HCC and Molecular Targeting Therapies: Back to the Future

Rinaldi, Luca; Vetrano, Erica; Rinaldi, Barbara; Galiero, Raffaele; Caturano, Alfredo; Salvatore, Teresa; Sasso, Ferdinando Carlo

doi:10.3390/biomedicines9101345

Cited by 34 publications

(21 citation statements)

References 126 publications

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“…PD-1 contributes to T-cell scarcity in the tumour microenvironment, and CTLA-4 inhibits activated and regulatory T cells in the lymphoid organs. Nivolumab, associated with ipilimumab, has proved efficacy in the therapy of renal carcinoma, lung cancer, melanoma, metastatic colorectal cancer, and hepatocellular carcinoma [ 140 ]. The combination of cabozantinib (VEGFR inhibitor) with nivolumab (anti-PD-1) and ipilimumab (anti-CTLA-4) is currently being investigated in patients with RAIR-DTC in a clinical trial (phase II), including 24 RAIR-DTC patients with disease progression after monotherapy with anti-VEGFR (NCT03914300).…”

Section: Immunotherapy Of Advanced Tcmentioning

confidence: 99%

State of the Art in the Current Management and Future Directions of Targeted Therapy for Differentiated Thyroid Cancer

Silaghi

Lozovanu²,

Georgescu

et al. 2022

IJMS

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Two-thirds of differentiated thyroid cancer (DTC) patients with distant metastases would be classified as radioactive iodine-refractory (RAIR-DTC), evolving into a poor outcome. Recent advances underlying DTC molecular mechanisms have shifted the therapy focus from the standard approach to targeting specific genetic dysregulations. Lenvatinib and sorafenib are first-line, multitargeted tyrosine kinase inhibitors (TKIs) approved to treat advanced, progressive RAIR-DTC. However, other anti-angiogenic drugs, including single targeted TKIs, are currently being evaluated as alternative or salvage therapy after the failure of first-line TKIs. Combinatorial therapy of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signalling cascade inhibitors has become a highly advocated strategy to improve the low efficiency of the single agent treatment. Recent studies pointed out targetable alternative pathways to overcome the resistance to MAPK and PI3K pathways’ inhibitors. Because radioiodine resistance originates in DTC loss of differentiation, redifferentiation therapies are currently being explored for efficacy. The present review will summarize the conventional management of DTC, the first-line and alternative TKIs in RAIR-DTC, and the approaches that seek to overcome the resistance to MAPK and PI3K pathways’ inhibitors. We also aim to emphasize the latest achievements in the research of redifferentiation therapy, immunotherapy, and agents targeting gene rearrangements in advanced DTC.

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Section: Immunotherapy Of Advanced Tcmentioning

confidence: 99%

State of the Art in the Current Management and Future Directions of Targeted Therapy for Differentiated Thyroid Cancer

Silaghi

Lozovanu²,

Georgescu

et al. 2022

IJMS

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“…In 1971, Folkman suggested potential strategies against tumor progression by blocking tumor angiogenesis ( 19 ). Angiogenesis inhibitors are administered to patients with HCC, including bevacizumab, cabozantinib, lenvatinib, ramucirumab, regorafenib, and sorafenib, based on the National Comprehensive Cancer Network guidelines ( 20 ). Placental growth factor (PLGF) is a pro-angiogenic factor belonging to the VEGF family, which is usually secreted under pathological conditions.…”

Section: Mechanisms Of Therapeutic Resistance In the Hcc Microenviron...mentioning

confidence: 99%

Overcoming the therapeutic resistance of hepatomas by targeting the tumor microenvironment

et al. 2022

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Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers and is the third leading cause of cancer-related mortality worldwide. Multifactorial drug resistance is regarded as the major cause of treatment failure in HCC. Accumulating evidence shows that the constituents of the tumor microenvironment (TME), including cancer-associated fibroblasts, tumor vasculature, immune cells, physical factors, cytokines, and exosomes may explain the therapeutic resistance mechanisms in HCC. In recent years, anti-angiogenic drugs and immune checkpoint inhibitors have shown satisfactory results in HCC patients. However, due to enhanced communication between the tumor and TME, the effect of heterogeneity of the microenvironment on therapeutic resistance is particularly complicated, which suggests a more challenging research direction. In addition, it has been reported that the three-dimensional (3D) organoid model derived from patient biopsies is more intuitive to fully understand the role of the TME in acquired resistance. Therefore, in this review, we have focused not only on the mechanisms and targets of therapeutic resistance related to the contents of the TME in HCC but also provide a comprehensive description of 3D models and how they contribute to the exploration of HCC therapies.

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“…Notably, the development of HCC is promoted by risk factors such as chronic hepatitis B and C, alcoholic and chronic liver disease, etc. (McGlynn et al, 2021;Rinaldi et al, 2021). Despite specific causes and advances in modern medical technology, the incidence and mortality of HCC remain unresolved.…”

Section: Introductionmentioning

confidence: 99%

Auranofin accelerates spermidine-induced apoptosis via reactive oxygen species generation and suppression of PI3K/Akt signaling pathway in hepatocellular carcinoma

Hwangbo¹,

Kim²,

Kim³

et al. 2023

Fish Aquat Sci

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Auranofin is a US Food and Drug Administration (FDA)-approved anti-arthritis medication that functions as a thioredoxin reductase inhibitor. Spermidine, a polyamine present in marine algae, can exert various physiological functions. Herein, we examined the synergistic anticancer activity of auranofin and spermidine in hepatocellular carcinoma (HCC). Combined treatment with auranofin and spermidine suppressed cell viability more efficiently than either treatment alone in HCC Hep3B cells. The isobologram plotted by calculating the half maximal inhibitory concentration (IC 50 ) values of each drug indicated that the two drugs exhibited a synergistic effect. Based on the analysis of annexin V and cell cycle distribution, auranofin and spermidine markedly induced apoptosis in Hep3B cells. Moreover, auranofin and spermidine increased mitochondria-mediated apoptosis by promoting mitochondrial membrane potential (Δψm) loss. Auranofin and spermidine significantly increased reactive oxygen species (ROS) production in Hep3B cells, and the blocking ROS suppressed apoptosis induced by spermidine and auranofin. In addition, auranofin and spermidine reduced the expression of phosphorylated phosphatidylinositol-3 kinase (PI3K) and protein kinase B (Akt), and PI3K inhibitor accelerated auranofin-and spermidine-induced apoptosis. Using ROS scavenger and PI3K inhibitor, we revealed that ROS acts upstream of auranofin-and spermidine-induced apoptosis. Collectively, our study suggests that combination treatment with auranofin and spermidine could afford synergistic anticancer activity via ROS overproduction and reduced PI3K/Akt signaling pathway.

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HCC and Molecular Targeting Therapies: Back to the Future

Cited by 34 publications

References 126 publications

State of the Art in the Current Management and Future Directions of Targeted Therapy for Differentiated Thyroid Cancer

State of the Art in the Current Management and Future Directions of Targeted Therapy for Differentiated Thyroid Cancer

Overcoming the therapeutic resistance of hepatomas by targeting the tumor microenvironment

Auranofin accelerates spermidine-induced apoptosis via reactive oxygen species generation and suppression of PI3K/Akt signaling pathway in hepatocellular carcinoma

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