An LSD1 inhibitor GSK2879552 can rescue the Id2 knockout phenotype in tumor-bearing mice. Inhibition of LSD1 increases the abundance of Slamf6Tim-3 Tex cells in tumors and the expression level of Tcf1 in Id2-deleted CD8 T cells. This study demonstrates that Id2-mediated transcriptional and epigenetic modification drives hierarchical CD8 T-cell exhaustion, and the mechanistic insights gained may have implications for therapeutic intervention with tumor immune evasion.

P1/2, N=126, Recruiting, Tango Therapeutics, Inc. | Not yet recruiting --> Recruiting

P1/2, N=126, Not yet recruiting, Tango Therapeutics, Inc.

Unlike previously developed pan-HDAC inhibitors, which are directly cytotoxic to cancer (and immune) cells, IND-enabling toxicology studies in rat and dog showed that TNG260 was well-tolerated at exposures predicted to be efficacious in humans, with bone marrow suppression only detectable at doses where TNG260 is no longer selective for CoREST inhibition. TNG260 clinical development will be among the first to combine the power of genetic patient selection and immunotherapy, evaluating patients with STK11 mutant cancers in a trial combining TNG260 and a checkpoint inhibitor.

We developed a LSD1/HDAC6 multitargeting inhibitor (iDual), a hydroxamic acid analogue of the clinical candidate LSD1 inhibitor GSK2879552. Remarkably, iDual synergized with doxorubicin, triggering significant levels of apoptosis with a sublethal concentration of the drug. While mechanistic studies did not reveal changes in DNA repair or drug efflux pathways, the expression of AGPAT9, ALOX5, BTG1, HIPK2, IFI44L, and LRP1, previously implicated in doxorubicin sensitivity, was significantly elevated.

Consistently, CoREST controls a gene signature involved in invasiveness in clinical breast tumors resistant to endocrine therapies. Our studies reveal CoREST functions that are co-opted to drive cellular plasticity and resistance to endocrine therapies and tumorigenesis, thus establishing CoREST as a potential therapeutic target for the treatment of advanced breast cancer.

Using our ZEB2 ETP-ALL mouse model we previously documented the potential utility of the catalytic LSD1 inhibitor (GSK2879552) for treating mouse/human ETP-ALL...Treatment with LSD1i (particularly with the steric inhibitor SP2509) restored the expression of ZEB2/LSD1 pro-apoptotic BIM (BCL2L11) target. In combination with a JAK/STAT pathway inhibitor (JAKi, Ruxolitinib) or with a direct inhibitor of the anti-apoptotic BCL2 protein (BCL2i, ABT-199) resistance of human and mouse ETP-ALL to LSD1i was reversed. This new combination approach efficiently inhibited the growth of human and mouse ETP-ALL cells in vivo by enhancing their differentiation and triggering an apoptotic response. These results set the stage for novel combination therapies to be used in clinical trials to treat ETP-ALL patients.

Our future work will focus on DNA sequencing of mDLC sub- components to identify sub-component specific driver mutations. Our findings will need further investigation in larger mDLC cohorts to better understand their clinical implications in terms of evolution of this disease and its prognosis.

It reverses the immune evasion phenotype caused by loss of STK11 and induces tumor regressions in an STK11-mutant model in combination with α-PD1. The TNG260 clinical development plan will be among the first to combine the power of genetic patient selection and immunotherapy, evaluating patients with STK11 mutant cancers in a trial combining TNG260 and a checkpoint inhibitor.

The Krüppel-like factor 4 (KLF4), repressor element-1 (RE-1)‍-silencing transcription factor (REST) corepressor 1 (RCOR1), lysine demethylase 1A (KDM1A), and C-terminal-binding protein 1/2 (CTBP1/2) chromatin regulators cooperate with ZNF750 to repress epidermal progenitor genes and activate the expression of epidermal terminal differentiation genes (Sen et al., 2012; Boxer et al., 2014). Besides, ZNF750 and the regulatory network composed of bone morphogenetic protein (BMP) signaling pathway, long non-coding RNAs (lncRNAs) (anti-differentiation non-coding RNA (ANCR) and tissue differentiation-inducing non-protein coding RNA (TINCR)), musculoaponeurotic fibrosarcoma oncogene (MAF)/MAF family B (MAFB), grainy head-like 3 (GRHL3), and positive regulatory domain zinc finger protein 1 (PRDM1) jointly promote epidermal cell differentiation (Sen et al., 2012).

Moreover, treatment of AML cells with the HDAC inhibitor, pracinostat, and LSD1 inhibitor, GSK2879552, resulted in growth inhibition both in vitro and in vivo. High BCL11A expression is associated with worse prognosis in human AML patients. Blocking of BCL11A expression upregulates the expression of PU.1 target genes, and inhibits the growth of HL-60 cells and their engraftment to the bone marrow, suggesting that BCL11A is involved in human myeloid malignancies via the suppression of PU.1 transcriptional activity.

Next, we compared two kinds inhibitors, and found that SP-2509 (Allosteric inhibitor) treatment suppress the cancer cell survival by blocking the LSD1-FBXW7 interaction, which is an effect that GSK-2879552 (catalytic inhibitor) cannot achieve. This work revealed a pivotal function of LSD1 in PCa, and indicated a new direction of LSD1 inhibitor research for PCa treatment.

Among the mediator complex subunits, MED28 might serve as a potential biomarker of unfavorable survival. Its overexpression increased CSC-like activity of OCSCC cells, the effect of which could be abrogated by RCOR1 via direct interaction.

Furthermore, the generated nomogram integrating the prognostic gene biosignature and clinical indices predicted LUAD OS with high efficiency and outperformed tumor-node-metastasis staging in LUAD survival prediction. These results demonstrated the efficacy of the epigenetic signature prognostic nomogram for reliably predicting LUAD OS and its potential application for informing clinical decision making and individualized treatment.

Targeting nLSD1p with selective nLSD1 inhibitors better inhibits the stem-like mesenchymal signature than traditional FAD-specific LSD1 catalytic inhibitors such as GSK2879552...Using novel antibodies to target these post-translational modifications, we show that EOMES demethylation/acetylation is reciprocally expressed in resistant and responder patients. Overall, we show for the first time that dual inhibition of metastatic cancer cells and re-invigoration of the immune system requires LSD1 inhibitors that target the nLSD1p axis.

We recreated the clustering and/or classification algorithms for each of the selected original publications in 180 samples of patients treated with R-CHOP or intensified rituximab with CHOP in the HOVON 84 trial, using Nanostring gene expression profile, fluorescence in situ hybridization for MYC, BCL2 and BCL6 and CNV results data obtained by low coverage whole genome sequencing...Conclusion The reproducibility of most of the published GEP classifiers is limited and the classes as defined in our cohort are not associated to each other. Our results emphasize the need to have good quality validation cohorts when doing GEP analysis in the heterogeneous group of DLBCL.

Finally, we further verified that LINC01198 hindered glioma tumour growth in vivo through AKT-dependent manner. Jointly, LINC01198 activates PI3 K/AKT signalling to exert oncogenic function in gliomagenesis by regulating PIK3CA and PTEN, which highlights a new approach for glioma treatment.

Materials/ Six SNSCC cell lines (SCCNC1, SCCNC4, SCCNC5, SCCNC6, SCCNC7, and UMSCC33) were treated with the indicated doses of cisplatin (Tocris) and the LSD1 inhibitor GSK2879552 (GlaxoSmithKline) alone or in combination. Inhibition of LSD1 sensitized several SNSCC cell lines to cisplatin. We are currently in the process of genotyping the SNSCC cell lines for mutations in H3K4 methyltransferase genes. If it is confirmed that a high proportion of SNSCC tumors harbor mutations in H3K4 methytransferases, further testing of LSD1 inhibitors or inhibitors of other H3K4 demethylases in in vivo models would be warranted with future possible translation to clinical trials.

Among these elements, depletion of both HMG20A and HMG20B, or GSE1 block GFI1B-mediated erythroid differentiation, phenocopying impaired differentiation brought on by LSD1 depletion or disruption of GFI1B-LSD1 binding. These findings demonstrate the central role of the GFI1B-LSD1 interaction as a determinant of BHC complex recruitment to enable cell fate decisions driven by GFI1B.

This effect was not seen in cells treated with GSK2879552 (irreversible LSD1 inhibitor) or veliparib. Combination olaparib/phenelzine synergistically inhibited CSCs in MDA-MB-231. LSD1 negatively regulated PD-L1 expression and reversed the effect of PARP1 on PDL1 status in this breast cancer model. These data support a novel combinatory approach to improve PARPi efficiency.