This study, led by Robert Nagourney, MD of the Nagourney Cancer Institute, explores whether a laboratory technique called functional precision oncology could identify drugs that might work against individual FLC tumors. The researchers collected tumor samples from 41 FLC patients and tested them using a proprietary platform called EVA/PCD™ (Ex Vivo Analysis of Programmed Cell Death). This method measures whether actual cancer cells die when exposed to different drugs or drug combinations. Eighteen (18) drugs** were included in the assay and evaluated both as single compounds and in combinations. They also analyzed blood samples from five (5) FLC patients to look for changes in how the cancer uses energy and nutrients.
A key finding was that FLC may depend heavily on altered mitochondrial function and metabolic pathways rather than the signaling pathways commonly targeted in conventional liver cancers. Three drugs stood out:
- vorinostat, an epigenetic drug that affects how genes are turned on and off
- phenformin, which interferes with how mitochondria produce energy, and
- DON (6-diazo-5-L-norleucine), which blocks a tumor’s ability to use glutamine, an important nutrient that some cancers (including FLC) rely on.
The study also identified several drug combinations that showed promising activity, including GEMOX (gemcitabine plus oxaliplatin) and 5-FU (5-fluoruracil) plus interferon. While these findings do not prove that these treatments will help patients, they suggest that certain carefully selected drugs and combinations may be more effective than many of the standard therapies commonly used for liver cancer.
Comparison with other recent research
The DON result is particularly noteworthy because it fits with a growing body of research suggesting that FLC may depend heavily on glutamine metabolism. DON itself is an older drug that was largely abandoned because it caused too many side effects. However, that same scientific idea led to the development of DRP-104, a newer version designed to deliver DON more selectively to tumors while reducing toxicity. FCF’s 2023 partnership with Dracen Pharmaceuticals and a clinical trial assessing DRP-104 at Johns Hopkins reflect the growing interest in exploiting glutamine dependence in FLC, not just as a direct tumor-killing strategy but also potentially as a way to reshape the tumor microenvironment to improve its responsiveness to immunotherapy. The Nagourney data therefore provides independent support for a therapeutic concept that has already moved into early clinical development (see information about active clinical trials here).
The Nagourney study’s findings also closely match what other researchers have been discovering about FLC biology. In particular, a major 2024 study led by Don Long and colleagues at Cornell University found that FLC cells have “rewired mitochondria.” Using a wide range of laboratory techniques, they showed that FLC appears unusually dependent on mitochondrial activity, glutamine metabolism, amino-acid processing, and other metabolic pathways that help the tumor generate energy and build new cellular material.
The Cornell findings also help explain why phenformin and DON performed well in the Nagourney study. If FLC cells depend heavily on mitochondria and glutamine for survival, then drugs that interfere with those systems should be particularly harmful to the tumor. The fact that two completely different research approaches—one focused on understanding FLC biology and the other focused on testing drugs directly against patient tumors—point to the same metabolic vulnerabilities makes the overall conclusion much stronger.
Comparison with prior drug screening efforts
Importantly, these results are consistent with an earlier high-volume drug-screening study from Sanford Simon’s lab at Rockefeller University that was published in 2021 (Lalazar, et al). That study tested more than 5,000 drugs for their ability to kill FLC cells and identified a different set of promising compounds, including HDAC inhibitors, translation inhibitors, topoisomerase inhibitors (like irinotecan), and drugs targeting cell-survival pathways (like Bcl-xL). Although the two studies did not highlight the same drugs, they both concluded that FLC has vulnerabilities that are different from those seen in traditional liver cancer, and patients are unlikely to benefit from a one-size-fits-all treatment approach.
In the Rockefeller paper, vorinostat was not reported as a drug “hit” and was not discussed. However, both panobinostat and quisinostat, which are also HDAC inhibitors, were identified as having strong positive results. HDAC inhibitors are drugs that blocks the activity of histone deacetylases (HDACs) — enzymes that help regulate which genes are turned on or off in a cell. Phenformin was not discussed in the Rockefeller work.
The two studies found different results largely because they used different methods. Nagourney’s team kept small pieces of tumor intact and also analyzed patients’ blood samples. This approach was especially good at identifying how FLC tumors produce energy and use nutrients, which led to findings about mitochondrial function, glutamine metabolism, and other metabolic vulnerabilities. By contrast, Simon’s team broke tumors into individual cells, used patient-derived tumor models, and tested thousands of drugs. This approach was particularly effective at finding drugs that directly stop cancer cells from growing or trigger them to die. As a result, the Nagourney study highlighted weaknesses in FLC’s metabolism, while the Rockefeller study emphasized vulnerabilities involving gene regulation, protein production, and cell-survival pathways.
Taken together, these studies suggest that FLC has several important weak points that may be exploited by different types of therapies, including:
- HDAC and other epigenetic therapies
- Metabolic therapies targeting mitochondrial function and glutamine utilization
- Translation-initiation inhibitors
- Bcl-xL–directed combination approaches
- Selected chemotherapy combinations rather than traditional single-agent regimens.
Although these findings are not yet sufficient to guide clinical treatment decisions, they provide important biologic validation and a strong rationale for future translational studies and clinical trials designed specifically for FLC.
The full text of the publication can be read or downloaded here.
** Specific drugs tested included: retinoic acid, alpelisib, irinotecan, celecoxib, cobimetinib, 6-diazo-5-L-norleucine (DON), everolimus, gemcitabine plus oxaliplatin, KAT/3-bromopyruvate, lenvatinib, navitoclax, panobinostat, phenformin, quercetin, regorafenib, vorinostat, 5-fluoruracil, and alpha-Interferon