Novel markers and therapeutic targets for autoimmune diseases and cancer
This lab is focused on the identification and validation of novel biomarkers for autoimmune diseases and cancer, that could be exploited to improve diagnosis, predict the most probable outcome of the diseases and monitor response to a given therapy. Moreover, we are interested in the selection and characterization on novel molecular targets to the development of innovative therapies. Two of our major current studies are outlined below.
Seronegative rheumatoid arthritis
Chronic inflammatory arthritis, such as rheumatoid arthritis (AR) and related forms (spondyloarthritis, juvenile chronic arthritis) are autoimmune diseases that affect 2% of the general population. They have a chronic course, with different aggressiveness. If not timely diagnosed and handled, they can damage to joint tissues and cause severe disabilities. Diagnosis is based on clinical evidence, imaging data and the recognition of biomarkers, including rheumatoid factor (RF) IgG-IgM-IgA, and anti-IgG citrullinated peptides (ACPA). However, at present there are not validated sensitive biomarkers to estimate treatment efficacy for a given patient. Moreover, a significant fraction of patients is negative for RF or ACPA (seronegative arthritis) making the diagnosis more difficult and delaying the pharmacological treatment. Objective of our study is the identification / validation of biomarkers able to fill the serological gap, to select potential therapeutic targets and offer new insights into the mechanisms underlying this pathology.
Novel targets for cancer immunotherapy
In oncologic patients, effective anti-tumor immune responses are suppressed by immunological pathways (immune checkpoints), cytokines and a subset of tumor infiltrating lymphocytes called T regulatory cells (Treg cells). Immune checkpoints inhibitors (e.g. anti-CTLA4, PD-1/PD-L1 monoclonal antibodies) able to unleash effective anti-tumor immune responses are emerging as breakthrough in the treatment of many cancers. However, approved monoclonal antibodies towards immune checkpoints often cause serious immune-related adverse events (irAEs) likely due to a general depression of the immune system. Although steroids can be used to reduce irAEs, the associated immune suppression can compromise therapy efficacy. We believe that irAEs could be overcome by a selective targeting of tumor-infiltrating T reg cells. Antibodies able to deplete this cell population should de-repress the local immune response in the tumor lesion, while maintaining safe therapeutic profiles.
In continuation with transcriptome studies so far conducted at INGM (Massimiliano Pagani and Sergio Abrignani), our group is interested in exploiting a gene signature associated to tumor infiltrating Tregs (De Simone M. et al., Immunity 2016) to select novel immune-modulators suitable for the generation of therapeutic monoclonal antibodies.
- Identification and validation of novel markers for seronegative rheumatoid arthritis
- Identification and validation of novel markers for liver autoimmune diseases
- Validation of a novel target for monoclonal antibody therapy of colorectal and pancreatic cancers
- Validation of novel targets over-expressed by tumor-infiltrating regulatory T cells suitable and for monoclonal antibody therapy
- Magnetically driven drug delivery systems improving targeted immunotherapy for colon-rectal cancer.
Grifantini R, Taranta M, Gherardini L, Naldi I, Parri M, Grandi A, Giannetti A, Tombelli S, Lucarini G, Ricotti L, Campagnoli S, De Camilli E, Pelosi G, Baldini F, Menciassi A, Viale G, Pileri P, Cinti C.
J Control Release (2018) pii: S0168-3659(18)30254-2 [Epub ahead of print]
- CombiROC: an interactive web tool for selecting accurate marker combinations of omics data.
Mazzara S, Rossi RL, Grifantini R, Donizetti S, Abrignani S, Bombaci M.
Sci Rep (2017) 7:45477
- ERMP1, a novel potential oncogene involved in UPR and oxidative stress defense, is highly expressed in human cancer.
Grandi A, Santi A, Campagnoli S, Parri M, De Camilli E, Song C, Jin B, Lacombe A, Castori-Eppenberger S, Sarmientos P, Grandi G, Viale G, Terracciano L, Chiarugi P, Pileri P, Grifantini R.
Oncotarget (2016) 7:63596-63610
- FAT1: a potential target for monoclonal antibody therapy in colon cancer.
Pileri P, Campagnoli S, Grandi A, Parri M, De Camilli E, Song C, Ganfini L, Lacombe A, Naldi I, Sarmientos P, Cinti C, Jin B, Grandi G, Viale G, Terracciano L, Grifantini R.
Br J Cancer (2016) 115:40-51
- Negatively charged AuNP modified with monoclonal antibody against novel tumor antigen FAT1 for tumor targeting.
Fan L, Campagnoli S, Wu H, Grandi A, Parri M, De Camilli E, Grandi G, Viale G, Pileri P, Grifantini R, Song C, Jin B.
J Exp Clin Cancer Res (2015) 34:103
- Angiopoietin-like 7, a novel pro-angiogenetic factor over-expressed in cancer.
Parri M, Pietrovito L, Grandi A, Campagnoli S, De Camilli E, Bianchini F, Marchio S, Bussolino F, Jin B, Sarmientos P, Grandi G, Viale G, Pileri P, Chiarugi P, Grifantini R.
Angiogenesis (2014) 17:881-96
- Multi high-throughput approach for highly selective identification of vaccine candidates: the Group A Streptococcus case.
Bensi G, Mora M, Tuscano G, Biagini M, Chiarot E, Bombaci M, Capo S, Falugi F, Manetti AG, Donato P, Swennen E, Gallotta M, Garibaldi M, Pinto V, Chiappini N, Musser JM, Janulczyk R, Mariani M, Scarselli M, Telford JL, Grifantini R, Norais N, Margarit I, Grandi G.
Mol Cell Proteomics (2012) 11:M111 015693
- Surface interactome in Streptococcus pyogenes.
Galeotti CL, Bove E, Pezzicoli A, Nogarotto R, Norais N, Pileri S, Lelli B, Falugi F, Balloni S, Tedde V, Chiarot E, Bombaci M, Soriani M, Bracci L, Grandi G, Grifantini R.
Mol Cell Proteomics (2012) 11:M111 015206
- Approach to discover T- and B-cell antigens of intracellular pathogens applied to the design of Chlamydia trachomatis vaccines.
Finco O, Frigimelica E, Buricchi F, Petracca R, Galli G, Faenzi E, Meoni E, Bonci A, Agnusdei M, Nardelli F, Bartolini E, Scarselli M, Caproni E, Laera D, Zedda L, Skibinski D, Giovinazzi S, Bastone R, Ianni E, Cevenini R, Grandi G, Grifantini R.
Proc Natl Acad Sci U S A (2011) 108:9969-74
- PerR confers phagocytic killing resistance and allows pharyngeal colonization by group A Streptococcus.
Gryllos I, Grifantini R, Colaprico A, Cary ME, Hakansson A, Carey DW, Suarez-Chavez M, Kalish LA, Mitchell PD, White GL, Wessels MR.
PLoS Pathog (2008) 4:e1000145
- Identification of iron-activated and -repressed Fur-dependent genes by transcriptome analysis of Neisseria meningitidis group B.
Grifantini R, Sebastian S, Frigimelica E, Draghi M, Bartolini E, Muzzi A, Rappuoli R, Grandi G, Genco CA.
Proc Natl Acad Sci U S A (2003) 100:9542-7
- Previously unrecognized vaccine candidates against group B meningococcus identified by DNA microarrays.
Grifantini R, Bartolini E, Muzzi A, Draghi M, Frigimelica E, Berger J, Ratti G, Petracca R, Galli G, Agnusdei M, Giuliani MM, Santini L, Brunelli B, Tettelin H, Rappuoli R, Randazzo F, Grandi G.
Nat Biotechnol (2002) 20:914-21