Abstract B165: A pharmacologic screen identifies drugs to be combined with the non-ATP competitive PI3Kδ inhibitor roginolisib (IOA-244) for an improved anti-tumor activity in lymphoma models

Abstract

Abstract Background. Despite a strong clinical activity against lymphomas, PI3Kδ inhibitors are now less used due to the risk of toxicities. Roginolisib is a non-ATP competitive PI3Kδ inhibitor (i) (Di Conza, SITC 2022; Johnson, Cancer Res Com 2023). Via a unique allosteric binding, it causes PI3Kδ inactive form stabilization without off-target effects typically seen with other PI3K inhibitors. Indeed, early clinical data show a very good safety profile (Di Giacomo, ASCO 2022; Carlo-Stella, ICML 2023). Here, we present an extensive combination study with roginolisib in lymphoma models. Methods. Cells were exposed (72h) to DMSO, 474 library compounds (5µM), single or with roginolisib (5µM), or roginolisib, followed by MTT assay. Library included 247 drugs of the Cambridge Cancer Compound Library, plus lymphoma treatment drugs or biologically relevant molecules. Hits were first validated in experiments with extended concentrations of both compounds in the same cell used in the screen. Combinations giving synergism/additivity according to Chou-Talalay algorithm were considered as beneficial. Results. A screen to identify active roginolisib-based combinations was done in two cell lines, SP-53 (mantle cell lymphoma, MCL), and HH (cutaneous T-cell lymphoma, CTCL). Combination partners identified and validated in both models included ruxolitinib (JAK1/2i), vorinostat (class I/II HDACi), venetoclax (BCL2i) BI-3802 (BCL6i), emavusertib (IRAK4i), safimaltib (MALT1i), tretinoin (all-trans-retinoic acid), and telaglenastat (glutaminase-i). Combinations with romidepsin (class I HDACi), valemetostat (EZH1/2i), diABZI (STING agonist), DNA methyltransferase i 5-azacytidine, and bromopyruvic acid (antimetabolite) were active only in the HH model. Multiple BTKi (ibrutinib, acalabrutinib, zanubrutinib, orelabrutinib, nemtabrutinib) showed increased activity when combined with roginolisib: validation was done using a 3rd generation BTK inhibitor, pirtobrutinib, observing a benefit in both cell lines. Selinexor (XPO1i) and pixantrone (chemo), with an already strong activity as single agents, showed benefit in both models. The combination of roginolisib with venetoclax or vorinostat was extended to eight more models of diffuse large B cell lymphoma (Farage, TMD8), MCL (Granta519, JVM2, SP49), chronic lymphocytic leukemia (MEC1), CTCL (MJ), NK cell lymphoma (YT), and to compounds with similar mechanism of action (class I/II HDAC i belinostat; BCL2 i S55746), and 2 MCL1i (S64315, S63845). Synergism or additivity were achieved with vorinostat, venetoclax and S63845 in 7/8 models, with belinostat and S55746 in 6/8 and with S64315 in 7/7. Roginolisib plus 5-azacytidine also achieved synergism/additivity in 5/8 cell lines. Finally, the addition of the JAK1/2i ruxolitinib to roginolisib was beneficial also in two Sezary syndrome cell lines (Hut78, H9). Conclusions. The study identified drugs that could be explored in combination with roginolisib for lymphoma patients taking advantage of the safe profile as single agent reported in clinical trials. Citation Format: Chiara Tarantelli, Elisa Civanelli, Eleonora Cannas, Filippo Spriano, Afua A. Mensah, Luciano Cascione, Alberto J Arribas, Anastasios Stathis, Karolina Niewola-Staszkowska, Giusy Di Conza, Michael Lahn, Francesco Bertoni. A pharmacologic screen identifies drugs to be combined with the non-ATP competitive PI3Kδ inhibitor roginolisib (IOA-244) for an improved anti-tumor activity in lymphoma models [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr B165.