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The FUNctional Genomics LAB

Roberto Piva - PI

Main group members

  • Elisabetta Mereu Postdoctoral fellow

  • Mariangela Porro, Michela Cumerlato, María Labrador, Nariman Gharari PhD students 

  • Beatrice Luciano, Pietro Astegiano, Hajar Mouahhid Graduate student

Research activity

Our laboratory is focused on the comprehensive study of Multiple Myeloma (MM) and other hematological malignancies (B and T cell lymphomas). We apply integrated functional screenings with the overarching goal of uncovering co-essential genes and pathways that can serve as novel therapeutic targets. Our objective is to enhance the effectiveness of current pharmacological strategies and prevent the emergence of drug resistance (Figure 1). 

A key focus of our investigations lies in proteasome inhibitors (PIs), a class of drugs commonly employed in clinical settings for treating MM patients. Despite their therapeutic efficacy, the development of resistance poses a significant challenge and complicates disease management. To address this issue, we have conducted a series of genetic screenings utilizing techniques such as shRNA and CRISPRa, alongside pharmacological screenings. These efforts are aimed at identifying new targets that can synergistically interact with the proteasome inhibitor Carfilzomib (CFZ) (Figure 2). 

We meticulously validate the therapeutic potential of these combination treatments in a diverse array of MM cell lines, encompassing both those sensitive and resistant to PIs. To mimic the tumor microenvironment, we assess the efficacy of these combinations in MM cells co-cultured with bone marrow stromal cells in 2D and 3D culturing systems. Additionally, we extend our investigations to primary cells from MM patients. The most promising combinations are then chosen for rigorous in-vivo assessments using zebrafish and mouse MM xenograft models. To gain comprehensive insights into the molecular mechanisms driving therapy response of the new drug combinations, we harness multi-omics approaches that will enable us to unravel the intricate interplay between genetic, epigenetic, and proteomic factors. Recognizing the challenges posed by low bioavailability and high toxicity associated with certain therapeutic agents, we are actively engaged in the refinement of drug delivery systems. Our approach involves encapsulating drugs within functionalized biomimetic lipid nanoparticles, designed for targeted delivery to tumor cells (Figure 3). 

Furthermore, we are keen on exploring the potential of these combinations in a broader range of hematologi cal malignancies and solid tumors.

Being aware of the complex genetic and molecular scenario of MM disease, we believe that there is an urgent need to explore novel cancer vulnerabilities and design new personalized therapeutic strategies. To this end, our functional workflow will be expanded to novel classes of molecules approved for the treatment of MM such as T-cell engagers, bispecific antibodies and chimeric antigen receptor (CAR) therapies. To more efficiently define the therapeutic efficacy of combination protocols, preclinical trials will be executed using patient-derived xenografts (PDX). A pivotal element of our future endeavors involves the integration of patient-derived xenografts (PDX) into our preclinical trial strategy. This approach, leveraging the transplantation of patient tumor samples into animal models, holds immense promise in replicating the complexities of human MM within an in vivo context. By employing PDX models, we aim to bridge the gap between bench and bedside, providing a more accurate representation of the disease microenvironment and therapeutic responses. This step is critical in evaluating the clinical relevance and efficacy of combination protocols, enabling us to make informed decisions on therapeutic approaches with the highest potential for success. In parallel, our laboratory remains committed to fostering collaborations with clinical researchers, pharmaceutical companies, and academic institutions. These partnerships are pivotal in translating our discoveries from the bench to the clinic, ensuring that our findings directly impact patient care and therapeutic decision-making.

  • 2019-2021: CRT Foundation: Richieste Ordinarie 2018 (PI) 

  • 2019-2024: AIRC, Investigator Grant (PI) 

  • 2020-2021: Compagnia di San Paolo: POC Instrument 2020 (Co-PI) 

  • 2022:2025: PRIN 2020; (Co-PI) 

  • 2023-2024: CRT Foundation: Richieste Ordinarie 2022 (PI) 

  • 2023-2024: Compagnia di San Paolo: POC Instrument 2022 (Co-PI)

Bandini C, Mereu E, Paradzik T, Labrador M, Maccagno M, Cumerlato M, Oreglia F, Prever L, Manicardi V, Taiana E, Ronchetti D, D’Agostino M, Gay F, Larocca A, Merlo G, Hirsch E, Ciarrocchi A, Inghirami G, Neri A, Piva R. Lysin (K)-Specifc Demethylase 1 Inhibition Enhances Proteasome Inhibitor Response and Overcomes Drug Resistance in Multiple Myeloma. Experimental Hematology and Oncology, 12: 71 (2023). https://doi.org/10.1186/s40164-023-00434-x 

Mereu E, Abbo D, Paradzik T, Cumerlato M, Bandini C, Labrador M, Maccagno M, Ronchetti D, Manicardi V, Neri A, Piva R. Euchromatic Histone Lysine Methyltransferase 2 Inhibition Enhances Carflzomib Sensitivity and Overcomes Drug Resistance in Multiple Myeloma Cell Lines. Cancers 15, 2199 (2023). https://doi. org/10.3390/cancers15082199 

Taiana E, Bandini C, Favasuli VK, Ronchetti D, Silvestris I, Puccio N, Todoerti K, Erratico S, Giannandrea D, Bolli N, Amodio N, Ciarrocchi A, Chiaramonte R, Torrente Y, Piva R, Neri A. Activation of lncRNA NEAT1 leads to survival advantage of multiple myeloma cells by supporting a positive regulatory loop with DNA repair proteins. Hematologica, 108: 219-233 (2022). https://doi.org/10.3324/haematol.2022.281167 

Cauda V, Xu TT, Nunes I, Mereu E, Villata S, Bergaggio E, Labrador M, Limongi T, Susa F, Chiodoni A, Cumerlato M, Rosso G, Stefania R, Piva R. Biomimetic mesoporous vectors enabling the eficient inhibition of wild-type isocitrate dehydrogenase in multiple myeloma cells. Microporous and Mesoporous Materials, 325, 111320 (2021). https://doi.org/10.1016/j. micromeso.2021.111320 

Sindi H, Russomanno G, Satta S, Abdul-Salam V, Beom Jo K, Chaudhry B, Ainscough A, Szulcek R, Bogaard H, Morgan C, Pullman Setti S, Alzaydi M, Rhodes C, Piva R, Eichstaedt C, Grünig E, Wilkins M, Wojciak-Stothard B. Krüppel-like factor 2-induced microRNAs: implications for treatment of pulmonary hypertension. Nat Commun, 11(1):1185 (2020). https://doi.org/10.1038/ s41467-020-14966-x 

Menotti M, Ambrogio C, Cheong TC, Pighi C, Mota I, Cassel SH, Compagno M, Wang Q, Dall’Olio R, Minero V, Poggio T, Sharma G, Patrucco E, Mastini C, Choudhary R, Pich A, Zamò A, Piva R, Giliani S, Mologni L, Collings CK, Kadoch C, Gambacorti-Passerini C, Notarangelo LD, Anton IM, Voena C, Chiarle R. Wiskott–Aldrich syndrome protein (WASP) is a tumor suppressor in T cell lymphoma. Nature Med, 25(1):130-140 (2019). https://doi:10.1038/s41591-018-0262-9 

Maura F, Agnelli L, Leongamornlert D, Bolli N, Chan J, Dodero A, Carniti C, Heavican T, Pellegrinelli A,Pruneri G, Butler A, Bhosle S, Chiappella A, Di Rocco A, Zinzani PL, Zaja F, Piva R, Inghirami G, Wang W, Palomero T, Iqbal J, Neri A, Campbell PJ, Corradini P. Integration of Transcriptional and Mutational Data improves the Stratifcation of Peripheral T-Cell Lymphoma. Am J Hematol, 94(6):628-634 (2019). https://doi:10.1002/ ajh.25450 

Bergaggio E, Riganti C, Garafo G, Mereu E, Vitale N, Bandini C, Pellegrino E, Omedè P, Todoerti K, Audrito V, Rossi A, Bertoni F, Deaglio S, Neri A, Palumbo A, Piva R. IDH2 inhibition enhances proteasome inhibitor responsiveness in hematological malignancies. Blood, 133(2):156-167 (2019). https://doi.org/10.1182/ blood-2018-05-850826 

Bandini C, Pupuleku A, Spaccarotella E, Pellegrino E, Wang R, Vitale N, Duval C, Cantarella D, Rinaldi A, Provero P, Di Cunto F, Medico E, Bertoni F, Inghirami G, Piva R. IRF4 mediates the oncogenic efects of STAT3 in Anaplastic Large Cell Lymphomas. Cancers, 10(1):21- 39 (2018). https://doi.org/10.3390/cancers10010021 

Scarfò I, Pellegrino E, Mereu E, Kwee I, Agnelli L, Bergaggio E, Garafo G, Vitale N, Caputo M, Machiorlatti R, Circosta P, Abate F, Barreca A, Novero D, Mathew S, Rinaldi A, Tiacci E, Serra S, Deaglio S, Neri A, Falini B, Rabadan R, Bertoni F, Inghirami G, Piva R. Identification of a new subclass of ALK-negative ALCL expressing aberrant levels of ERBB4 transcripts. Blood, 127(2):221-32 (2016). https://doi-org.bibliopass.unito.it/10.1182/blood-2014-12-614503 

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