The process of drug discovery is based on the evaluation of the efficacy of thousands of compounds in modulating the read-out of an assay. One of the key point of the pipeline is the quality of the assay used: if the assay is robust and informative, the hit molecules will have a bigger probability of being developed as potential drugs. The activity of the Laboratory is aimed at exploiting the information derived from “omic” sciences to develop more rational and efficient drug screening assays.
Development of HuR (ELAVL1) inhibitors: HuR is an RNA binding protein involved in tumorigenesis and cancer progression. The main interest of the Lab is devoted to the synthesis and characterization of new HuR inhibitors. We developed an high-throughput screening assay to measure the binding affinity of HuR to target RNA probes. Through a drug screening approach and using this assay, we identified a number of hits able to disrupt the binding of HuR to target RNA. The aim of this project is to show the feasibility of targeting a post-transcriptional regulator of gene expression to obtain a specific therapeutic effect. We are now characterizing the anti-tumor effects of these new molecules.
NAMPT inhibition in cancer cells: Metabolic dysregulation is an hallmark of cancer cells. NAMPT catalyzes the limiting reaction of NAD synthesis from nicotinamide and is a promising target for anticancer therapy. We have been investigating the mechanism of action of NAMPT inhibitors by genome-wide studies and we identified synergistic therapeutic drug combination to treat cancer cells.
RNA binding protein in ALS: Familial amyotrophic lateral sclerosis (ALS) is a motor neuron degenerative disease characterized by the pathological mutations of a number of RNA biding proteins such as FUS, TDP-43 and MATR3. We are developing a screening strategy to identify the common determinants of the same pathological onset due to different causative mutations.
- Alessandro Provenzani, PI
- Vito Giuseppe D'Agostino, post-doc
- Rosa Loffredo, post-doc
- Chiara Zucal, post-doc
- Natthakan Thongon, PhD student
- Preet Lal, PhD student
- Isabelle Bonomo, PhD student
- Nausicaa Valentina Licata, pre-doc fellowship
- Nencioni A. University of Genoa, Italy.
- Poletti A. University of Milan, Italy
- Peyron JF, Inserm, Nice, France
- Gaestel M, University of Hannover, Germany
- Fragai M, University of Florence, Italy
- Marinelli L, University of Neaples, Italy
The GSK3β inhibitor BIS I reverts YAP-dependent EMT signature in PDAC cell lines by decreasing SMADs expression level. Thongon N, Castiglioni I, Zucal C, Latorre E, D’Agostino V, Bauer I, Pancher M, Ballestrero A, Feldmann G, Nencioni A, Provenzani A. Oncotarget, 2016 Mar 28. doi: 10.18632/oncotarget.8437.
The ribonucleic complex HuR-MALAT1 represses CD133 expression and suppresses epithelial-mesenchyme transition in breast cancer. Latorre E, Carelli S, Raimondi I, D'Agostino VG, Castiglioni I, Zucal C, Moro G, Luciani A, Ghilardi G, Monti E, Inga A, Di Giulio AM, Gorio A, Provenzani A. Cancer Research, in press.
Transcriptional induction of the heat shock protein B8 mediates the clearance of misfolded proteins responsible for motor neuron diseases. Crippa V, D’Agostino V, Cristofani R, Rusmini P, Cicardi M, Messi E, Loffredo R, Pancher M, Piccolella M, Galbiati M, Meroni M, Cereda C, Carra S, Provenzani A, Poletti A., Sci Rep 2016 Mar 10;6:22827. doi: 10.1038/srep22827
Human antigen R binding and regulation of SOX2 mRNA in human mesenchymal stem cells. Carelli S, Latorre E, Caremoli F, Giallongo T, Colli M, Canazza A, Provenzani A, Di Giulio AM, Gorio A. Mol Pharmacol. 2015 Dec 16. mol.115.100701.
The CDKN2A/p16INK 4a 5'UTR sequence and translational regulation: impact of novel variants predisposing to melanoma. Andreotti V, Bisio A, Bressac-de Paillerets B, Harland M, Cabaret O, Newton-Bishop J, Pastorino L, Bruno W, Bertorelli R, De Sanctis V, Provenzani A, Menin C, Fronza G, Queirolo P, Spitale RC, Bianchi-Scarrà G, Inga A, Ghiorzo P. Pigment Cell Melanoma Res. 2015 Nov 18. doi: 10.1111/pcmr.12444.
Dihydrotanshinone-I interferes with the RNA-binding activity of HuR affecting its post-transcriptional function. D’Agostino VG, Lal P, Mantelli B, Tiedje C, Zucal C, Thongon N, Gaestel M, Latorre E, Marinelli L, Seneci P, Amadio M, Provenzani A. Sci Rep. 2015 Nov 10;5:16478. doi: 10.1038/srep16478.
EIF2A-dependent translational arrest protects leukemia cells from the energetic stress induced by NAMPT inhibition. Zucal C, D’Agostino VG, Casini A, Mantelli B, Thongon N, Soncini D, Caffa I, Ballestrero A, Quattrone A, Indraccolo S, Nencioni a, Provenzani A. BMC Cancer. 2015 Nov 5;15(1):855. doi: 10.1186/s12885-015-1845-1.
The 5'-untranslated region of p16INK4a melanoma tumor suppressor acts as a cellular IRES, controls mRNA translation during hypoxic stress, and is a target of YBX1. Bisio A, Latorre E, Andreotti V, Bressac-de Paillerets B, Harland M, Bianchi Scarra G, Ghiorzo P, Spitale RC, Provenzani A, Inga A. Oncotarget 2015 Nov 24;6(37):39980-94. doi: 10.18632/oncotarget.5387.
APO866 increases anti-tumor activity of cyclosporin-A by inducing mitochondrial and endoplasmic reticulum stress in leukemia cells. Cagnetta A, Soncini D, Caffa I, Acharya C, Acharya P, Adamia S, Pierri I, Bergamaschi M, Garuti A, Fraternali-Orcioni G, Provenzani A, Mastracci L, Zucal C, Damonte G, Salis A, Patrone F, Ballestrero A, Gobbi M, Montecucco F, Bruzzone S, Nencioni A, Cea M. Clin Cancer Res. 2015 May 11. pii: clincanres.3023.2014.
Fasting potentiates the anticancer activity of tyrosine kinase inhibitors by strengthening MAPK signaling inhibition. Caffa I, D'Agostino V, Damonte P, Soncini D, Cea M, Monacelli F, Odetti P, Ballestrero A, Provenzani A, Longo VD, Nencioni A. Oncotarget. 2015 Mar 30.