UOSD PRECLINICAL MODELS AND NEW THERAPEUTIC AGENTS
Head: Anna Bagnato
STAFF
- Valeriana Di Castro
- Donatella Del Bufalo
- Rossella Galati
- Daniela Trisciuoglio
- Rosanna Sestito
- Piera Tocci
- Simona D’Aguanno
- Marta Di Martile
- Elisabetta Valentini
- Valeria Pecci, PhD
- Ilenia Masi, PhD
- Anna Maria Lucianò, PhD Student
- Alessia Ricci, PhD Student
- Adele Petricca
- Aldo Lupo
- Valentina Caprara
- Barbara Nuvoli
- Andrea Cerri
- Alessandro Renna
- Federica Timoteo
- Federica Badoni
- Valentina Pau
- Matteo Brignone
The ultimate goal of this Unit is to develop meaningful combinatorial strategies leading to rationally-designed (and potentially personalised) novel treatment regimens for specific cancers, exploring in pertinent preclinical models how cancer cells respond to perturbations of specific pathways and how resistance to therapies arises, being transformed into a set of mechanistic rules. The activity of the Unit concerns patient-centred research, learning from every patient the complexity of disease biology.
PI Bagnato
- Di Castro Valeriana
- Rosanna Sestito
- Piera Tocci
- Valentina Caprara
- Adele Petricca
- Aldo Lupo
- Cela Roman de la Calle
We focused beyond cell intrinsic factors alone and explored the role of the surrounding cells or stroma, including the extracellular matrix. We discovered the alliance between endothelin-1 and YAP pathway, regulating mutant p53-mediated transcriptional networks acting as a therapeutic escape route of drug-resistant ovarian cancer (OC) cells. In our study, we provided valuable insights into mechanisms of response to platinum and PARP inhibitor (PARPi) therapy supporting the premise that both molecular and spatial features in the tumor microenvironment (TME) are potentially linked to response to therapy. Our study highlights that targeting endothelin-1 receptor (ET-1R) activities in tumor and TME elements may disclose unexplored opportunities for OC therapy. To design and identify more effective integrated treatments, we combined drugs (platinum or PARPi), with the dual ET-1R antagonists that work on targets expressed in tumoral and stromal compartment in complementary pathways so that they can be given at a lower and less toxic doses whilst maintaining efficacy and reducing side effects. In this context, we designed sequential drug treatment protocols in which new vulnerabilities (such as the transcriptional complex YAP/mutant p53/HIF-1α) can be targeted. It is expected that the validation of proposed mechanistic rules for potential combinatorial treatments in realistic preclinical models will be an essential aspect for the successful translation to early-phase clinical trials. The future scientific strategies to address our mission will be implemented through the integration of single-cell spatially resolved data and pertinent patient-derived models that might provide valuable information on the determinants of response to therapy, and reveal new treatment modalities, fulfilling the gap between basic researches and clinical practice.
PI Del Bufalo
- Simona D’Aguanno
- Marta Di Martile
- Elisabetta Valentini
- Chiara Bazzichetto
- Marica Di Caprio
- Matteo Brignone
- Fabiana Conciatori
- Martina Chiacchiarini
- Valentina Salvati
- Ilaria Perinelli
- Daniela Trisciuoglio
By using melanoma preclinical models, we provided new insights into the roles of bcl-2 family members in melanoma progression and therapy. In particular, we explored the crosstalk between melanoma cells overexpressing bcl-2 protein and TME. We demonstrated that bcl-2 in melanoma cells i) regulates interleukin-1β (IL-1β) expression, ii) induces M2 polarization/recruitment of macrophages through a NF-kB-dependent mechanism, iii) correlates with increased infiltration of M2-polarized macrophages in tumor specimens from metastatic melanoma patients. A melanoma syngeneic mouse model evidenced the ability of bcl-2 to impair T cell response, through reduced production of interferon γ and the effector T cells population, thus indicating bcl-2 ability to impair specific antitumor immunity. Taken together, our results show that melanoma-specific bcl-2 controls an IL-1β-driven axis of macrophage diversion that establishes TME conditions favouring melanoma progression indicating that interfering with this pathway might provide novel therapeutic strategies. In a search for new therapeutic agents, we discovered the antitumoral activity of i) a lysine acetyltransferase inhibitor, CPTH6, acting as antiangiogenic agent; ii) novel quinoline compounds acting at the same time as DNA methyltransferase inhibitors and degraders, iii) dual enhancer of zeste homolog 2/histone deacetylases inhibitor, iv) M2 muscarinic receptor agonist.
PI Galati
- Barbara Nuvoli
The aim of the study is to investigate new combination therapies to improve their effectiveness in the treatment of different tumors, including malignant mesothelioma. Based on previous studies highlighting that the induction of cyclooxygenase-2 (COX-2) and high prostaglandin E2 (PGE2) levels contribute to the pathogenesis of mesothelioma, as well as that PGE2 upregulates aromatase (CYP19A1) expression in other cancers, we investigated the interplay between COX-2 and CYP19A1 in the pathogenesis of mesothelioma. The insights obtained on a panel of 2D and 3D mesothelioma cell cultures and in mesothelioma specimens highlighted a novel COX2/CYP19A1 axis in the pathogenesis of mesothelioma that can be pharmacologically targeted, opening new therapeutic options.