Hepatocellular Carcinoma: Beyond the Border of Advanced Stage Therapy

Abstract

Hepatocellular carcinoma (HCC) is the deadliest emergent health issue around the globe. The stronger oncogenic effect, proteins, and weakened immune response are precisely linked with a significant prospect of developing HCC. Several conventional systemic therapies, antiangiogenic therapy, and immunotherapy techniques have significantly improved the outcomes for early-, intermediate-, and advanced-stage HCC patients, giving new hope for effective HCC management and prolonged survival rates. Innovative therapeutic approaches beyond conventional treatments have altered the landscape of managing HCC, particularly focusing on targeted therapies and immunotherapies. The advancement in HCC treatment suggested by the Food and Drug Administration is multidimensional treatment options, including multikinase inhibitors (sorafenib, lenvatinib, regorafenib, ramucirumab, and cabozantinib) and immune checkpoint inhibitors (atezolizumab, pembrolizumab, durvalumab, tremelimumab, ipilimumab, and nivolumab), in monotherapy and in combination therapy to increase life expectancy of HCC patients. This review highlights the efficacy of multikinase inhibitors and immune checkpoint inhibitors in monotherapy and combination therapy through the analysis of phase II, and III clinical trials, targeting the key molecular pathways involved in cellular signaling and immune response for the prospective treatment of advanced and unresectable HCC and discusses the upcoming combinations of immune checkpoint inhibitors-tyrosine kinase inhibitors and immune checkpoint inhibitors-vascular endothelial growth factor inhibitors. Finally, the hidden challenges with pharmacological therapy for HCC, feasible solutions for the future, and implications of possible presumptions to develop drugs for HCC treatment are reported.

Keywords: combination therapy; hepatocellular carcinoma; hepatocytes; immune checkpoint inhibitors; immune microenvironment; immune system; multikinase inhibitors.

Figure 1

Effect of sorafenib on the RAS/RAF cascade and specific receptors to initiate apoptosis. The drug inhibits phosphorylation of eIF4E to stop the initiation of transcription of RAS/RAF cascades. The resultant deficiency of proteins prevents cell division to stop tumor growth.

Figure 2

Lenvatinib inhibits both the vascular endothelial growth factor and fibroblast growth factor pathways to stop the development, survival, the proliferation of tumor cells, and endothelial cells involved in angiogenesis.

Figure 3

The primary molecular targets and signaling pathways for HCC targeted therapy. We listed the functional molecules with their regulators in signaling cascades as well as significant signaling pathways that are important for HCC development. Finally, we listed the targeted drugs currently being tested in clinical trials for advanced-stage HCC. SOS, son of sevenless; GRB2, growth factor receptor-bound protein 2; eIF4E, eukaryotic translation initiation factor 4E; RHEB, RAS homolog enriched in brain; PTEN, phosphatase and tensin homolog; TSC1/2, tuberous sclerosis ½; S6K, S6 kinase; 4EBP1/2, eukaryotic translation initiation factor 4E-binding protein; mTORC1/2, mammalian target of rapamycin complex ½; ½ JAKs, Janus kinase; SOCS, suppressors of cytokine signaling; STAT, signal transducers and activators of transcription; PIAS, protein inhibitors of activated STAT; PTP, protein tyrosine phosphatase; FGFR4, fibroblast growth factor receptor-4; FGF19, fibroblast growth factor-19; FRS2/3, fibroblast growth factor receptor substrate 2 and 3; GAB1, GRB2-associated binding protein 1; DAG, diacylglycerol; PLCγ, phospholipase C gamma; c-MET, mesenchymal–epithelial transition factor; WNT, wingless related integration site; CK1α, casein kinase 1α; DVL, disheveled; APC, adenomatous polyposis coli; GSK3β, glycogen synthase kinase 3β.

Figure 4

The synergistic therapeutic efficacy of antiangiogenic agents and immune checkpoint inhibitors involves unraveling underlying mechanistic insights. Combining immune checkpoint inhibitors with tyrosine kinase inhibitors or antiangiogenic antibodies together with locoregional treatment might increase response rates by infiltrating immune cells into “cold” tumors and transforming them into “hot” tumors. This synergy might involve several processes, including the activation of different anti-immune cells, the inhibition of immune cell types that promote tumor growth, or vascular normalization, and enhances immunological infiltration and drug delivery.

Figure 5

PD-1 binds with PDL1 to inhibit the growth and development of T-killer cells and causes T cells to become exhausted. CTLA4 attaches to CD80/86 to prevent T cells from becoming activated. Immunological checkpoint inhibition prevents immunity exhaustion, diminishes regulatory T cell activity, and triggers the recurrence of the antitumor immunological response.

Figure 6

Natural history, current treatment approaches, and future advancements in immunotherapy for the effective management of HCC. The Barcelona Clinic Liver Cancer (BCLC) staging system categorizes HCC into five stages based on factors such as the extent of disease and liver function. These are some ongoing trials for early-stage HCC investigating the safety and efficacy of drugs in monotherapy or combination therapy for recurrence-free survival. In intermediate and advanced stages of HCC, ICIs are often used in combination with targeted therapy to increase the overall response and objective response rate.