Curaxin CBL0137 eradicates drug resistant cancer stem cells and potentiates efficacy of gemcitabine in preclinical models of pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDA) continues to be one of the deadliest cancers due to the absence of effective treatment. Curaxins are a class of small molecules with anti-cancer activity demonstrated in different models of cancer in mice. The lead curaxin compound, CBL0137, recently entered Phase I clinical trials. Curaxins modulate several important signaling pathways involved in the pathogenesis of PDA through inhibition of chromatin remodeling complex FACT. FACT is overexpressed in multiple types of tumor, with one of the highest rate of overexpression in PDA (59%). In this study, the efficacy of CBL0137 alone or in combination with current standard of care, gemcitabine, was tested against different models of PDA in vitro and in mouse models. It was found that CBL0137 alone is a potent inducer of apoptosis in pancreatic cancer cell lines and is toxic not only for proliferating bulk tumor cells, but also for pancreatic cancer stem cells. In mice, CBL0137 was effective against several PDA models, including orthotopic gemcitabine resistant PANC-1 model and patient derived xenografts, in which CBL0137 anti-tumor effect correlated with overexpression of FACT. Moreover, we observed synergy of CBL0137 with gemcitabine which may be explained by the ability of CBL0137 to inhibit several transcriptional programs induced by gemcitabine, including NF-kappaB response and expression of ribonucleotide reductase, one of the targets of gemcitabine in cells. This data suggest testing of CBL0137 efficacy in Phase II trial in PDA patients alone and in combination with gemcitabine.

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

“…7 Upregulation of p53, with regulation of its responsive protein Hdm2, and downregulation of NF-ĸB downstream targets that we observed in GBM cells show that both lines have functional p53 and support the proposed mechanism of action of CBL0137 on p53 and NF-ĸB through FACT inhibition. Burkhart et al 14 saw similar results on downstream NF-ĸB-responsive genes in human pancreatic cancer cells after CBL0137 administration. It is possible that the suggested difference in reliance on the NF-ĸB pathway, as seen in the 100-fold difference in TNF-induced induction of IL-8 expression between A1207 and U87MG cells, may translate into a marker for patient response to CBL0137.…”

“…7 This drug candidate is effective in preventing and delaying mammary tumor onset and increasing survival of mice with tumors, without affecting normal organs and tissues. 16 It is also effective in preclinical models of pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, renal cell carcinoma, and melanoma 7,14 and is being administered in clinical trials for advanced solid neoplasms (https://www.clinicaltrials.gov/ ct2/show/NCT01905228). The proposed mechanism of action of CBL0137 is inactivation of the transcription elongation factor FACT, which blocks NF-ĸB transcription and activates p53, two factors often dysregulated in GBM.…”

The FACT inhibitor CBL0137 Synergizes with Cisplatin in Small-Cell Lung Cancer by Increasing NOTCH1 Expression and Targeting Tumor-Initiating Cells

“…CBL0137 (or the related drug quinacrine) has been shown to have potent anticancer activity in NSCLC (12), pancreatic cancer (13), breast cancer (14), and neuroblastoma (15). CBL0137 targets Facilitates Chromatin Transcription (FACT), a histone chaperone that is expressed at high levels in tumors.…”

Chemoresistance in pancreatic cancer: Emerging concepts

“…Hypoxia also results in the accumulation of lactate dehydrogenase-A, which assists in the maintenance of the hypoxic phenotype and increasing chemoresistance (11). Novel molecular targets and molecules that have been identified include: Protein tyrosine kinase-6 (12); vitamin D receptor (VDR) (13); mucin-1 (MUC1) (14); ormeloxifene that targets the sonic hedgehog pathway (15); sodium metaarsenite (KML001) that targets the epidermal growth factor receptor (EGFR) and matrix metalloproteinase (MMP) 2 (16); the quinazolinedione-based redox modulator QD232 that targets proto-oncogene tyrosine-protein kinase/focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 phosphorylation (17); aspirin, which was revealed to reduce tumor growth and sensitize cells to gemcitabine (18); the curaxin CBL0137, which targets NF-κB and ribonucleotide reductase (19) and sepantronium bromide (YM155) (20)(21)(22), which inhibits the action of inhibitor of apoptosis protein family members (20), as summarized in Table I.…”