Simonetta Andrea Licandro

Curriculum vitae

Simonetta Andrea Licandro is an employee at Italfarmaco S.p.A., a private multinational pharmaceutical Company (Cinisello Balsamo, Italy) mainly oriented towards the cardiovascular, immuno-oncologic, gynecological, osteoporosis and neurologic areas. She is also a PhD Executive student in Experimental Neuroscience at the University of Milano-Bicocca (Monza, Italy). She actually works as a researcher on muscle and nervous degeneration projects. In particular, she studies the molecular mechanisms involved in epigenetic alterations in neuromuscular diseases such as Duchenne Muscular Dystrophy and she tests (in vivo) new drugs that are developed by the Company to correct these epigenetic alterations.

Simonetta received Master’s Degree in Industrial Biotechnologies in 2012 (University of Milano-Bicocca – Milan, Italy). After her thesis (oncology; IRCCS- Istituto di Ricerche Farmacologiche “Mario Negri”, Milan), she was enrolled as research fellow at “Scuola per Specialisti in Ricerca Biomedica” (IRCCS- Istituto di Ricerche Farmacologiche “Mario Negri”, Milan) and received (2015) the qualification as Biomedical Research Specialist (in vivo – oncology). From 2015 to 2017 she was enrolled as research fellow at “Scuola Avanzata in Farmacologia Applicata” (IRCCS- Istituto di Ricerche Farmacologiche “Mario Negri”, Milan) and received the qualification as Specialist in Pharmacology (in vivo – oncology).

 

PhD research project

Evaluation of the pharmacological effect of compounds modulating the fibrotic process in dystrophinopathy in fibro-degenerative diseases murine models

  • Tutors: Dr. Carozzi (UNIMIB) and Dr. Leoni (Italfarmaco)
  • Track: Experimental Neuroscience

Her PhD research project is aimed to test HDAC inhibitors potentially effective in the treatment of fibrosis, in dystrophic muscle, tumors and in other organs, such as heart or lung to better understand the mechanism of action of these compounds.

Background

Fibrosis is a process that leads to the excessive or unregulated deposition of extracellular matrix components during the restoration of damaged tissues resulting in the loss of their structure and functionality. Fibro-degenerative diseases are often associated with a chronic inflammatory response and abnormal repair processes in several tissues upon injury, including liver, lung, heart, kidney and skeletal muscle. In human muscle, fibrosis is mainly associated with muscle wasting caused by dystrophinopathies. In particular, fibrosis is a specific hallmark in Duchenne Muscular Dystrophy (DMD) as a result of skeletal muscle degeneration, inflammatory pathways activation and loss of regenerative capacity by satellite cells of muscle tissue (1).

DMD is a lethal X-linked disorder that leads to muscle wasting with an average incidence of 1:3500 newborn males. DMD is due to mutations in the gene encoding dystrophin, a structural protein that plays a critical role in the membrane mechanical stability during muscle contraction. Mutations in this gene cause the absence of dystrophin and the lack of this protein leads to muscle fiber degeneration, activation of chronic inflammatory pathways and progressive muscle tissue replacement by fibroblasts and adipocytes, triggering the process leading to fibrosis development (1).

The main causes of the reduced life span of DMD patients are both severe respiratory insufficiency, due to the weakening of the diaphragm, or cardiac failure, due to the TGFβ-dependent fibrosis in cardiac muscle.

Data generated in our Laboratories demonstrate that Givinostat, a pan-histone deacetylase (HDAC) inhibitor currently in phase III clinical trial for the DMD treatment, counteracts the atrophy program induced by TNFα in healthy skeletal muscle cells and suggest that a similar mechanism may take place in DMD muscle cells. Pharmacological blockade using HDAC inhibitors (HDACi), decreases fibrosis and promotes compensatory regeneration in the mdx mouse model (2-6). 

We also observed that the in vivo treatment with Givinostat has been effective in mdx mice in ameliorating morphology, reducing significantly fibrosis and increasing the cross sectional area (CSA) of myofibers, and muscular function, enhancing their performance in the treadmill test (5). 

Fibrotic processes are also involved in other fibro-degenerative disorders, such as in pulmonary fibrosis, primary myelofibrosis, cardiac fibrosis and acute respiratory distress syndrome (ARDS). Although the organs involved are different, fibrosis also occurs in these diseases as a consequence of the systemic inflammatory response of the organism, following the damage of the organ of interest, characterized by the release of a large amount of pro-inflammatory cytokines (including TNFα).

Aims

The objectives of this project are the following: 

  • to test HDAC inhibitors (including Givinostat) potentially effective in the treatment of fibrosis, both in dystrophic muscle and in other organs such as heart or lung and to better understand the mechanism of action of these compounds;
  • monitoring the fibrotic processes and the in vivo pharmacological effect of HDAC inhibitors by imaging techniques in both DMD mouse models and fibro-degenerative disease models (ARDS, pulmonary fibrosis, cardiac fibrosis) developed by different Research Groups at the School of Medicine and Surgery – University of Milano-Bicocca.
References
  1. Flanigan KM. Duchenne and Becker Muscular Dystrophies. Neurol Clin. 2014; 32(3):671-88.
  2. Minetti GC, Colussi C, Adami R, Serra C, Mozzetta C, Parente V, Fortuni S, Straino S, Sampaolesi M, Di Padova M, Illi B, Gallinari P, Steinkühler C, Capogrossi MC, Sartorelli V, Bottinelli R, Gaetano C, Puri PL. Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitors. Nat Med 2006; 12:1147–1150.
  3. Colussi C, Mozzetta C, Gurtner A, Illi B, Rosati J, Straino S, Ragone G, Pescatori M, Zaccagnini G, Antonini A, Minetti G, Martelli F, Piaggio G, Gallinari P, Steinkühler C, Clementi E, Dell’Aversana C, Altucci L, Mai A, Capogrossi MC, Puri PL, Gaetano C et al. HDAC2 blockade by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatment. Proc Natl Acad Sci USA 2008; 105:19183–19187.
  4. Colussi C, Brioschi M, Tremoli E, Straino S, Spallotta F, Mai A, Rotili D, Capogrossi MC, Gaetano C. Proteomic profile of differentially expressed plasma proteins from dystrophic mice and following suberoylanilide hydroxamic acid treatment. Proteomics Clin Appl 2010; 4:71–83.
  5. Consalvi S, Mozzetta C, Bettica P, Germani M, Fiorentini F, Del Bene F, Rocchetti M, Leoni F, Monzani V, Mascagni P, Puri PL, Saccone V. Preclinical studies in the mdx mouse model of duchenne muscular dystrophy with the histone deacetylase inhibitor givinostat. Mol Med. 2013; 19:79-87. 
  6. Bettica P, Petrini S, D’Oria V, D’Amico A, Catteruccia M, Pane M, Sivo S, Magri F, Brajkovic S, Messina S, Vita GL, Gatti B, Moggio M, Puri PL, Rocchetti M, De Nicolao G, Vita G, Comi GP, Bertini E, Mercuri E. Histological effects of givinostat in boys with Duchenne muscular dystrophy. Neuromuscul Disord. 2016; 26(10):643-649.

Invited speaker at national meetings

Licandro SA. (2020). Congresso: “Malattie rare e farmaci orfani”. Università degli Studi di Milano-Bicocca (Monza), February 1, 2020.  

National and international conferences

  • October 1-5, 2019. 24th International Annual Congress of the World Muscle Society, Tivoli Garden Copenhagen (Denmark).
  • April 13-17, 2019. MDA Clinical and Scientific Conference 2019, Hyatt Regency Orlando (Orlando, Florida). Poster session.
  • February 15-17, 2019. 17th International Conference on Duchenne and Becker Muscular Dystrophy. Duchenne Parent Project, Ergife Palace Hotel (Rome). 
  • November 9-11, 2018. “The Action Duchenne International Conference 2018”, The Hilton Birmingham Metropole (Birmingham). Poster session.
  • February 16-18, 2018. 16th International Conference on Duchenne and Becker Muscular Dystrophy. Duchenne Parent Project, Ergife Palace Hotel (Rome). 

Selected publications

She authored 12 publications on peer-review international journals. Here are reported the most relevant publications:

  • Application of 3D Mass Spectrometry Imaging to TKIs. Morosi L, Giordano S, Falcetta F, Frapolli R, Licandro SA, Matteo C, Zucchetti M, Ubezio P, Erba E, Visentin S, D’Incalci M, and Davoli E. Clin Pharmacol Ther. 2017 Nov; 102(5):748-751 [Pubmed: 29023728].

IF: 7.226

IF: 6.176 

IF: 5.228 

IF: 5.531 [*equal contribution]

  • Mode of action of trabectedin in myxoid liposarcomas. Di Giandomenico S, Frapolli R, Bello E, Uboldi S, Licandro SA, Marchini S, Beltrame L, Brich S, Mauro V, Tamborini E, Pilotti S, Casali PG, Grosso F, Sanfilippo R, Gronchi A, Mantovani R, Gatta R, Galmarini CM, Sousa-Faro JM, D’Incalci M. Oncogene. 2014 Oct 30; 33(44):5201-10. [PubMed: 24213580]

IF: 8.459

IF: 6.107

Further details

Elisabetta Donzelli
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