Posted: Wednesday, August 2, 2023
Findings presented in Nature Communications by Jun Yang, PhD, of St. Jude Children’s Research Hospital, Memphis, and colleagues suggest that a combination treatment of protein-kinase DNA-activated catalytic subunit (PRKDC) inhibition plus doxorubicin-based chemotherapy may enhance the efficacy of the chemotherapy for pediatric hepatoblastoma. These findings were based on research using a novel liver cancer model that reflects both the pathology and genomics of the disease. New information that sheds light on the cancer cells’ genetic response to chemotherapy may help drive development of more effective therapies.
“Our model recapitulates a high degree of tumor heterogeneity, which mimics the level of heterogeneities observed in patient tumors,” commented coauthor Xiang Chen, PhD, also of St. Jude Children’s Research Hospital, in an institutional press release.
The researchers created a murine tumor model that resembled high-risk human hepatoblastoma. The hepatocyte-specific multifocal model was driven by the myelocytomatosis oncogene. Transcriptomics such as bulk RNA sequencing, single-cell RNA sequencing, and pathology-based spatial transcriptomics echoed pathologic features of embryonal hepatoblastoma. Cell lines taken from the murine model underwent CRISPR-Cas9 screening to map cancer dependency genes and identify treatment targets available in human hepatoblastoma, such as CDK7, CDK9, PRMT1, and PRMT5. Oncogenes and tumor suppressor genes that interact with various targetable cancer signaling pathways were also identified.
A genome-wide CRISPR-Cas9 screen was used to map cellular response to doxorubicin chemotherapy and to identify genes that enhance or dampen the effects of the treatment. This process revealed that PRKDC synergizes with doxorubicin’s effects, whereas apoptosis genes antagonized those effects.
“Based upon this screen, a combination therapy is developed that shows better efficacy than doxorubicin treatment alone,” concluded the authors. “These patients are routinely treated with chemotherapy for high-risk disease, but—especially when talking about hepatoblastoma in children who are still developing—the long-term effects can be a big concern,” commented Dr. Yang in the press release.
Disclosure: The study authors reported no conflicts of interest.