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