- Rhabdoid tumor is a pediatric cancer characterized by the biallelic inactivation of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex. SMARCB1 inactivation leads to SWI/SNF redistribution to favor a proliferative dedifferentiated cellular state. Although this deletion is the known oncogenic driver, SWI/SNF therapeutic targeting remains a challenge.
- Mithralog EC-8042 evicts mutated SWI/SNF from chromatin and is effective in rhabdoid tumor. SWI/SNF blockade triggers chromatin compartment remodeling and promoter reprogramming leading to differentiation and amplification of H3K27me3, the catalytic mark of PRC2. Treatment of rhabdoid rumor xenografts with EC-8042 leads to marked, durable tumor regression and differentiation of the tumor tissue into benign mesenchymal tissue, including de novo bone formation.
The results of a collaborative research between EntreChem SL, Van Andel Research Institute (Grand Rapids, MI, USA) and The Children’s Hospital of Philadelphia (Philadelphia PA, USA), among others, focused on new strategies against Rhabdoid Tumor (RT), a pediatric tumor whose four-year survival is still 10–40%, in great need for more effective and less toxic targeted therapy, have been published in the journal EMBO Molecular Medicine.
The research, led by Dr. Patrcik Grohar, focuses on the inactivation of SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex. Although this deletion is the known oncogenic driver, there are limited effective therapeutic options for these patients. An unbiased screening of cell line panels identified a heightened sensitivity of rhabdoid tumor to mithramycin and the mithralog EC-8042. The sensitivity was superior to traditional DNA damaging agents and linked to the causative mutation of the tumor, SMARCB1 deletion. Mithramycin blocks SMARCB1-deficient SWI/SNF activity and displaces the complex from chromatin to cause an increase in H3K27me3. This triggers chromatin remodeling and enrichment of H3K27ac at chromHMM-defined promoters to restore cellular differentiation. These effects occurred at concentrations not associated with DNA damage and were not due to global chromatin remodeling or widespread gene expression changes.
Importantly, a single 3-day infusion of EC-8042 caused dramatic regressions of RT xenografts, recapitulated the increase in H3K27me3, and cellular differentiation described in vitro, resulting in permanent cures in 3/8 mice.
Similar to the in vitro results, there was striking evidence of mesenchymal differentiation of the xenograft treated with EC-8042 with the appearance of trabecular-like ossification as well as cartilage and adipocytes. The presence of osteoblasts and embedded osteocytes in the trabecular architecture provides further support for EC-8042 inducing osteogenesis.
For full details, see: Chasse MH, et al, Mithramycin induces promoter reprogramming and differentiation of rhabdoid tumor, EMBO Mol Med. 2021, doi: 10.15252/emmm.202012640
EC-8042 shows a favorable toxicity profile, and these results establish EC-8042 as a novel clinical candidate for rhabdoid tumor and tumors with mutated or dysregulated SWI/SNF.
EC-8042 has just completed preclinical development by EntreChem SL, and is ready for clinical trials (Investigator Brochure available under CDA). EC-8042 is a hybrid natural product obtained from genetically modified bacteria by combinatorial biosynthesis.
More information:
Dr. Patrick Grohar: groharp@chop.edu
Dr. Francisco Morís: fmv@entrechem.com
and also:
EntreChem SL: www.entrechem.com