FACT is an “accelerator” of malignant transformation and...FACT is an “accelerator” of...
Transcript of FACT is an “accelerator” of malignant transformation and...FACT is an “accelerator” of...
FACT is an “accelerator” of malignant transformation and
potential marker and target of aggressive cancer Henry Garcia1, Alfiya Safina1, Daria Fleyshman1,, Jeffrey C Miecznikowski3, Carl Morrison2, Katerina V Gurova1
1Department of Cell Stress Biology, 2Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, 3Department of Biostatistics, SUNY Buffalo, NY, USA;
Funding: Cleveland BioLabs, Inc, Buffalo, NY, USA; INCURON, Inc. Moscow, Russia
Background
Curaxins , small molecule FACT inhibitors
• Were identified in the chemical screening of simultaneous activators of p53 and inhibitors of NF-kB in tumor cells
• Effect of curaxins on p53, NF-kB and toxicity to tumor cells result from depletion of active FACT in cells
Anti-tumor effect of FACT inhibition
Snapshot of FACT expression FACT is a marker of normal and tumor stem cells
SSRP1 is a marker of poorly differentiated aggressive cancers
Breast adenocarcinoma Bladder Adenocarcinoma NSCLC
Transcription factors involved in the regulation of expression of SSRP1-enriched genes
TF family TF Major functional role Defined role in cancer References (reviews)
OCT OCT1, OCT3/4early embryonic
development
OCT3/4 is overexpressed in
poorly differentiated cancers
Chiou et al., 2008, Wen et al.,
2013
AP1 binding JUN, ATF1,
ATF2, ATF3,
ATF6
Proliferation several members are oncogenesEychene et al., 2008, Gozdecka
and Breitwieser, 2012
EGR EGR1 Differentiation, mitogenesis oncogenic or tumor suppressor Pagel and Deindl, 2011
ets ETS1, ELK1,
GABPinduction of proliferation oncogenes Shaikhibrahim et al., 2012
Myc and myc
binding
Myc, Max, Maz,
Mybproliferation oncogenes Dang, 2012
NF-kB Rel, RelAinflammation, negative
regulation of apoptosispromotion of tumorigenesis Gudkov et al., 2011
CREBCREB1, CEBPA,
CEBPB, various
promotes proliferation of tumor
cellsXiao et al., 2010
TP53 TP53 control of genomic stability tumor suppressor Lane and Levine, 2010
Sp/KLF
familySp1 early development
inductor of cell proliferation,
positive regulation of tumor cell
growth
Li and Davie, 2010
SRF SRF cell cycle regulation,
apoptosis, cell growth, and
promotes proliferation and
invasion of tumor cellsKim et al., 2011
GLI-Kruppel YY1 various oncogene Nicholson et al., 2011
Lead FACT inhibitor, CBLC137
SSRP1-GFP SSRP1-GFP
Curaxin
• Water soluble, orally
bioavailable
• Not a substrate of multidrug
transporters
• Penetrates blood brain barrier
• Is in Phase I trial against
advanced treatment resistant
cancers and refractory
lymphomas
1 2 3 4 5 6
1 2 3 4 5 6
Breast cancer
Lung cancer
Transformation of HMEC
genetic
Benzo(a)pyrene
Transformation of MCF10A with H-RasV12
Genome wide distribution of FACT
Conclusions
FACT is a marker of aggressive poorly differentiated tumors
FACT is expressed at the highest levels in normal and cancer stem cells
FACT selectively assists transcription of genes involved in cancer and maintenance of pluripotency
Targeting of FACT is a promising anti-cancer strategy