Liver cancer genetic study reveals new drugs

image: Histological photos of aggressive hepatic tumors obtained from transgenic mice (by injection into the tail vein of transposable genetic elements) with induced overexpression of MAGEA3.
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Credit: Craig AJ et al., 2021, PLOS Genetics

Drugs targeting the MAGEA3 gene may help block the growth of hepatocellular carcinoma (HCC), the most common type of primary liver cancer and one of the leading causes of cancer death in the country. That’s one of the findings of a new study analyzing the genetics of HCC tumors published June 24 in the journal PLOS genetics by Augusto Villanueva of the Icahn School of Medicine at Mount Sinai and colleagues.

Scientists have already discovered several genes responsible for the growth of HCC tumors, but the therapeutic benefits of approved drugs are still limited. In the new study, Villanueva and her colleagues collected 44 tumor biopsies from 12 HCC patients. The researchers used RNA sequencing to study which genes were more highly expressed in high-grade regions of a tumor compared to low-grade regions of the same tumor.

One family of genes – the cancer testis antigens (CTA) – was recurrently overexpressed in the most aggressive regions of the tumours. CTAs, most of which are located on the X chromosome, are typically expressed in male germ cells of the testes and are believed to play a role in spermatogenesis as well as protecting germ cells from stressors and cell death. Villanueva’s team found that CTAs, and in particular MAGEA3, are associated with poor prognosis in HCC. Moreover, when the group blocked the expression of MAGEA3 in isolated HCC cells, the cells could no longer proliferate and eventually died. When the group overexpressed MAGE3 in the liver cells of HCC-prone mice, the animals died of cancer more quickly. Future studies are needed to replicate the results in larger patient populations and determine whether MAGEA3 itself, or its downstream targets, are more effective at targeting therapeutically.

“The study revealed the role of cancerous testicular antigens, particularly MAGEA3, in the progression of liver cancer,” adds Villanueva. “This demonstrates how selective inhibition of MAGEA3 has anti-tumor effects in experimental models of this disease. Overall, the study provides the proof of principle for testing MAGEA3 inhibition in early phase clinical trials for patients with primary liver cancer.

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Peer-reviewed; Experimental study; People

In your coverage, please use this URL to provide access to the article available for free in PLOS genetics: http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009589

Quote: Craig AJ, Garcia-Lezana T, Ruiz de Galarreta M, Villacorta-Martin C, Kozlova EG, Martins-Filho SN, et al. (2021) Transcriptomic characterization of testicular cancer antigens identifies MAGEA3 as a driver of tumor progression in hepatocellular carcinoma. PLoS Genet 17(6): e1009589. https://doi.org/10.1371/journal.pgen.1009589

Funding: JvF was supported by the German Research Foundation (FE1746/1-1). It was supported by a grant from the Swiss National Science Foundation (http://www.snf.ch/fr/Pages/default.aspx), the Roberto & Gianna Gonella Foundation and the SICPA Foundation (https: //www.sicpa.com/sustainability/switzerland-institution-research-paraplegia). MRdG was supported by the Fundación Alfonso Martín Escudero Fellowship (https://fundame.org/) and the Damon Runyon-Rahleff Innovation Prize (DR52-18). EB was supported by the Damon Runyon-Rahleff Innovation Prize (DR52-18). AL was supported by Damon Runyon-Rachleff Innovation Award (DR52-18), R37 Merit Award (R37CA230636) and DoD Translational Team Science Award (CA150272P2) and Icahn School of Medicine at Mount Sinai (https://icahn.mssm.edu /). The Tisch Cancer Institute and related research facilities are supported by P30 CA196521. AV is supported by the DoD Translational Team Science Award (CA150272P3). JML has been supported by the European Commission (EC)/Horizon 2020 Program (HEPCAR, Ref. 667273-2), EIT Health (CRISH2, Ref. 18053), Accelerator Award (CRUCK, AEEC, AIRC) (HUNTER, Ref. C9380 /A26813), National Cancer Institute (P30-CA196521), US Department of Defense (CA150272P3), Samuel Waxman Cancer Research Foundation (https://www.waxmancancer.org), Spanish National Health Institute (SAF2016-76390) and Generalitat de Catalonia /AGAUR (SGR-1358). TGL is supported by the Spanish Association for the Study of the Liver (https://ww2.aeeh.es/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: I have read the journal policy and the authors of this manuscript have the following competing interests: AL has received grants from Pfizer and Genentech, and conference fees from Exelixis for unrelated projects. MRdG received a grant from Genentech for unrelated projects. AV has received consulting fees from Guidepoint and Fujifilm; advisory board fees from Exact Sciences, Nucleix and NGM Pharmaceuticals. JML has received grants from Bayer HealthCare Pharmaceuticals, Eisai Inc, Bristol-Myers Squibb, Boehringer-Ingelheim and Ipsen and consulting fees from Bayer HealthCare Pharmaceuticals, Merck, Eisai Inc, Bristol-Myers Squibb, Celsion Corporation, Eli Lilly, Roche , Genentech, Glycotest, Nucleix, Can-Fite Biopharma, AstraZeneca and Exelixis.


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