Pharmacological Targeting of the Histone Chaperone Complex FACT Preferentially Eliminates Glioblastoma Stem Cells and Prolongs Survival in Preclinical Models

Abstract

The nearly universal recurrence of glioblastoma (GBM) is driven in part by a treatment-resistant subpopulation of GBM stem cells (GSCs). To identify improved therapeutic possibilities, we combined the EGFR/HER2 inhibitor lapatinib with a novel small molecule, CBL0137, which inhibits FACT (Facilitates Chromatin Transcription), a histone chaperone complex predominantly expressed in undifferentiated cells. Lapatinib and CBL0137 synergistically inhibited the proliferation of patient-derived GBM cells. Compared to non-stem tumor cells (NSTCs) enriched from the same specimens, the GSCs were extremely sensitive to CBL0137 monotherapy or FACT knockdown. FACT expression was elevated in GSCs compared to matched NSTCs, and decreased in GSCs upon differentiation. Acute exposure of GSCs to CBL0137 increased asymmetric cell division, decreased GSC marker expression, and decreased the capacity of GSCs to form tumor spheres in vitro and to initiate tumors in vivo. Oral administration of CBL0137 to mice bearing orthotopic GBM prolonged their survival. Knockdown of FACT reduced the expression of genes encoding several core stem cell transcription factors (SOX2, OCT4, NANOG and OLIG2), and FACT occupied the promoters of these genes. FACT expression was elevated in GBM tumors compared to non-neoplastic brain tissues, portended a worse prognosis, and positively correlated with GSC markers and stem cell gene expression signatures. Preferential targeting of GSCs by CBL0137 and synergy with EGFR inhibitors support the development of clinical trials combining these two agents in GBM.

SSRP1 Cooperates with PARP and XRCC1 to Facilitate Single-Strand DNA Break Repair by Chromatin Priming

“…Access and restore require the disassembly and reassembly of the chromatin structure around damage sites, which involves chromatin remodeling factors and histone chaperones (8,9). The high-mobility group (HMG)-1-like structure-specific recognition protein-1 (SSRP1) is one of the critical components of the Facilitate Chromatin Transcription (FACT) complex together with suppressor of Ty homolog-16 (SPT16) (10), which also has been implicated in cancers (11,12). FACT is a histone H2A/H2B chaperone that regulates chromatin dynamics during transcription (13), replication (14,15) and DNA damage repair.…”

Anticancer drug candidate CBL0137, which inhibits histone chaperone FACT, is efficacious in preclinical orthotopic models of temozolomide-responsive and -resistant glioblastoma

“…18,19 GBM stem cells from patient samples which express FACT show an increase in apoptosis upon treatment with CBL0137. 20 These results further suggest that glioma is responsive to CBL0137 and that CBL0137 would be a beneficial treatment.…”

Potent antileukemic activity of curaxin CBL0137 against MLL‐rearranged leukemia

“…[13][14][15][16][17][18][19] CBL0137 acts through a novel, nongenotoxic anticancer mechanism that is based on inducing chromatin disassembly in cells without causing DNA damage, thereby triggering several pathways with anticancer effects. [13][14][15][16][17][18][19] CBL0137 acts through a novel, nongenotoxic anticancer mechanism that is based on inducing chromatin disassembly in cells without causing DNA damage, thereby triggering several pathways with anticancer effects.…”