Lenvatinib as a therapy for unresectable hepatocellular carcinoma

Spallanzani, Andrea; Orsi, Giulia; Andrikou, Kalliopi; Gelsomino, Fabio; Rimini, Margherita; Riggi, Laura; Cascinu, Stefano

doi:10.1080/14737140.2018.1524297

Cited by 25 publications

(26 citation statements)

References 40 publications

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“…This implied that patients with CK19-positive HCC could benefit from sorafenib administration after surgery. As Govaere et al 55 demonstrated that CK19 could be progressed through PDGFRα-LAMB1-CK19 axis, inhibitors of PDGFRα such as imatinib 76 , regorafenib 77 and lenvatinib 78 might exert specific effect on CK19-positive HCC. Therefore, the above-named first-line or second-line multi-targeted tyrosine kinase inhibitors (TKI) approved by FDA for HCC are supposed to have therapeutic priority to CK19-positive HCC.…”

Section: The Detective and Therapeutic Strategy For Ck19 Positive Hccmentioning

confidence: 99%

CK19-positive Hepatocellular Carcinoma is a Characteristic Subtype

Zhuo

Tan

et al. 2020

J. Cancer

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The heterogeneity of hepatocellular carcinoma (HCC) commonly leads to therapeutic failure of HCC. Cytokeratin 19 (CK19) is well acknowledged as a biliary/progenitor cell marker and a marker of tumor stem cell. CK19-positive HCCs demonstrate aggressive behaviors and poor outcomes which including worse overall survival and early tumor recurrence after hepatectomy and liver transplantation. CK19-positive HCCs are resistant to chemotherapies as well as local treatment. This subset of HCC is thought to derive from liver progenitor cells and can be induced by extracellular stimulation such as hypoxia. Besides being a stemness marker, CK19 plays an important role in promoting malignant property of HCC. The regulatory network associated with CK19 expression has been summarized that extracellular stimulations which transmit into cytoplasm through signal transduction pathways (TGF-β, MAKP/JNK and MEK-ERK1/2), further induce important nuclear transcriptional factors (SALL4, AP1, SP1) to activate CK19 promoter. Novel noncoding RNAs are also involved in the regulation of CK19 expression. TGFβR1 becomes a therapeutic target for CK19-positive HCC. In conclusion, CK19 can be a potential biomarker for predicting poor prognosis after surgical and adjuvant therapies. CK19-pisitive HCCs exhibit distinctive molecular profiling, should be diagnosed and treated as a separate subtype of HCCs.

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Section: The Detective and Therapeutic Strategy For Ck19 Positive Hccmentioning

confidence: 99%

CK19-positive Hepatocellular Carcinoma is a Characteristic Subtype

Zhuo

Tan

et al. 2020

J. Cancer

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“…At first, lenvatinib was approved for the treatment of radioiodine-refractory differentiated thyroid cancer, as a single agent, and for the treatment of advanced renal cell carcinoma in combination with everolimus[79,88-90]. On August 2018, based on positive results of the REFLECT trial (NCT01761266), the FDA approved lenvatinib as a first-line treatment in patients with advanced and unresectable HCC[91,92].…”

Section: Pharmacogenetics Of Approved Drugsmentioning

confidence: 99%

Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma

Mattia

Cecchin

Guardascione

et al. 2019

WJG

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Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative therapies ( i.e ., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other small-molecule multikinase inhibitors ( e.g ., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors ( e.g ., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors ( e.g ., palbociclib, ribociclib), are in earlier stages of clinical development, and the c-MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and critically discuss the pharmacogenetic literature evidences, with particular attention to sorafenib and regorafenib, which have been used longer than the others in HCC treatment.

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“…Additional multi-kinase inhibitors recently approved for HCC treatment include regorafenib (for secondary treatment after sorafenib), as well as levatinib (another first-line drug to treat HCC besides sorafenib). However, neither provide much more additional benefit than sorafenib treatment[13,14]. As such, better treatment options are still needed.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of hepatocellular carcinoma progression

Ogunwobi

Harricharran

Huaman

et al. 2019

WJG

182

118

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Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver. It is the second leading cause of cancer-related deaths worldwide, with a very poor prognosis. In the United States, there has been only minimal improvement in the prognosis for HCC patients over the past 15 years. Details of the molecular mechanisms and other mechanisms of HCC progression remain unclear. Consequently, there is an urgent need for better understanding of these mechanisms. HCC is often diagnosed at advanced stages, and most patients will therefore need systemic therapy, with sorafenib being the most common at the present time. However, sorafenib therapy only minimally enhances patient survival. This review provides a summary of some of the known mechanisms that either cause HCC or contribute to its progression. Included in this review are the roles of viral hepatitis, non-viral hepatitis, chronic alcohol intake, genetic predisposition and congenital abnormalities, toxic exposures, and autoimmune diseases of the liver. Well-established molecular mechanisms of HCC progression such as epithelial-mesenchymal transition, tumor-stromal interactions and the tumor microenvironment, cancer stem cells, and senescence bypass are also discussed. Additionally, we discuss the roles of circulating tumor cells, immunomodulation, and neural regulation as potential new mechanisms of HCC progression. A better understanding of these mechanisms could have implications for the development of novel and more effective therapeutic and prognostic strategies, which are critically needed.

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Lenvatinib as a therapy for unresectable hepatocellular carcinoma

Cited by 25 publications

References 40 publications

CK19-positive Hepatocellular Carcinoma is a Characteristic Subtype

CK19-positive Hepatocellular Carcinoma is a Characteristic Subtype

Pharmacogenetics of the systemic treatment in advanced hepatocellular carcinoma

Mechanisms of hepatocellular carcinoma progression

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