UOSD PRECLINICAL MODELS AND NEW THERAPEUTIC AGENTS
Head: Dr. Anna Bagnato
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 A. Bagnato
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 L. Rosanò
To unravel the complex mechanisms governing the early steps of OC metastatic dissemination we characterized tumor-stroma interactions guiding tumor cells to attach in the metastatic sites, as the peritoneum and omentum. Specifically, we uncovered the interactions of OC cells with the normal cells surrounding them to understand how matrix and TME cells affect the growth and plasticity of cancer cells, elucidating how mesothelial cells and cancer cell interactions promote OC invasion in the metastatic niche. This study led us to identify the crosstalk between ET-1R and integrin pathways as a bridge of adhesive and proteolytic signals directing invadopodia-mediated invasion, and metastatic spread. These findings are expected to provide the scientific rational for the design of novel opportunities for defeating metastatic OC.
PI D. Del Bufalo
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.
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.