Lymphomas are among the most common human cancers and represent the cause of death for still too many patients. The B-cell receptor with its downstream signaling pathways represents an important ...therapeutic target for B-cell lymphomas. Here, we evaluated the activity of the MEK1/2 inhibitor pimasertib as single agent and in combination with other targeted drugs in lymphoma preclinical models.
Cell lines derived mature B-cell lymphomas were exposed to increasing doses of pimasertib alone. Immunoblotting and gene expression profiling were performed. Combination of pimasertib with idelalisib or ibrutinib was assessed.
Pimasertib as single agent exerted a dose-dependent antitumor activity across a panel of 23 lymphoma cell lines, although at concentrations higher than reported for solid tumors. Strong synergism was observed with pimasertib combined with the PI3K inhibitor idelalisib and the BTK inhibitor ibrutinib in cell lines derived from diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma. The data were confirmed in an in vivo experiment treating DLBCL xenografts with pimasertib and ibrutinib.
The data presented here provide the basis for further investigation of regimens including pimasertib in relapsed and refractory lymphomas.
An abstract of the study of Gaudio et. al. about the novel BTK and PI3K-delta inhibitors acalabrutinib (ACP-196) and ACP-319 show activity in pre-clinical B-cell lymphoma models is presented. Among ...other things BTK and PI3K-delta inhibitors are among the most promising classes of anti-lymphoma agents, as demonstrated by the FDA approval of ibrutinib and idelalisib. Acalabrutinib (ACP-196) and ACP-319 are novel BTK and PIK3-delta selective inhibitors, respectively, under clinical evaluation. Acalabrutinib and ACP-319 showed both in vitro and in vivo anti-lymphoma activity. In vitro synergism was observed in some cell lines where single agent activity of either agent was modest or absent. Further preclinical and clinical studies are suggested.
An abstract of a study by Tarantelli et al on the novel mTORC1/2 inhibitor PQR620 has in vitro and in vivo activity in lymphomas is presented. Proliferation and caspase 3/7 activation were assessed ...in 44 lymphoma cell lines treated with increasing doses of PQR620. Baseline gene expression profiling was obtained with the lllumina-HumanHT-12 Expression-BeadChips and analyzed with GSEA. Results indicated that PQR620 showed potent anti-proliferative activity in most of the cell lines tested. There was no association between sensitivity to PQR620 and TP53 inactivation. Apoptosis induction was seen more frequently with PQR620 than with the other 2 compounds: 6/44 cell lines for everolimus and 3/44 for AZD8055. The study concludes that PQR620 showed wide activity in lymphoma models as single agent and also in combination with venetoclax.
An abstract of a study by Arribas et al on PQR309, idelalisib, duvelisib and ibrutinib that lead to similar gene expression changes in activated B-cell like (ABC) diffuse large B-cell lymphoma ...(DLBCL) is presented. Gene expression profiling was obtained with the lllumina-HumanHT-12 Expression-BeadChips and analyzed with limma t-test. A GSEA was performed using the limma-derived gene expression profiling signatures obtained for each drug. The study demonstrated the targeted fundamental pathways of all models sustaining lymphoma cell proliferation and survival. Their early effects on the lymphoma cell transcriptome were very similar, but with varied degree of changes among drugs, possibly reflecting their main targets.
An abstract of the study of Bernasconi et al. about the BET bromodomain inhibitor (BET-i) BAY 1238097: Mechanism of action and pre-clinical activity in diffuse large B-cell lymphoma (DLBCL) is ...presented. Among other things BAY 1238097 is a novel BET-i, active in lymphoma models (ENA2015). Here, we characterize its mechanism of action and report further in vitro and in vivo activity data in DLBCL. BAY 1238097 affected the growth of both GCB and ABC DLBCL xenografts: treated tumors resulted 6-8 fold smaller in volume respect to controls. At GEP, BAY 1238097 decreased target genes of Myc, Notch and E2F, members of the NFKB/MYDB8 and mTORIAKT signaling. The up- regulated transcripts were mainly represented by histones. The GEP signatures highly overlapped with the signatures obtained with other BET Bromodomain inhibitors and partially overlapped with HDAC-i, mTOR-i and demethylatirig agents. BAY 1238097 has anti lymphoma in vivo activity, and is able to interfere with pathways relevant for lymphoma cells and is synergistic with EZH2-i and mTOR-i.
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