KDM1A regulates CRC progression by modulating epithelial-mesenchymal transition (EMT), metabolism, and Wnt signaling. Targeting KDM1A with GSK2879552 represents a promising therapeutic strategy for CRC treatment.

Early clinical data from an ongoing trial (NCT05887492) show increased histone acetylation and CD8+ T-cell infiltration in patient tumors treated with TNG260 and pembrolizumab. We also outline key questions for future investigation, including durability of immune response, tumor-type specificity, and biomarker strategies for patient selection and response monitoring. See related article by Ahronian et al., p. 3966.

P2, N=30, Recruiting, The Christ Hospital

In the tumors of patients with STK11-deficient cancers on a clinical trial (NCT05887492), treatment with a combination of TNG260 and pembrolizumab increased intratumoral histone acetylation, PD-L1 tumor proportion scores, and T cell infiltration into the tumor microenvironment. This study illustrates a promising treatment strategy for addressing immune evasion in STK11-mutant NSCLC patients.

In both orthotopic and metastatic tumor models, as well as in vitro cell cultures, the LSD1 inhibitor GSK2879552 demonstrated potent efficacy in suppressing PCa progression. To sum up, this study not only uncovers the oncogenic role of LSD1 in PCa but also validates the therapeutic promise of GSK2879552, furnishing novel perspectives and prospective targets for the clinical management of PCa.

P1/2, N=126, Recruiting, Tango Therapeutics, Inc. | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Jan 2025 --> Jan 2026

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.