magistretti P, Melzi R, Mercalli A, Nano R, Sordi V, Secchi A, Piemonti L

Nanoscale novembre 2014

Targeting FR-expressing cells in ovarian cancer with Fab-functionalized nanoparticles: a full study to provide the proof of principle from in vitro to in vivo

Alessandra Quarta, Davide Bernareggi, Fabio Benigni, Elena Luison, Giuseppe Nano, Simone Nitti, Maria Candida Cesta, Luciano Di Ciccio, Silvana Canevari, Teresa Pellegrino and Mariangela Figini

Cancer Immunology, Immunotherapy ottobre 2014

Armed antibodies for cancer treatment: A promising tool in a changing era

Riccardo Danielli, Roberto Patuzzo, Pier Adelchi Ruffini, Andrea Maurichi, Leonardo Giovannoni, Giuliano Elia, Dario Neri, Mario Santinami

Biodrugs : Clinical Immunotherapeutics, Biopharmaceuticals and Gene Therapy giugno 2014

Safety and pharmacokinetics of escalating doses of human recombinant nerve growth factor eye drops in a double-masked, randomized clinical trial

MP Ferrari et al.

Toxicol In Vitro marzo 2014

Oxidative stress and innate immunity responses in cigarette smoke stimulated nasal epithelial cells

E. Pace, M. Ferraro, S. Di Vincenzo, S. Gerbino, A. Bruno, L. Lanata, M. Gjomarkaj.

Annals of the Rheumatic Diseases gennaio 2014

A phase IB clinical trial in rheumatoid arthritis of dekavil (F8-IL10), a novel anti-inflammatory immunocytokine

M. Galeazzi, L. Bazzichi, G. Sebastiani, D. Neri, L. Giovannoni, F. Bacchion, J. Wilton, E. Garcia Gonzalez, P. Ruffini, M. Bardelli, C. Baldi, E. Selvi, G. Minisola, R. Caporali, E. Prisco, S. Bombardieri

Clin Exp Rheumatol. maggio 2013

Efficacy of ketoprofen vs. ibuprofen and diclofenac: a systematic review of the literature and meta-analysis

P. Sarzi-Puttini, F. Atzeni, L. Lanata, M. Bagnasco.

J Pain Symptom Manage dicembre 2012

Episodic (breakthrough) pain prevalence in a population of cancer pain paitents. Comparison of clinical diagnoses with the QUDEI - Italian Questionnaire for intense episodic pain

A. Caraceni,, O. Bertetto, R. Labianca, M. Maltoni, S. Mercadante, G. Varrassi, G. Zaninetta, F. Zucco, M. Bagnasco, L. Lanata, F. De Conno

The Journal of Clinical Investigation ottobre 2012

CXCR1/2 inhibition enhances pancreatic islet survival after transplantation

Antonio Citro, Elisa Cantarelli,Paola Maffi,Rita Nano,Raffaella Melzi,Alessia Mercalli,Erica Dugnani,Valeria Sordi, Paola Magistretti,Luisa Daffonchio, Pier Adelchi Ruffini, Marcello Allegretti, Antonio Secchi, Ezio Bonifacio and Lorenzo Piemonti

Trends Med ottobre 2012

A new ketoprofen lysine salt formulation: 40 mg orodispersible granules

A.E. Panerai, L. Lanata, M. Ferrari, M. Bagnasco

Transplantation International settembre 2012

CXCR2 inhibition improves islet transplantation

Antonio Citro, Elisa Cantarelli, Paola Maffi, Rita Nano, Raffaella Melzi, Alessia Mercalli, Erica Dugnani, Valeria Sordi, Paola Magistretti, Luisa Daffonchio, Pier Adelchi Ruffini, Marcello Allegretti, Antonio Secchi, Ezio Bonifacio, Lorenzo Piemonti

Immunology letters luglio 2012

Current Status of Chemokine Receptor Inhibitors in Development

M Allegretti et al.

ACS Medicinal Chemistry Letters agosto 2011

Aryltriflates as a Neglected Moiety in Medicinal Chemistry: A Case Study from a Lead Optimization of CXCL8 Inhibitors

A Moriconi et al.

British Journal of Pharmacology giugno 2011

Receptor binding mode and pharmacological characterization of a potent and selective dual CXCR1/CXCR2 non-competitive allosteric inhibitor

R. Bertini, L.S. Barcelos, A.R. Beccari, B. Cavalieri, A. Moriconi, C. Bizzarri, P. Di Benedetto, C. Di Giacinto, I. Gloaguen, E. Galliera, M.M. Corsi, R.C. Russo, S.P. Andrade, M.C. Cesta, G. Nano, A. Aramini, J.C. Cutrin, M. Locati, M. Allegretti and M.M. Teixeira

Health and Quality of Life Outcomes aprile 2011

Comparison of numerical and verbal rating scales to measure pain exacerbations in patients with chronic cancer pain

C. Brunelli, E. Zecca, C. Martini, T. Campa, E. Fagnoni, M. Bagnasco, L. Lanata, A. Caraceni

The Journal of Clinical Investigation febbraio 2010

CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts

Christophe Ginestier, Suling Liu, Mark E. Diebel, Hasan Korkaya, Ming Luo, Marty Brown, Julien Wicinski, Olivier Cabaud, Emmanuelle Charafe-Jauffret, Daniel Birnbaum, Jun-Lin Guan, Gabriela Dontu, and Max S. Wicha

Journal of bone and mineral research dicembre 2009

Tartronates: A New Generation of Drugs Affecting Bone Metabolism

G Caselli et al.

Bioorganic & medicinal chemistry letters agosto 2009

Structure-Activity Relationship of Novel Phenylacetic CXCR1 Inhibitors

MR Sablone et al.

Journal of chromatography B luglio 2009

Development and Validation of an LC-MS/MS Method for Determination of Methanesulfonamide in Human Urine

R Anacardio et al.

Arthritis and Rheumatism agosto 2008

The chemokine receptors CXCR1/CXCR2 modulate antigen-induced arthritis by regulating adhesion of neutrophils to the synovial microvasculature

Fernanda M Coelho, Vanessa Pinho, Flávio A Amaral, Daniela Sachs, Vívian V Costa, David H Rodrigues, Angélica T Vieira, Tarcília A Silva, Daniele G Souza, Riccardo Bertini, Antônio L Teixeira, Mauro M Teixeira

American Journal of Respiratory Cell and Molecular Biology luglio 2008

Role of the chemokine receptor CXCR2 in bleomycin-induced pulmonary inflammation and fibrosis

Remo C. Russo, Rodrigo Guabiraba, Cristiana C. Garcia,  Lucíola S. Barcelos,  Ester Roffê,  Adriano L. S. Souza, Flávio A. Amaral,  Daniel Cisalpino, Geovanni D. Cassali, Andrea Doni, Riccardo Bertini, Mauro M. Teixeira 

Neuroimmunomodulation aprile 2008

Chemokine MIP-2/CXCL2, acting on CXCR2, induces motor neuron death in primary cultures

Massimiliano De Paola, Pasquale Buanne, Leda Biordi, Riccardo Bertini, Pietro Ghezzi, Tiziana Mennini

Journal of leukocyte biology novembre 2007

Crucial pathophysiological role of CXCR2 in experimental ulcerative colitis in mice

P Buanne et al.

British Journal of Pharmacology settembre 2007

Blockade of the chemokine receptor CXCR2 ameliorates adjuvant-induced arthritis in rats

M M Barsante, T M Cunha, M Allegretti, F Cattani, F Policani, C Bizzarri, W L Tafuri, S Poole, F Q Cunha, R Bertini, M M Teixeira

Journal of Pharmacology and experimental Therapeutics giugno 2007

Reparixin, an inhibitor of CXCR2 function, attenuates inflammatory responses and promotes recovery of function after traumatic lesion to the spinal cord

Alfredo Gorio, Laura Madaschi, Giorgia Zadra, Giovanni Marfia, Barbara Cavalieri, Riccardo Bertini, Anna Maria Di Giulio

Transplantation Proceedings maggio 2007

Protective effect of an inhibitor of interleukin-8 (Meraxin) from ischemia and reperfusion injury in a rat model of kidney transplantation

F Neri, L Puviani, M Tsivian, D Prezzi, V Pacilé, G Cavallari, R Bertelli, E Bianchi, G L Piras, M Pariali, B Cavalieri, R Bertini, A Faenza, B Nardo

Molecular Medicine aprile 2007

The interleukin-8 (IL-8/CXCL8) receptor inhibitor reparixin improves neurological deficits and reduces long-term inflammation in permanent and transient cerebral ischemia in rats

Pia Villa, Sara Triulzi, Barbara Cavalieri, Rosa Di Bitondo, Riccardo Bertini, Sara Barbera, Paolo Bigini, Tiziana Mennini, Paolo Gelosa, Elena Tremoli, Luigi Sironi, Pietro Ghezzi

Journal of Medical Chemistry gennaio 2007

Design of Noncompetitive Interleukin-8 Inhibitors Acting on CXCR1 and CXCR2

Alessio Moriconi, Maria Candida Cesta, Maria Neve Cervellera, Andrea Aramini, Silvia Coniglio, Sandro Colagioia, Andrea Rosario Beccari, Cinzia Bizzarri, Michela Rita Cavicchia, Massimo Locati, Emanuela Galliera, Paola Di Benedetto, Paolo Vigilante, Riccardo Bertini and Marcello Allegretti

International Journal of Immunopathology and Pharmacology gennaio 2007

Reparixin, a specific interleukin-8 inhibitor, has no effects on inflammation during endotoxemia

J M Leitner, F B Mayr, C Firbas, A O Spiel, B Steinlechner, R Novellini, B Jilma

Pharmacology & therapeutics ottobre 2006

ELR+ CXC Chemokines and Their Receptors (CXC Chemokine Receptor 1 and CXC Chemokine Receptor 2) as New Therapeutic Targets

C Bizzarri et al.

Xenobiotica maggio 2006

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Antioxid Redox Signal ottobre 2005

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Storie su Chemochine

LDX0219

A Single Dose Study About the Influence of Food on the Oral Bioavailability of Ladarixin Capsule in Healthy Volunteers

Brief summary

Primary objective:

Secondary objectives:

detailed description

This is a Single center, single dose, open label, randomized, two-way, crossover, food effect on bioavailability study.

More precisely, a single oral dose of 400 mg of ladarixin (two 200 mg capsules) was administered to healthy male and female volunteers under fed (Test treatment) and fasting (Reference treatment) conditions in two consecutive study periods, according to a two-way crossover design, with a wash-out interval of at least 14 days between the two administrations.

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LDX0119

Ladarixin in obese pre-diabetic patients eligible to bariatric surgery

Brief summary

Effect of oral ladarixin 400 mg twice a day on insulin sensitivity. A phase 2, randomized, double-blind, placebo-controlled explorative study in obese patients with pre-diabetes eligible to bariatric surgery.

detailed description

Effect of the experimental drug ladarixin administered orally at a dose of 400 mg twice a day on insulin sensitivity. A phase 2, randomized, double-blind, placebo-controlled explorative study in obese patients with pre-diabetes eligible to bariatric surgery.

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LDX0419

A Study to Assess Efficacy/Safety of Ladarixin in Type 1 Diabetes Patients With Preserved ß-cell Function at Baseline

Brief summary

The objectives of this clinical trial are:

detailed description

The study is a phase 2, multicenter, double-blind, placebo-controlled study. It will randomize approximately 75 adult patients with new-onset type 1 diabetes (T1D) and preserved beta-cell function (fasting C-peptide >0.205 nmol/l) at baseline. Patients will be assigned (2:1) to receive either oral ladarixin treatment (400 mg b.i.d. for 13 cycles of 14 days on/14 days off - treatment group) or placebo (control group).

Recruitment will be competitive among the study sites, until the planned number of patients is randomized.

Ladarixin and placebo will be both administered for 1 year. All patients will be followed-up for 18 months from the 1st administration of the study medication. The study database will be locked and data analyzed when the last patient randomized has completed month 12 follow-up visit. After this time point, the follow-up will continue under open-label conditions up to month 18.

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LDX0319

A Study of Oral Ladarixin in New-onset Type 1 Diabetes and a Low Residual β-cell Function

Brief summary

The objective of this clinical trial is to assess whether ladarixin treatment is effective in preserving beta-cell function and delaying the progression of type 1 diabetes (T1D) in adolescent and adult patients. The safety of ladarixin in the specific clinical setting will be also evaluated.

detailed description

This is a phase 3, multicenter, double-blind, placebo-controlled study. It has been designed to further evaluate whether ladarixin is effective in preserving beta-cell function and slowing-down the progression of T1D) in patients with a more severe disease presentation.

The study is planned to be performed at about 40 study centers in EU, US and in other countries, if appropriated. At each study center, the Principal Investigator (PI) will be responsible for ensuring that the investigation is conducted according to the signed Investigator agreement, the protocol, GCP guidelines, and local regulations.

The study is planned to involve -327 patients with new-onset T1D, to include about 200 adolescents (14-17 years). Patients will be randomly (2:1) assigned to receive either ladarixin treatment (400 mg b.i.d. for 13 cycles of 14 days on/14 days off - treatment group) or matched placebo (control group). The two groups will be balanced within centers.

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MEX0114

A Phase 2, Multicentre, Randomized, Double-blind, Placebo-controlled Study in Patients With New-onset Type 1 Diabetes

Brief summary

The objective of this clinical trial is to investigate whether ladarixin has sufficient activity (preservation of β-cell function and slow-down of the progression of T1D) to warrant its further development (proof of concept trial). The safety of ladarixin in the specific clinical setting will be also evaluated.

The study is a phase 2, multicentre, double-blind study. 72 patients with new-onset type 1 diabetes (T1D) were planned to be involved, randomly (2:1) assigned to receive either ladarixin treatment (400 mg b.i.d. for 3 cycles of 14 days on/14 days off - treatment group) or placebo (control group).

Recruitment was competitive among the study sites, until the planned number of patients was enrolled. A total of 76 patients were actually recruited.

detailed description

T1D is an organ-specific autoimmune disease in which the immune system attacks the insulin-producing β-cells. The onset of the disease typically occurs before adulthood and seriously affects a person's quality of life.

T1D is treated with life-long daily exogenous insulin injections and monitoring of blood glucose levels. However, even optimization of glucose control through the most recent technologies cannot adequately substitute for the finely tuned normal balance of the glucose levels. Therefore, despite marked improvements in diabetes care in recent years, insulin-dependent diabetes results in secondary long-term complications and is one of the leading causes of end-stage renal disease, blindness and amputation. Additionally, hypoglycaemia unawareness is a serious consequence of recurrent hypoglycaemia often requiring emergency care.

Maintenance of residual β-cell function (as measured by C-peptide response) was demonstrated to be associated with reduced rate of microvascular complications and hypoglycaemia, improved quality of life, and overall reduction in morbidity and associated management costs. Therefore, pharmacological approaches aimed at controlling the autoimmune response and restoring self-tolerance to pancreatic β-cells had attracted the clinical/scientific interest.

Among these, rituximab, CD3-specific monoclonal antibodies, GAD65, DiaPep277 have progressed to phase III clinical trials. Other agents, including cytokines modulators such as anti-TNF or anti-IL1, are under clinical evaluation. Unfortunately, even if safe preservation of β-cell function and improvement of glycaemic control have been evidenced for some of the pharmacological approaches evaluated so far, none has been definitely approved for the "treatment" of diabetes onset. New strategies are being evaluated which combine agents targeting sequential arms of the immune and inflammatory response involved in β-cell disruption. In this regard, IL-8 appears to be an important mediator in the progression of type 1 diabetes. Production and secretion of pro-inflammatory IL-8 has been demonstrated from human pancreatic islets upon enterovirus infections, and LPS-induced production of IL-8 by neutrophils is increased in type 1 pre-diabetic and diabetic patients. In parallel, circulating levels of IL-8 were elevated in children with T1D compared to non-diabetic controls. Specifically, levels of IL-8 correlate with glycaemic control, higher level being associated to poorer or unfavorable glucose control.

As a result of these findings, the modulation or inhibition of IL8 activity is considered a valid target for the development of innovative treatments aimed to control the progression of T1D.

Results obtained with ladarixin in mouse models of T1D, and particularly reversal of "diabetes" in the NOD mice, clearly showed the ability of this CXCR1/2 inhibitor to protect β-cells and either prevent or delay the progression of hyperglycaemia. The positive effects of ladarixin, coupled with the safety shown in phase 1 studies, provided a sound rationale for a clinical study aimed at evaluating the effect of ladarixin in patients with new onset diabetes and supported the conduct of the present study.

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REP0220

Study on Efficacy and Safety of Reparixin in the Treatment of Hospitalized Patients With Severe COVID-19 Pneumonia

Brief summary

The study objective is to assess Efficacy and safety of Reparixin treatment as compared to placebo (both on top of standard treatment) in adult patients with severe COVID-19 pneumonia.

detailed description

This is a phase 3 clinical trial designed as a randomized, double-blind, placebo-controlled, multicentre study to evaluate the efficacy and safety of Reparixin in hospitalized adult patients with severe COVID-19 pneumonia.

Patients will be screened for the participation in the study and eventually randomized based on an unbalanced randomization scheme (2:1) to Reparixin oral tablets (2 x 600 mg TID) for up to 21 days or to placebo.

An unequal randomization is justified by the need to gain experience and more safety data with the investigated treatment and by an expected better acceptability of the trial by patients.

The placebo control arm is justified by the unavailability of a well-defined standard of care for subjects with COVID-19 pneumonia who are candidates for this study.

All patient will receive the standard supportive care based on the patient's clinical need. Follow-up information on the patient's clinical condition will be collected until day 90.

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REP0114

A Double-blind Study of Paclitaxel in Combination With Reparixin or Placebo for Metastatic Triple-Negative Breast Cancer (FRIDA)

Brief summary

The Objectives of this study:

The primary objective of the study was to evaluate progression-free survival (PFS) (defined as the number of days between the date of randomization and the date of clinical disease progression (PD) according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria version 1.1, as assessed by Independent Radiology Review, or death for any cause, whichever occured first) in patients with metastatic triple-negative breast cancer (TNBC) treated with the combination of paclitaxel and orally administered reparixin compared to paclitaxel alone.

The secondary objectives were:

detailed description

The study is a two arm, phase 2 study to evaluate the efficacy of the combination of paclitaxel and reparixin compared to paclitaxel and placebo in metastatic TNBC patients.

In the study two groups There were two groups:

Group 1: paclitaxel 80 mg/m2 intravenous (i.v.) (Days 1, 8, and 15 of 28-day cycle) + reparixin oral tablets 1200 mg three times a day (t.i.d.) continuing from Day 1 to Day 21.

Group 2: paclitaxel 80 mg/m2 i.v. (Days 1, 8, and 15 of 28-day cycle) + placebo oral tablets 1200 mg t.i.d. continuing from Day 1 to Day 21.

Study drug (reparixin/placebo) was administered with water prior to the start of the i.v. paclitaxel infusion on Cycle 1, Day 1 and then administered approximately every eight hours (six to ten hours) for 21 consecutive days during each cycle with seven days off-treatment between each cycle. It was preferable that reparixin was taken with food. However, if the patient was unable to eat, study drug was allowed to be administered. When in combination with paclitaxel (Day 1, 8 and 15 of each cycle), reparixin or placebo was administered every approximately eight hours with about 250 mL water and a light meal or snack. Paclitaxel was administered in combination with study drug (reparixin/placebo) as an i.v. infusion on Days 1, 8 and 15 of each 28-day cycle.

On Cycle 1, Day 1, paclitaxel was administered at the clinic after the administration of study drug (reparixin/placebo). From that point forward, study drug (reparixin/placebo) was self-administered t.i.d. for 21 days. Combination treatment (three weeks on and one week off) continued until PD according to RECIST criteria version 1.1, withdrawal of consent or unacceptable toxicity, whichever occurred first.

The next clinic visits were on Days 8 and 15 when a paclitaxel infusion was administered to the patient. The patients returned to the clinic again on Day 29/Day 1 of the next cycle.

Tumor response and/or progression assessments were performed and documented every eight weeks according to RECIST criteria version 1.1. Metastatic tissue samples were analyzed for evaluation of CD24-CD44+ and aldehyde dehydrogenase positive (ALDH+) CSCs.

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REP0210

Pilot Study to Evaluate Safety & Biological Effects of Orally Administered Reparixin in Early Breast Cancer

Brief summary

This is a pilot "window of opportunity" clinical study in patients with operable breast cancer investigating use of reparixin as single agent in the time period between clinical diagnosis and surgery.

The primary objectives of this study were:

1- to evaluate the effects of orally administered reparixin on CSCs in the primary tumor and the tumoral microenvironment in an early breast cancer population:

A. CSC were measured in tissue samples by techniques that could include: ALDEFLUOR assay and assessment of CD44/CD24 by flow cytometry, or examination of RNA transcripts by RT-PCR, aldehyde dehydrogenase-1, CD44/CD24 and epithelial mesenchymal transition markers (Snail, Twist, Notch) by immunohistochemistry (IHC). CSC were defined as ALDEFLUOR positive (ALDH-1+) and/or CD44 high/CD24 low by flow cytometry or RT-PCR and IHC and by the detection of ALDH-1+ cells with or without epithelial mesenchymal transition (EMT) transcription factor in IHC assays.

B. Serine-threonine protein kinase (AKT), focal adhesion kinase (FAK), phosphatase and tensin homolog (PTEN) and chemokine receptor-1 (CXCR1) levels were measured in tissue samples by IHC.

C. Measurement of markers of inflammation (interleukin-1beta [IL-1β], interleukin-6 [IL-6], interleukin-8 [IL-8], tumor necrosis factor-alpha [TNF-α], granulocyte macrophage colony stimulating factor [GM-CSF], vascular endothelial growth factor [VEGF], basic fibroblast growth factor [b-FGF] and high-sensitivity C-reactive protein [hsCRP]) in plasma, leukocyte subsets (enumerate T subsets, B, and natural killer/natural killer T [NK/NKT] cells) and study polymorphonuclear leukocyte [PMN] biology in peripheral blood samples. D. Measurement of markers of angiogenesis (CD31 staining), tumor-infiltrating leukocytes (CD4, CD8, NK and macrophages), autophagy (P62 and LC3 by IHC), EpCAM and EMT markers (CD326, CD45, Twist1, SNAIL1, SLUG, ZEB1, FOXC2, TG2, Akt2, P13k and CK19 by RT-PCR) and tissue cellularity (residual disease characterization in tumor bed) in tumor tissue samples.

2. To evaluate the safety of oral reparixin administered three times daily (t.i.d.) for 21 consecutive days.

The secondary objective was to define the pharmacokinetic (PK) profile of orally administered reparixin.

detailed description

According to the cancer stem cell (CSC) model, tumors are organized in a cellular hierarchy maintained by a subpopulation of cells displaying stem cell properties. These properties include self-renewal (which drives tumorigenesis) and differentiation (which generates the tumor bulk and contributes to cellular heterogeneity).

CSCs were first observed in hematological malignancies but have also been identified in solid tumors of breast, prostate, brain, colon and pancreas. CSCs are thought to be resistant to conventional chemotherapies and this may be why relapse occurs in many patients and this might explain the failure to develop therapies that are consistently able to eradicate solid tumors. Although currently available drugs can shrink metastatic tumors, these effects are usually transient and often do not appreciably extend the life of patients. One reason for the failure of these treatments is the acquisition of drug resistance by the cancer cells as they evolve; another possibility is that existing therapies fail to kill CSCs effectively. Existing therapies have been developed largely against the bulk population of tumor cells because they are often identified by their ability to shrink tumors. Because most cancer cells have limited proliferative potential, an ability to shrink a tumor mainly reflects an ability to kill these cells. It seems that normal stem cells from various tissues tend to be more resistant to chemotherapeutics than mature cell types from the same tissues. The reasons for this are not clear, but may relate to high levels of expression of anti-apoptotic proteins or adenosine triphosphate-binding cassette transporters such as the multidrug resistance gene. If the same were true of CSCs, then one would predict that these cells would be more resistant to chemotherapeutics than tumor cells with limited proliferative potential. Even therapies that cause complete regression of tumors might spare enough CSCs to allow re-growth of the tumors. Therapies that are more specifically directed against CSCs might result in much more durable responses and even cures of metastatic tumors.

There are limited data on the impact of treatment tailoring based on CSC detection. Gene profiling of CSCs could lead to identification of therapeutic targets on CSCs (e.g. hormone receptors (HR), human epidermal growth factor receptor-2 [HER-2] expression, epidermal growth factor receptor [EGFR] expression), and could represent tumor biopsy in "real time". Several groups showed frequent discordance of HER-2 status between primary tumor and CSCs, and case reports showed clinical utility for the use of trastuzumab-based therapy based on HER-2 CSCs status. Similarly, the hormonal status of CSCs could be different from that of the primary tumor, which could lead to increase the number of patients suitable for endocrine therapy, but also could explain why endocrine therapy fails in a subset of HR positive (HR+) patients. More specifically, a recent observation from Ginestier et al. demonstrated that over expression of chemokine receptor 1 (CXCR-1) is associated with the aldehyde dehydrogenase positive (ALDH+) cells. In breast carcinomas, the ALDEFLUOR+ phenotype shows partial overlap with the CD44+CD24-Lin-CSC phenotype. Cellular hierarchies have been identified in a series of molecularly characterized breast cancer cell lines and it has been demonstrated that these lines contained ALDEFLUOR+ components that were both tumorigenic and metastatic in NOD/SCID mice. Furthermore, previous observations demonstrated that the addition of recombinant interleukin-8 (IL-8) increased the CSC population as well as increasing its propensity for invasion. Moreover, tissue damage induced by chemotherapeutic agents may induce IL-8 as part of the injury response. This suggests that strategies aimed at interfering with the IL 8/CXCR-1 axis may be able to target CSCs, increasing the efficacy of current therapies. This experimental data provides another therapeutic target in breast cancer.

Reparixin seems to be a good candidate for use in breast cancer patients because of its very acceptable toxicity profile shown in the Phase I and II clinical trials conducted so far, along with its observed activity in vitro against breast cancer cell lines and in vivo in tumor xenografts in mice. A phase 1 study is currently underway to study the effects of reparixin in combination with paclitaxel in metastatic breast cancer.

This small pilot study aims at exploring the effects on breast CSC markers as well as the safety and PK profile of orally administered single agent reparixin in HER-2 negative (HER-2-) early breast cancer patients in the 3 weeks prior to surgery.

The study will be performed in the interval between disease diagnosis and planned surgery and may lead to a minimal delay in surgery. This is balanced by the potential benefits of the study by evaluating CSCs and their prognostic importance as well as obtaining information about the impact of reparixin therapy.

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REP0111

Pilot Study to Evaluate Reparixin With Weekly Paclitaxel in Patients With HER 2 Negative Metastatic Breast Cancer (MBC)

Brief summary

This is a phase I study to evaluate the safety and define the pharmacokinetic (PK) profile of orally administered reparixin in combination with paclitaxel in HER 2 (Human epidermal growth factor receptor-2) negative metastatic breast cancer patients.

The primary objective of this study was to evaluate the safety and define the pharmacokinetic (PK) profile of orally administered reparixin in combination with paclitaxel in HER-2 negative MBC patients.

The secondary objectives were to:

  1. Evaluate the effects of orally administered reparixin on cancer stem cell (CSC) markers, the tumoral microenvironment and markers of cytokine inflammation;
  2. Evaluate peripheral blood samples for enumeration of circulating tumor cells (CTCs), molecular characterization as CSCs and perform epithelial-mesenchymal transition (EMT) biomarker profiling;
  3. Assess disease response for indication of efficacy.

detailed description

The CSC (Cancer stem cell) concept has important implications for understanding carcinogenesis as well as for the development of cancer therapeutics. According to this concept, tumors are initiated and maintained by a cellular subcomponent that displays stem cell properties. These properties include self-renewal, which drives tumorigenesis, and differentiation (albeit aberrant), which contributes to tumor cellular heterogeneity. The existence of CSCs has been described in a variety of hematologic and solid tumors including those of the breast, brain, colon, pancreas, lung, liver, and head and neck. In addition to driving tumorigenesis, CSCs may contribute to tumor metastasis as well as to tumor recurrence after treatment.

One of the therapeutic strategies being pursued to target CSCs involves inhibition of self renewal or survival pathways in these cells. These pathways include NOTCH (Notch signaling pathway), Hedgehog, and WNT (Wnt signaling pathway). Such strategies may be limited by the role of these pathways in normal stem cell function, which could result in systemic toxicities from pathway inhibition. In addition to intrinsic pathways regulating stem cell functions, normal and malignant stem cells are regulated by extrinsic signals generated in the microenvironment or CSC niche. In the breast, this niche is composed of immune cells, mesenchymal elements that include fibroblasts, endothelial cells, adipocytes, and extracellular matrix components. These components play an important role in normal breast development and carcinogenesis. If the cellular microenvironment plays an important role in the regulation of CSC growth and survival, then strategies aimed at interfering with these interactions represent a rational approach to target breast CSCs.

There are limited data on the impact of treatment tailoring based on CSCs detection. Gene profiling of CSCs could lead to identification of therapeutic targets on CSCs (e.g. hormone receptors, HER-2 [Human epidermal growth factor receptor-2] expression, EGFR [Epidermal growth factor receptor] expression), and could represent tumor biopsy in "real time". Several groups showed frequent discordance of HER-2 status between primary tumor and CSCs, and case reports showed clinical utility to use of trastuzumab-based therapy based on HER-2 CSCs status. Similarly, the hormonal status of CSCs could be different from that of the primary tumor, which could lead to increase the number of patients suitable for endocrine therapy, but also could explain why endocrine therapy fails in a subset of hormone receptor-positive patients. The study provided the in vivo demonstration that CXCR-1 (Chemokine receptor 1) targeting with specific blocking antibodies or reparixin is associated with reduced systemic metastases. The experimental data provides another therapeutic target in metastatic disease and warrants a pilot study investigation in humans to further explore effects of reparixin on breast CSCs and the tumoral microenvironment.

Reparixin seems to be a good candidate for use in breast cancer patients because of its very acceptable toxicity profile shown in the Phase I and II clinical trials conducted so far, along with its observed activity in vitro against breast cancer cell lines and in vivo in tumor xenografts in mice. It potentially addresses another therapeutic target in metastatic disease. The current pilot study thus aims at exploring the safety and PK profile of orally administered reparixin in HER-2 negative metastatic breast cancer patients and its effects on breast CSC markers.

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Dompé farmaceutici S.p.A. Socio Unico / Capitale sociale € 50.000.000,00
REA MI 289519 - Registro Imprese di Milano / Codice Fiscale e Partita IVA (VAT) IT00791570153

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