ECEESPE2025 Poster Presentations Adrenal and Cardiovascular Endocrinology (169 abstracts)
AZD1775: effect of monotherapy or EDP-M combination in the treatment of ACC preclinical models
Emma Nozza 1,2 , Rosa Catalano 1 , Genesio di Muro 1 , Sonia di Bari 1,2 , Gianluca Lopez 3,4 , Giusy Marra 1 , Emanuela Esposito 1 , Federica Mangili 5 , Donatella Treppiedi 5 , Michele Battistin 6,7 , Giovanna Mantovani 1,5 & Erika Peverelli 1,5
1Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; 2PhD Program in Experimental Medicine, University of Milan, Milan, Italy; 3Pathology Unit, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy; 4Department of Biomedical, Surgical, and Dental Sciences, University of Milan, Milan, Italy; 5Endocrinology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 6Center for Preclinical Research, Fondazione IRCCS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy; 7Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
JOINT1321
Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine cancer. The current treatment for advanced ACC is represented by EDP-M (etoposide, doxorubicin, cisplatin + mitotane), but its efficacy is limited and new therapeutic approaches are needed. Previous in vitro findings of our group showed that AZD1775, an inhibitor of the G2/M checkpoint gatekeeper Wee1, reduces proliferation and increases apoptosis in ACC cell lines and primary cultured cells. Aim of this study was to test in vitro, in vivo, and ex-vivo the effects of the combined AZD1775+EDP-M therapy, as well as to validate AZD1775 antitumoral efficacy in a preclinical mouse model of ACC. In human ACC H295R cells the coincubation of AZD1775 and EDP-M showed synergistic effects in reducing both cell viability and cell proliferation (HSA Synergy Score 11.86 and 17.63, respectively). The growth of H295R-derived tumor xenografts in athymic nude mice was significantly reduced after single or combined treatment vs. control group (tumor volume increase in untreated +168(32–253)% after 21 days, +24.5(7–75)% in AZD1775 group, +53(6–116.8)% in EDP-M group, and +45.5(13–84.5)% in AZD1775+EDP-M group). All treatments were well tolerated and histological examination of hearts and kidneys of treated animals did not reveal signs of toxicity. Interestingly, AZD1775 was the most efficient drug in inducing tumor cell necrosis. At last, ex vivo primary cultures of untreated and AZD1775+EDP-M treated tumor xenografts were incubated with single or combined drugs. Cell proliferation assays demonstrated that cells derived from mice treated with combination therapy for 21 days were less responsive to AZD1775 or to EDP-M compared to cells derived from untreated mice, suggesting the possible onset of resistance mechanisms. Interestingly, the co-incubation of these cells with AZD1775+EDP-M maintained a strong inhibitory effect (−60.7% of cell proliferation in pre-treated cells vs −80.7% in naïve cells). In conclusion, we showed the high efficiency of AZD1775 therapy on H295R xenografts, which resulted comparable to EDP-M monotherapy, without any off-target toxicity. Furthermore, the combined therapy AZD1775+EDP-M synergistically reduced cell proliferation and viability in vitro, impaired tumor growth of H295R xenografts, and was efficient even upon re-exposure of cells derived from treated mice. Our data support AZD1775 as a novel therapeutic option for ACC, as well as its combination with EDP-M as a useful strategy to enhancing drug efficacy, possibly reducing the therapeutic dose, minimizing side effects and preventing the development of drug resistance.
Volume 110
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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