Experimental Therapeutics

Members

Aleksandra Kokanovic, MS stage
Andrea Timpanaro, MS student
Carlo Catapano, MD, PhD Group Leader
Demetra Vanni, MS Student
Enrica Mira Catò
Giada Zoppi, MS Student
Gianluca Civenni, PhD
Jessica Merulla, PhD
Ramiro Vazquez, PhD
Sarah Mapelli, PhD student / Bioinformatics

Overview

Current objectives of the research in my group are the investigation of transcriptional and epigenetic mechanisms in human cancers and the development of innovative therapeutic strategies. Transcription factors are central nodes in multiple oncogenic pathways and represent attractive targets for development of new cancer therapeutics. However, very few direct pharmacological inhibitors of transcription factors are currently available. My group is investigating various approaches, including small molecule inhibitors, small interfering RNAs and oligonucleotides, to block the activity of oncogenic transcription factors. Furthermore, extensive modifications of the epigenetic landscape occur along with deregulated activity of transcription factors and are at the basis of the phenotypic reprogramming associated with tumor development, progression and treatment resistance. We are investigating the role of epigenetic regulators in tumor progression and treatment resistance and the impact of specific inhibitors on these processes. Novel epigenetic effectors, such as promoter-associated long noncoding RNAs, microRNAs and RNA binding proteins, are also investigated as potential targets for innovative therapeutic strategies. Ultimately, stem-like tumor cells in human tumors are emerging as important players in tumor progression, metastasis and treatment failure. It is therefore becoming apparent that it is necessary to block the cancer stem-like cell subpopulation in order to have an effective and lasting impact of the disease. With this intent we are exploring the biological pathways responsible for self-renewal, expansion and maintenance of stem-like tumor cells in human cancers. A major focus is on the processes that underlie the epigenetic and metabolic reprogramming and sustain the stem-like phenotype. In collaboration with the prostate cancer biology group at the IOR, we have established protocols and experimental models to study cancer cells with stem-like features in vitro and in vivo. These systems are used to study the specific features of cancer stem cells and test inhibitors of key pathways to establish their potential for therapeutic applications.

Current projects

  • Targeting metabolic reprogramming and plasticity of cancer stem cells to impact on tumor progression and treatment resistance
  • Novel therapeutic strategies to prevent disease progression in ERG fusion positive prostate cancer
  • Promoter proximal long noncoding RNA and epigenetic regulatory networks in human cancer
  • Targeting Lin28-dependent cancers
  • Structural basis for the inhibition of STAT3 transcription factor by small molecules
  • Biological and genetic determinants of response to transcriptional inhibitors in human cancers
  • Novel epigenetic targets for cancer therapy

Recent publications

  • Genini D, Brambilla L, Laurini E, Merulla J, Civenni G, Pandit S, D’Antuono R,Perez L, Levy DE, Pricl S, Carbone GM, Catapano CV. Mitochondrial dysfunction induced by a SH2 domain-targeting STAT3 inhibitor leads to metabolic synthetic lethality in cancer cells. Proc Natl Acad Sci U S A. 2017 Jun 20;114(25):E4924-E4933.
  • Pisignano G, Napoli S, Magistri M, Mapelli SN, Pastori C, Di Marco S, Civenni G, Albino D, Enriquez C, Allegrini S, Mitra A, D’Ambrosio G, Mello-Grand M,Chiorino G, Garcia-Escudero R, Varani G, Carbone GM, Catapano CV. A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers. Nat Commun. 2017 May 30;8:15622.
  • Stathis A, Hess D, von Moos R, Homicsko K, Griguolo G, Joerger M, Mark M, Ackermann CJ, Allegrini S, Catapano CV, Xyrafas A, Enoiu M, Berardi S, Gargiulo P, Sessa C; Swiss Group for Clinical Cancer Research (SAKK). Phase I trial of the oral smoothened inhibitor sonidegib in combination with paclitaxel in patients with advanced solid tumors. Invest New Drugs. 2017 Mar 20.
  • Dallavalle C, Albino D, Civenni G, Merulla J, Ostano P, Mello-Grand M, Rossi S, Losa M, D’Ambrosio G, Sessa F, Thalmann GN, Garcia-Escudero R, Zitella A, Chiorino G, Catapano CV, Carbone GM. MicroRNA-424 impairs ubiquitination to activate STAT3 and promote prostate tumor progression. J Clin Invest. 2016 Dec 1;126(12): 4585-4602.
  • Albino D, Civenni G, Dallavalle C, Roos M, Jahns H, Curti L, Rossi S, Pinton S, D’Ambrosio G, Sessa F, Hall J, Catapano CV, Carbone GM. Activation of the Lin28/let-7 Axis by Loss of ESE3/EHF Promotes a Tumorigenic and Stem-like Phenotype in Prostate Cancer. Cancer Res. 2016 Jun 15;76(12):3629-43.
  • Roos M, Pradère U, Ngondo RP, Behera A, Allegrini S, Civenni G, Zagalak JA, Marchand JR, Menzi M, Towbin H, Scheuermann J, Neri D, Caflisch A, Catapano CV, Ciaudo C, Hall J. A Small-Molecule Inhibitor of Lin28. ACS Chem Biol. 2016 Oct 21;11(10):2773-2781.
  • Albino D, Civenni G, Rossi S, Mitra A, Catapano CV, Carbone GM. The ETS factor ESE3/EHF represses IL-6 preventing STAT3 activation and expansion of the prostate cancer stem-like compartment. Oncotarget. 2016 Nov 22;7(47):76756-76768.
  • Civenni G, Longoni N, Costales P, Dallavalle C, García Inclán C, Albino D, Nuñez LE, Morís F, Carbone GM, Catapano CV. EC-70124, a Novel Glycosylated Indolocarbazole Multikinase Inhibitor, Reverts Tumorigenic and Stem Cell Properties in Prostate Cancer by Inhibiting STAT3 and NF-κB. Mol Cancer Ther. 2016 May;15(5):806-18.