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.
Highlights
Mortality from pancreatic cancer is close to 100% due to the absence of effective treatment approaches
Consistent with this observation, we did not see any biochemical signs of cell death, such as caspase activation or PARP1 cleavage, when we analyzed extracts of cells treated with gemcitabine using immunoblotting, while the same signs were evident in extracts of cells treated with CBL0137 (Fig.1C, D)
CBL0137 is toxic for pancreatic cancer cells independently of their sensitivity to gemcitabine and, is able to increase the sensitivity of both gemcitabine-sensitive and resistant Pancreatic ductal adenocarcinoma (PDA) cells to gemcitabine
Summary
Mortality from pancreatic cancer is close to 100% due to the absence of effective treatment approaches. CBL0137 is a member of a new class of recently discovered candidate anti-cancer agents, named curaxins, that modulate several important signaling pathways involved in the pathogenesis of pancreatic ductal adenocarcinoma (PDA, [4]). The effects of CBL0137 on these pathways, culminating in tumor cell death, are mediated by the inhibition of FACT [4], a chromatin remodeling complex composed of SSRP1 and SPT16 subunits, that is involved in the transcription of genes with highly ordered chromatin structure, replication, and mitosis [9,10,11]. Curaxins are indirect inhibitors of FACT: they bind DNA without causing DNA breaks or any other sort of damage and without activating DNA damage sensitive signaling pathways [4]. FACT binds with high affinity to DNA in the presence of curaxins and is unable to bind histones to perform its normal chromatin remodeling function [4]
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