Long considered a type of common liver cancer, fibrolamellar hepatocellular carcinoma (FLC) deserves recognition as a distinct illness. Currently, researchers are exploring a new combination drug therapy specifically aimed at FLC tumors.
Fibrolamellar hepatocellular carcinoma (FLC) aggressively affects a small group of individuals, particularly children, teenagers, and young adults. Due to its varying symptoms, it often goes undetected or misdiagnosed until it spreads and becomes deadly. Furthermore, treatments designed for common liver cancers can be ineffective and even harmful for those with FLC.
Recent discoveries about this condition, along with the initiation of a clinical trial for an innovative drug treatment, hold the potential for significant improvements in patient health. Researchers at Rockefeller University’s Laboratory of Cellular Biophysics, under the guidance of Sanford M. Simon, have identified a unique transcriptomic “signature” consisting of a group of active genes that sets FLC apart from other liver cancers.
“Pinpointing the molecular changes that define FLC is crucial for understanding its development and progression, which may open up new treatment possibilities,” says lead author David Requena, a senior researcher in the lab. “Our objective is to enhance disease detection, optimize treatment strategies, and boost survival rates for patients.”
The research findings, published in Nature Communications, coincide with Simon’s lab launching a clinical trial that combines two medications, which initial results suggest are very effective against FLC.
A decade of insights
In 2014, Simon’s team—partially led by his teenage daughter, Elana, who was diagnosed with FLC a few years earlier—uncovered that the disease results from the fusion of two genes, DNAJB1 and PRKACA, due to a small deletion in chromosome 19.
Recently, they determined that the fusion’s significance lies not in its formation but in the resultant increase in PRKACA levels, the catalytic subunit of protein kinase A. This increase is the fundamental cause of the disease. FLC tumor cells experience a molecular imbalance: an excess of catalytic PKA proteins and an insufficiency of inhibitory proteins that normally regulate its activity. Consequently, the unrestrained PKA causes cellular chaos.
The researchers aimed to discover whether there is a shared pathway of disease following the surge of PKA proteins. While some liver tumors exhibit “FLC-like” features, they lack the fusion protein. Are these tumors actually FLC? Additionally, since FLC does not respond to treatments that are effective on other liver cancers, what sets it apart from these other diseases?
The signature
To explore these questions, the researchers conducted an extensive analysis of multiomics sequencing data from 1,412 tumors representing various liver cancers, marking the largest such study to date with 220 FLC samples included—over six times more than in previous studies.
This analysis allowed the team to identify the transcriptomic signature for each tumor, highlighting which dysregulations are specific to certain tumor types versus those that are common among all. Performing single-cell analysis with spatial resolution revealed how different cell types contribute to the tumor’s overall transcriptome.
The outcome revealed that FLC stands out distinctly. “We pinpointed 301 genes that exhibited different expressions in FLC compared to other tumors, emphasizing its uniqueness among liver cancers,” Requena notes. “Of these, 35 were found to be highly expressed only in FLC, suggesting potential diagnostic applications in clinical settings.”
Additionally, they discovered that any genetic alteration leading to a higher ratio of the catalytic subunit to the regulatory one resulted in similar transcriptomic changes. Some patients showed a fusion with PRKACA in liver ductal cells, resulting in cholangiocarcinoma, or in pancreatic ductal cells, leading to intraductal pancreatic oncolytic neoplasms (IOPNs). These diverse fusions, identified outside of hepatocytes (where FLC is typically found), consistently produced the same transcriptomic alterations. Even in cases where patients only lacked the regulatory subunit, similar changes were noted.
Recently, Simon’s lab also demonstrated that these conditions respond to treatments similarly to FLC.
“We propose that the cancer’s definition should focus not on the DNA changes but on how these changes impact the overall protein activity within the cell,” Simon, the Günter Blobel Professor at Rockefeller, explains.
Moreover, they compared the tumor transcriptomes with samples from healthy tissue adjacent to the tumors in FLC patients, unexpectedly finding one sample that retained the FLC signature. Upon further investigation, they observed fibrous structures characteristic of the disease and cells containing the DNAJB1::PRKACA fusion transcript. This indicated that the tumor removal did not eliminate all FLC cells, which could potentially lead to new cancer development.
“This observation highlights the necessity for thorough examination of tumor margins,” Simon emphasizes.
A promising clinical trial
Equipped with this new understanding, the researchers have embarked on a clinical trial to assess the effectiveness of combining two anti-cancer agents, DT2216 and irinotecan. Previous research from the lab published in 2022 suggested that this combination could be particularly effective for FLC. This initiative receives support from the Children’s Oncology Group and the Pediatric Early Phase Clinical Trials Network of the NIH.
Simultaneously, the Simon Lab is working on developing alternative treatments, backed by the Cancer Grand Challenge, a highly selective program by Cancer Research (UK) and the National Cancer Institute (US) that provides substantial funding for collaborative research efforts. Simon’s lab is a member of the KOODAC team, which aims to degrade an oncoprotein—in Simon’s case, fusions involving PRKACA—to prevent or eradicate tumors. The findings are expected to be presented at the annual meeting of the American Association for Cancer Research in late April.
“A decade ago, we hoped that by thoroughly investigating this specific and rare condition, we could quickly progress toward developing diagnostics and treatments not only for FLC but also providing insights applicable to other diseases,” he states. “Our recent findings validate that vision and offer hope that these insights might also be useful for other cancers—like Ewing sarcoma, rhabdomyosarcoma, and neuroblastoma—as well as health issues requiring the elimination of non-functioning proteins.”
