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Experimental Therapeutics

Group Leader: Catapano Carlo, MD PhD

Our research aims to develop innovative strategies for cancer treatment by understanding the complex interplay between epigenetic, genetic, and metabolic processes underpinning cancer evolution, cancer stem cell biology, and treatment resistance.

Epigenetic and transcriptional regulators
Epigenetic processes and transcription factor activity underlie the phenotypic reprogramming associated with tumor evolution. We are studying the contribution of various epigenetic and transcriptional regulators (BET proteins, EZH2, STAT3, c-MYC) to these processes and as targets for cancer therapy. We have made considerable progress in determining the therapeutic potential of drugs, like BET inhibitors, for reversing changes in the epigenetic landscape of cancer cells and overcoming treatment resistance. This approach would be particularly effective in drug combination strategies, where the concomitant administration of epigenetic drugs could enhance the activity of standard anticancer treatment. We are currently investigating several novel clinical-stage inhibitors of epigenetic regulators, focusing on their ability to reprogram the cancer cell transcriptome and prevent drug resistance. One of our goals is to combine different anticancer drugs taking advantage of the novel opportunities offered by recent advances in the nanotechnology and nanomedicine fields. These combinatorial therapies could effectively avoid treatment failures and disease recurrence by preventing the emergence of drug-resistant tumor cells.

Cancer stem cell biology and novel therapeutic approaches
Cancer stem cells (CSCs) are critical players in tumor progression, metastasis, and treatment failure. Therapeutic strategies that target CSCs could determine a fundamental shift in the current approaches to cancer treatment. We focus on the molecular and biological processes that underlie the acquisition and maintenance of the stem-like phenotype in cancer cells to find targetable pathways for novel CSC-directed therapies. We have developed experimental approaches enabling the functional characterization of stem-like tumor cells in cell cultures, tumor xenografts, and genetic mouse models. Using these approaches, we are exploring the link between cancer stemness, epigenetic and metabolic processes. We are currently focusing on the role of mitochondrial biogenesis and dynamics in determining the fate of CSCs. Factors involved in mitochondrial dynamics and ER-mitochondria transactions may directly impact on self-renewal and tumor-initiating capability of CSCs. These mitochondrial processes represent a critical vulnerability to exploit therapeutically to induce the progressive elimination of CSCs.

Our studies are funded by grants from SNSF, Swiss Cancer League, Fondazione San Salvatore, Fondazione Barletta and Fondazione Ticinese per la Ricerca sul Cancro.

The Experimental Therapeutics group participates in the EU COST Action CA17140 “Cancer Nanomedicine: from the bench to the bedside. Nano2Clinic and Prof. Catapano leads the Working group (WG3) on Preclinical studies of nanodrugs. For further information: (https://www.nano2clinic.eu/).

Members

Catapano Carlo, Group Leader
Civenni Gianluca, Research Associate
Federici Elisa, Visiting Student (Master)
Giamogante Flavia, PostDoc
Giugni Nicole, Visiting Student (Master)
Merulla Jessica, Research Associate
Mosole Simone, Research Associate
Sandrini Giada, PhD Student
Storelli Elisa, Research Associate
Uboldi Valeria, PhD Student
Zaldivar Strozzi Giulia, Visiting Student (Master)

Current projects

  • Mitochondrial dynamics at the crossroad between stemness and treatment resistance in prostate cancer
  • Targeting mitochondrial dynamics and cancer cell plasticity in human cancers
  • Metabolic reprogramming and impact on tumor progression and treatment resistance
  • Nanoparticle-based delivery and combinatorial therapies for cancer
  • Epigenetic cross-talks and novel therapeutic strategies to prevent disease progression in prostate cancer
  • Epigenetic drugs in prostate and liver cancer
  • Targeting Lin28-dependency in cancer

Relevant publications

  • Civenni G, Bosotti R, Timpanaro A, Vazquez R, Merulla J, Pandit S, Rossi S, Albino D, Allegrini S, Mitra A, Mapelli SN, Vierling L, Giurdanella M, Marchetti M, Paganoni A, Rinaldi A, Losa M, Mira-Cato E, D'Antuono R, Morone D, Rezai K, D'Ambrosio G, Ouafik L, Mackenzie S, Riveiro ME, Cvitkovic E, Carbone GM and Catapano CV. Epigenetic Control of Mitochondrial Fission Enables Self-Renewal of Stem-like Tumor Cells in Human Prostate Cancer. Cell Metab (2019) 30, 303-318 e306. https://www.ncbi.nlm.nih.gov/pubmed/31130467.
  • Mapelli SN, Napoli S, Pisignano G, Garcia-Escudero R, Carbone GM and Catapano CV. Deciphering the complexity of human non-coding promoter-proximal transcriptome. Bioinformatics (2019) 35, 2529-2534. https://www.ncbi.nlm.nih.gov/pubmed/30535182.
  • Civenni G, Albino D, Shinde D, Vazquez R, Merulla J, Kokanovic A, Mapelli SN, Carbone GM and Catapano CV. Transcriptional Reprogramming and Novel Therapeutic Approaches for Targeting Prostate Cancer Stem Cells. Front Oncol (2019) 9, 385. https://www.ncbi.nlm.nih.gov/pubmed/31143708.
  • Civenni G, Carbone GM and Catapano CV. Mitochondrial fission and stemness in prostate cancer. Aging (Albany NY) (2019) 11, 8036-8038. https://www.ncbi.nlm.nih.gov/pubmed/31575828.
  • 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 and Catapano CV. A promoter-proximal transcript targeted by genetic polymorphism controls E-cadherin silencing in human cancers. Nat Commun (2017) 8, 15622. https://www.ncbi.nlm.nih.gov/pubmed/28555645.
  • Genini D, Brambilla L, Laurini E, Merulla J, Civenni G, Pandit S, D'Antuono R, Perez L, Levy DE, Pricl S, Carbone GM and 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) 114, E4924-E4933. https://www.ncbi.nlm.nih.gov/pubmed/28584133.
  • Roos M, Pradere 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 and Hall J. A Small-Molecule Inhibitor of Lin28. ACS Chem Biol (2016) 11, 2773-2781. https://www.ncbi.nlm.nih.gov/pubmed/27548809.
  • Civenni G, Malek A, Albino D, Garcia-Escudero R, Napoli S, Di Marco S, Pinton S, Sarti M, Carbone GM and Catapano CV. RNAi-mediated silencing of Myc transcription inhibits stem-like cell maintenance and tumorigenicity in prostate cancer. Cancer Res (2013) 73, 6816-6827.

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