studies

460A AASLD ABSTRACTS HEPATOLOGY, October, 2015
cedure. A novel surgical approach, ALPPS (Associating Liver
Partition and Portal Vein Ligation for Staged Hepatectomy),
which combines PVL with parenchymal transition, may be used
for unresectable disease due to its ability to markedly accelerate
liver regeneration via unknown mechanisms. We hypothesize
that transection is sufficient to activate plasma proteins
necessary for accelerated liver regeneration, and that portal
vein ligation (PVL) is necessary to stimulate liver growth. Aim
Using a novel mouse model, we aim at studying the molecular
mechanisms underlying the accelerated liver growth associated
with ALPPS. Methods Liver tissue was collected at early time
points after ALPPS (30min, 1h, 4h, 8h, 12h) and analysed by
RNA deep sequencing. Plasma samples were collected 30min
after ALPPS Step 1 for proteomics analysis by protein enrichment,
albumin depletion, and mass spectrometry. Each protein
fraction is confirmed for activity by inducing accelerated regeneration
upon injection into mice treated with PVL only. Results
Injection of plasma, derived from mice, subjected to ALPPS,
into PVL alone mice is sufficient to accelerate liver regeneration
as observed following ALPPS surgery. Likewise, a comparable
response is induced in PVL alone mice by plasma from
mice subjected to transection only. Plasma proteins appear
to chiefly account for the accelerated liver growth. Transcript
analysis shows that differential gene expression occurs 4 hours
post ALPPS. The accelerated liver growth is characterized by
a hyperplastic reaction reflected in an increased number of
hepatocytes entering the cell cycle as early as 8 hours after
surgery. Conclusions ALPPS is conducive to accelerated liver
regeneration through proteins circulating in the plasma as early
as 30 minutes after the transection step. ALPPS-specific gene
expression changes are observed in liver at early times after
surgery and are consistent with the induction of regenerative
pathways. Identification of plasma proteins stimulating liver
growth and associated regenerative pathways may have a
high therapeutic value in expanding the surgical cure of liver
disease previously deemed unresectable.
Disclosures:
The following authors have nothing to disclose: Magda Langiewicz, Andrea
Schlegel, Bostjan Humar, Rolf Graf, Pierre-Alain Clavien
500
Identifying novel therapeutic targets in HCC through
an integrated transcriptomics and pharmacogenomics
approach
Bin Chen 1 , Li Ma 2 , Mei-Sze Chua 2 , Atul Butte 1 , Samuel K. So 2 ;
1 Institute for Computational Health Sciences, UCSF, San Francisco,
CA; 2 Asian Liver Center, Stanford University, Stanford, CA
Background Large-scale gene expression profiling of disease
systems perturbed by chemical agents in preclinical models
allows the understanding of underlying cellular responses
induced by the chemicals. Such information may guide the discovery
of new therapeutic drugs and targets in specific disease
systems. Using hepatocellular carcinoma (HCC) as our disease
model, we hypothesized that genes whose expressions are specifically
reversed by anti-cancer drugs may be potentially novel
therapeutic targets in HCC. Methods and Materials We compiled
data on IC 50
s of anti-cancer drugs from ChEMBL (a chemical
database of bioactive molecules with drug-like properties),
and drug-induced gene expression signatures from LINCS (a
database containing perturbation profiles of 1,000 genes in
HCC cell lines) and from CMap (a database containing whole
genome perturbation profiles in all cancer cell types). Additionally,
we computed gene expression signatures of HCC and
non-tumor liver samples from TCGA. We compared the HCC
gene expression signature with the drug signatures, and computed
the ability of each drug to reverse the HCC signature.
Each drug was associated with a Reversing Gene Expression
Score (RGES), and the correlation between the IC 50
s and RGES
of 36 drugs was examined. We further identified genes that
are specifically reversed by anti-cancer drugs with IC 50
s