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Armengol et al. Hepatoma Res 2021;7:50 https://dx.doi.org/10.20517/2394-5079.2021.19 Page 9 of 12

[67]
patients . Inhibition of MDM4 by its inhibitors NSC207895 and ATSP-7041 as well as short hairpin RNA-
mediated knockdown of MDM4 expression led to upregulation of p53 activity and a subsequent inhibition
of tumor cell growth. The in vivo efficacy of MDM4 inhibition was proven with the orthotopic HepT1
[67]
xenograft model in mice using NSC207895 .

FUTURE ASPECTS
In recent decades, great advances in the comprehension of the molecular pathogenesis of HB have been
made. Currently, there is a need to better understand rare and aggressive forms of childhood liver cancer
(i.e., metastatic/recurrent tumors, HB with HCC-like features, and HB with AFP < 100 ng/mL), all of which
have been little studied due to the difficulty of obtaining biological specimens. Additionally, there is also a
pressing need to incorporate molecular data into clinical risk stratification of patients to improve clinical
management of childhood liver cancer. To address these shortcomings, emerging artificial intelligence tools
can be applied to study the public datasets obtained from the molecular profiling of tumors (i.e., genome,
transcriptome, and methylome), which have been generated in recent years thanks to the advances and the
decreasing costs of molecular measurement technologies. It is clear that the application of big data in the
field of cancer has a huge potential, and, in the case of rare cancers, it is useful not only to analyze molecular
data associated with clinical and pathological parameters in depth but also to increase the sample size of the
studies. Moreover, it is vital to promote the establishment of centralized biorepositories of human samples,
including living tumors (i.e., cell lines, organoids, and murine models), to validate biomarkers and test new
therapies to move personalized medicine for pediatric patients with liver cancer forward.

The ongoing international clinical trial PHITT is designed to meet the above-mentioned needs. In parallel
to an improvement in treatments for patients, it is intended to establish one of the largest and most
complete biorepositories in the world, which will include tissue, blood, and urine samples at different times
of treatment as well as living tumors (i.e., patient-derived xenografts and organoids). The samples are
already being collected and molecularly profiled, and the omics databases will be exploited through
sophisticated computational and artificial intelligence tools with the aim of identifying new biomarkers and
signaling pathways involved in highly aggressive pediatric liver malignances, so as to be able to provide a
comprehensive and highly-validated panel of diagnostic and prognostic biomarkers. One of the important
objectives of the PHITT is to improve the current molecular knowledge of childhood liver cancer and its
clinical management by integrating the use of biomarkers into clinical practice with the final aim of
advancing the improvement of quality of life and survival of children suffering from primary liver cancers.

DECLARATIONS
Authors’ contributions
Review conception and design, draft manuscript preparation and approval of the final version of the
manuscript: Armengol C, Cairo S, Kappler R

Availability of data and materials
Not applicable.

Financial support and sponsorship
This article was possible thanks to the inputs from AGAUR (2017-SGR-490), the European Union's
Horizon 2020 research and innovation programme under grant agreement No 668596 (ChiLTERN) and
grant agreement No 826121 (iPC). CA was supported by Ramón y Cajal (RYC-2010-07249) program of the
Ministry of Science and Innovation of Spain and RK by the Bettina Bräu foundation Munich and the
Gänseblümchen foundation Voerde.