Two-Drug Combo Supercharges Liver Cancer Therapy in Preclinical Study
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Researchers report that pairing regorafenib with the experimental PD-1/PD-L1 inhibitor BMS-1 produces a synergistic anti-tumor effect in liver cancer models.
A combination of two existing drug classes may pack a far stronger punch against hepatocellular carcinoma than either agent alone, according to a new preclinical study published in the open-access journal Heliyon. Researchers report that pairing regorafenib, a multi-kinase inhibitor already approved as a second-line therapy for advanced liver cancer, with BMS-1, an experimental small-molecule inhibitor of the PD-1/PD-L1 immune checkpoint, produced synergistic anti-tumor effects in laboratory models of the disease. The findings, while still far from the clinic, offer a tantalizing glimpse of a strategy that could one day lower drug doses, reduce toxicity, and extend survival for patients with one of the world’s deadliest cancers.
Hepatocellular carcinoma, the most common form of liver cancer, is notorious for its silent progression. Global cancer statistics from 2018 ranked liver cancer as the sixth most common malignancy and the fourth leading cause of cancer death worldwide. Because most patients are diagnosed only after the disease has reached intermediate or advanced stages, surgical resection is often no longer an option. For these individuals, treatment relies on non-curative approaches such as chemotherapy, targeted drug therapy, and immunotherapy, making any improvement in the effectiveness of these tools a matter of life and death.
Tyrosine kinase inhibitors, or TKIs, form the backbone of pharmacological treatment for advanced liver cancer. First-line drugs such as sorafenib and lenvatinib block the signaling pathways that tumor cells use to proliferate and survive, but many patients eventually progress or develop resistance. Regorafenib, approved by the U.S. Food and Drug Administration in 2017 for patients whose disease advances on sorafenib, targets a broad panel of receptors including VEGFR1-3, PDGFR-beta, KIT, RET, and RAF, and uniquely also hits fibroblast growth factor receptors and the angiopoietin 1 receptor known as TIE2. Preclinical work has suggested regorafenib is pharmacologically more potent than sorafenib, capable of blocking angiogenesis, tumorigenesis, and metastasis while also modulating tumor immunity. Earlier studies showed it can drive liver cancer cells into apoptosis by directly activating the phosphatase SHP-1, which suppresses phosphorylated STAT3, an effect independent of its anti-angiogenic activity.
On the immunotherapy side, the team turned to BMS-1, a small molecule first described in a 2015 patent filed by Bristol-Myers Squibb as part of a series of compounds that disrupt the interaction between the immune checkpoint proteins PD-1 and PD-L1. Antibody drugs such as atezolizumab and avelumab have shown promise against several malignancies, but antibodies suffer from drawbacks including immunogenicity and poor penetration of tumor tissue, which contribute to low response rates in some patients. Small-molecule checkpoint inhibitors could, in principle, sidestep these limitations, and combining them with other agents has become an active research frontier.
One of the most intriguing findings emerged when the team introduced immune cells into the picture. Hepatocellular carcinoma cells barely expressed PD-L1 when grown alone, but when the researchers co-cultured them with peripheral blood mononuclear cells isolated from healthy volunteers, PD-L1 expression surged, mimicking the immune pressure of a real tumor microenvironment. Under those conditions, regorafenib pushed PD-L1 levels down, BMS-1 had a modest effect, and the combination drove PD-L1 expression down significantly. The authors speculate that regorafenib’s shared target FGFR4, which lenvatinib uses to promote proteasomal degradation of PD-L1 through the FGFR4-glycogen synthase kinase 3-beta pathway, may underlie this effect, though they caution that the exact mechanism remains unproven.
