Life science
Medical & healthcare, Reagent Development

Discovery of biomarkers to predict therapeutic efficacy ofpharmacotherapy for hepatocellular carcinoma
Department of Gastroenterology and Hepatology, Graduate School of Medicine
Assistant Professor Takahiro Kodama

Researchmap https://researchmap.jp/takahirokodama

Professor Tetsuo Takehara

Researchmap https://researchmap.jp/takeharatetsuo

Randomactivation ofoncogenes intumors

High-throughput
analysis of oncogene
abundance in tumors

FGF19
p <0.05

inib
icle
vatvehlen
FGF19-driven tumors
were eliminated bylenvatinib

Normal LivertumorliverFigure 1.

Proportion of oncogene（％）

vehicleHydrodynamic
tail vein injection

The novel mouse model that reproduces the inter-tumor oncogene heterogeneity of liver tumors

Figure1. Thenovelmouseofmodelthat reproduces
thetreatment
inter-tumor oncogene hetand discoveryof highsusceptibility
FGF19-driven
tumors to lenvatinib
erogeneity of liver tumors and discovery of high susceptibility of FGF19-driven
tumors to lenvatinib treatment
Liver cancer cell lines

Serum Biomarker
FGF19
highST6GAL1
liver tumor＋ーFGF19inhibition

FGF19 levels
Surgically-resectedliver tumor patients

Survival rate (%)

Serum ST6GAL1 low
Serum ST6GAL1 high

Recurrence free survival（days）

1-Specificity(%)

Poor prognosticandlenvatinib-sensitive
liver tumors

Serum ST6GAL1-highliver tumor patients

Utility of serum ST6GAL1 fordiagnosing FGF19-high liver tumor
Sensitivity(%)

Early detection of HCC is extremely important, especially forhighly malignant HCC, but the sensitivity of currently used tumor
markers is not sufficient. In addition, the efficacy of various molecular targeted therapies currently used for advanced HCC is lessthan 30%, but there are no useful biomarkers that can predict theefficacy of drugs and serve as indicators for drug selection. HCC
is known to have a variety of genetic abnormalities that vary frompatient to patient. On the other hand, the impact of this inter-tumor
heterogeneity on the therapeutic effect of drug therapy is not wellunderstood. We hypothesized that inter-tumor heterogeneity due
to differences in oncogenes affects the grade of cancer and thetherapeutic effect of drug therapy. First, we established a method
to introduce multiple oncogenes into hepatocytes at once, andsucceeded in creating a novel mouse model that develops HCC
with high inter-tumor heterogeneity in which oncogenes are randomly activated. The percentage of tumors expressing the FGF19
gene was significantly reduced when this model was treated withlenvatinib, indicating that FGF19-driven HCC is highly sensitive
to lenvatinib. Next, we identified ST6GAL1, a secreted protein
whose expression is regulated by FGF19. We also found that serum ST6GAL1 can be used to select HCC with poor prognosis that
express high levels of FGF19. Furthermore, by stratifying patients
based on serum ST6GAL1 levels, we found that the prognosis ofpatients in the high ST6GAL1 group treated with lenvatinib wassignificantly longer than that of patients treated with other drugs.
These results indicate that serum ST6GAL1 levels may be useful asa biomarker for the identification of high-grade HCC and the selection of optimal drugs in liver cancer drug therapy.

Treatment

lenvatinib

ST6GAL1 levels▍ Background & Results

Oncogenelibrary

ST6GAL1 levels

Patients with chronic liver disease are known to develop hepatocellular carcinoma (HCC) as the disease progresses, and its development has a significant impact on their prognosis. The efficacy ofvarious molecular targeted therapies currently used for advanced
HCC is less than 30%, but there are no useful biomarkers that canpredict the efficacy of drugs. HCC is known to have a variety of genetic abnormalities that vary from patient to patient. But the impactof this inter-tumor heterogeneity on the effecacy of drug therapy
is not well understood. We have developed a screening model inwhich the inte-tumor heterogeneity of oncogenes is recapitulated
in mice, and found that FGF19-driven HCC is malignant but highly
sensitive to lenvatinib, a molecular targeted therapy used in HCC.
In addition, we identified that serum levels of ST6GAL1, which isregulated by the FGF19 gene, are useful for detecting FGF19-driven HCC and lenvatinib-sensitive HCC.

to contribute to the detection of highly-malignant HCC and to theselection of the most appropriate drug for patients with advanced
HCC, thereby improving their prognosis.

Survival rate (%)

Life scienceAbstract

Lenvatinib
Sorafenib

Overall survival（days）

Figure 2.
2. SerumSerum ST6GAL1
is aisnovel
biomarker
for predicting
the poor prognostic
FigureST6GAL1a novel
biomarker
for predicting
the poor prognostic
and lenvatinib-sensitive liver cancer

and lenvatinib-sensitive liver cancer▍ Significance of the research and Future perspective
The clinical application of the biomarker ST6GAL1 is expected

P a t e n t Japanese Patent Application No. 2020-165604
Myojin, Y; Kodama, T; Maesaka, K et al. ST6GAL1 is a Novel Serum Biomarker for Lenvatinib-susceptible FGF19-driven Hepatocellular Carcinoma. Clin
Tr e a t i s eCancer Res. 2021 Feb 15; 27(4): 1150-1161. doi: 10.1158/1078-0432.CCR-20-3382.
https://www.med.osaka-u.ac.jp/activities/results/2020year/2020myojin-kodama
URL
https://www.amed.go.jp/news/release_20201208-01.html
K e y w o r d hepatocellular carcinoma, mouse model, FGF19, ST6GAL1, molecular targeted therapy