Researchers at Rockefeller University have uncovered unique molecular characteristics of fibrolamellar hepatocellular carcinoma (FLC), a rare liver cancer affecting children and young adults. This discovery has paved the way for a new clinical trial evaluating a combination therapy of DT2216 and irinotecan, offering hope for improved outcomes in this challenging disease.
The study, led by Sanford M. Simon, head of the Laboratory of Cellular Biophysics, identified a distinct transcriptomic signature in FLC tumors. This signature, characterized by a specific set of activated genes, differentiates FLC from other liver cancers and could lead to more accurate diagnostic methods and targeted treatments.
Unveiling the Molecular Signature of FLC
To identify the unique features of FLC, the researchers conducted an extensive analysis of multiomics sequencing data from 1,412 liver tumors, including 220 FLC samples. This represents the largest analysis of FLC tumors to date, providing a comprehensive view of the disease's molecular landscape.
The analysis revealed 301 genes that were expressed differently in FLC compared to other liver cancers, with 35 genes being highly expressed exclusively in FLC. According to David Requena, senior researcher and first author of the study, these genes could serve as potential diagnostic markers in the clinic.
The team also discovered that any DNA change that increased the ratio of the catalytic subunit of protein kinase A (PRKACA) relative to its regulatory subunit resulted in similar changes in the transcriptome, regardless of the specific fusion or cell type involved. This suggests that the imbalance in protein activity, rather than the specific genetic mutation, may be the primary driver of the disease.
"Thus, we suggest that the cancer perhaps should be defined not by its DNA change but by the change it produces in the net balance of protein activity in the cell," says Simon.
Clinical Trial and Therapeutic Development
Based on these insights, Simon's lab has initiated a clinical trial to evaluate the efficacy of combining DT2216 and irinotecan in treating FLC. Previous research from the lab indicated that this combination is effective against FLC. The trial is supported by the Children's Oncology Group and the Pediatric Early Phase Clinical Trials Network of the NIH.
In addition to the clinical trial, the Simon Lab is also pursuing alternative therapeutic strategies through the Cancer Grand Challenge, a collaborative initiative focused on degrading the PRKACA fusion protein to prevent or kill tumors. Simon aims to present their findings at the annual meeting of the American Association for Cancer Research in late April.
Importance of Tumor Margin Examination
The researchers also compared tumor transcriptomes with normal tissue samples from FLC patients and found that some normal tissue samples exhibited the FLC signature. Further examination revealed fibrous spans and cells with the DNAJB1::PRKACA fusion transcript, indicating that FLC cells can persist even after tumor removal. This highlights the importance of thoroughly examining tumor margins to prevent recurrence.
"This finding really demonstrates the importance of a complete examination of the margins of the tumor," says Simon.
