apatinib and Bile-Duct-Neoplasms

Intrahepatic cholangiocarcinoma (ICC) is a highly aggressive malignancy rising from the biliary tree with poor prognosis. We report the feasibility and efficacy of transarterial chemoembolization (TACE) combined with PD-1 inhibitor and apatinib for the treatment of a patient with unresectable ICC. A 70-year-old female presented with intermittent right upper abdominal distension, abdominal pain, and vomiting after eating for more than one month. Enhanced computed tomography (CT) and magnetic resonance imaging (MRI) scan revealed multiple intrahepatic lesions, retroperitoneal lymph node, and left lung metastasis. Based on the patient's medical history and pathology, the diagnosis was confirmed as locally advanced unresectable ICC. Multimodal therapy was applied to the ICC. The therapy comprised TACE every three months, and a combination regimen of the PD-1 inhibitor camrelizumab and the antiangiogenic agent apatinib. The patient underwent microwave ablation for a lesion on the left lung that had not responded to systemic therapies. Enhanced CT scan after every 2-3 months was performed. After several sessions, the primary lesion reduced dramatically in size. At 20 months from diagnosis, the patient was alive, in good condition, and stable. The patient experienced no critical complications and toxicity associated with the administered therapies. This case suggests that treatment with TACE combined with systemic therapy of camrelizumab combined with apatinib may be a safe and effective treatment option for patients with inoperable ICC.

Topics: Aged; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Cholangiocarcinoma; Humans; Immune Checkpoint Inhibitors; Liver Neoplasms

Intrahepatic cholangiocarcinoma (ICC) originates from the secondary branch of the bile duct and the intrahepatic bile duct epithelial cells, and is a rare pathological type of primary liver cancer. Recently, apatinib has been successfully used for a variety of malignancies.. A 23-year-old female was noted with intermittent right upper abdominal distension, abdominal pain, and vomiting after eating for more than 1 month. The enhanced CT scan revealed multiple intrahepatic lesions, portal vein and right branch tumor emboli were present.. Combined with the patient's medical history and pathology and immunohistochemistry, the diagnosis was confirmed as locally advanced unresectable ICC (cT4N1M1, Stage IVB).. The disease progressed after six cycles of gemcitabine plus capecitabine chemotherapy. She received oral apatinib treatment since September 30, 2017. Due to related adverse reactions, the patient could not tolerate the treatment, and the subsequent reduction therapy was given.. On April 11, 2018, the review of CT evaluation suggested that the disease was progressed. Hence, in this patient, apatinib as second-line treatment for advanced ICC showed a progression-free survival with 6 months.. Apatinib as second-line treatment for advanced ICC is effective, and the adverse effects are tolerable. However, the efficacy and safety of apatinib in the treatment of ICC need to be further confirmed by large sample of prospective randomized controlled trials.

Topics: Antineoplastic Agents; Bile Duct Neoplasms; Cholangiocarcinoma; Female; Humans; Pyridines; Retreatment; Young Adult

Intrahepatic cholangiocarcinoma (ICC), which is difficult to diagnose and is usually fatal due to its late clinical presentation and a lack of effective treatment, has risen over the past decades but without much improvement in prognosis.. The study aimed to investigate the role of apatinib that targets vascular endothelial growth factor receptor-2 (VEGFR2) in ICC.. MTT assays, cell scratch assays, and tube formation assays were used to assess the effect of apatinib on human ICC cell line (HuCCT-1) and RBE cells proliferation, migration, and angiogenic capacity, respectively. Expression of vascular endothelial growth factor (VEGF), VEGFR2, signal transducer and activator of transcription factor 3 (STAT3), pSTAT3, and hypoxia inducible factor 1 subunit alpha (HIF-1α) pathway proteins was assessed using Western blotting and mRNA expression analysis in HuCCT-1 was performed using RT-qPCR assays. The pcDNA 3.1(-)-VEGFR2 and pcDNA 3.1(-)-HIF-1α were transfected into HuCCT-1 and RBE cells using Lipofectamine 2,000 to obtain overexpressed HuCCT-1 and RBE cells.. We found that apatinib-inhibited proliferation, migration, and angiogenesis of HuCCT-1 and RBE cells in vitro in a dose-dependent manner. We also proved that apatinib effectively inhibits angiogenesis in tumor cells by blocking the expression of VEGF and VEGFR2 in these cells. In addition, we demonstrated that apatinib regulates the expression of STAT3 phosphorylation by inhibiting VEGFR2. Finally, we showed that apatinib regulates ICC angiogenesis and HIF-1α/VEGF expression via STAT3.. Based on the above findings, we conclude that apatinib inhibits HuCCT-1 and RBE cell proliferation, migration, and tumor angiogenesis by inhibiting the VEGFR2/STAT3/HIF-1α axis signaling pathway. Apatinib can be a promising drug for ICC-targeted molecular therapy.

Topics: Antineoplastic Agents; Bile Duct Neoplasms; Cell Line, Tumor; Cell Proliferation; Cholangiocarcinoma; Dose-Response Relationship, Drug; Humans; Hypoxia-Inducible Factor 1; Neovascularization, Pathologic; Pyridines; Signal Transduction; Transcription Factor 3; Vascular Endothelial Growth Factor Receptor-2

Cholangiocarcinoma (CCA) is a form of cancer that easily aggress to contiguous structures. Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2) are increased in majority species of cancers and suppress tumor progression by blocking VEGF/VEGFR2. Apatinib is a highly selective VEGFR2 antagonist which has inhibitive effect on antiapoptotic and cell growth in CCA. While, the effect of apatinib cell migration and invasion in CCA is still unknown.. CCA cell lines QBC939 and TFK-1 were transfected with siKDR to establish the KDR function loss cell model, and recombined human VEGF (rhVEGF) protein was added into the culture medium to enhance the VEGF expression. RT-qPCR and western bloting were used to detect the mRNA and protein expression levels of VEGFR2 to investigate whether it was effectively repressed or activated with rhVEGF or apatinib treatment. Then, MTT, wound healing assay, and transwell matrix assay were applied to measure the effect of apatinib and rhVEGF on cell viability, migration and invasion, respectively.. The mRNA and protein expressions of VEGFR2 were significantly reduced with KDR RNAi in both QBC939 and TFK-1 cells, and rhVEGF treatment increased these expression levels (p < 0.05). Apatinib dramatically suppressed VEGF-mediated cell migration and invasion at the concentration of 100 nM treatment and significantly decreased the expression of metastasis-associated protein such as Slug, snail and MMP9. Moreover, all of these inhibiting effects of apatinib depended on the VEGFR2 existence. In addition, VEGFR2/RAF/MEK/ERK and PI3K/AKT signal pathways were enhanced by the introduction of rhVEGF, but were dramatically suppressed after the apatinib treatment.. Apatinib inhibit VEGF-mediated cell migration and invasion in CCA cell lines via inhibiting the VEGFR2/RAF/MEK/ERK and PI3K/AKT pathways. It will be a potentially effective targeted drug for CCA.

Topics: Antineoplastic Agents; Bile Duct Neoplasms; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cholangiocarcinoma; Humans; MAP Kinase Signaling System; Neoplasm Invasiveness; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-akt; Pyridines; raf Kinases; Vascular Endothelial Growth Factor Receptor-2

Tumor cells co-express vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) that interact each other to support a self-sustainable cell growth. So far, this autocrine VEGF loop is not reported in human intrahepatic cholangiocarcinoma (ICC). Apatinib is a highly selective VEGFR2 inhibitor, but its effects on ICC have not been investigated. In this study, we reported that VEGF and phosphorylated VEGFR2 were expressed at a significantly high level in ICC patient tissues (P<0.05). In vitro, treating ICC cell lines RBE and SSP25 with recombinant human VEGF (rhVEGF) induced phosphorylation of VEGFR1 (pVEGFR1) and VEGFR2 (pVEGFR2); however, only the VEGFR2 played a role in the anti-apoptotic cell growth through activating a PI3K-AKT-mTOR anti-apoptotic signaling pathway which generated more VEGF to enter this autocrine loop. Apatinib inhibited the anti-apoptosis induced by VEGF signaling, and promoted cell death in vitro. In addition, Apatinib treatment delayed xenograft tumor growth in vivo. In conclusion, the autocrine VEGF/VEGFR2 signaling promotes ICC cell survival. Apatinib inhibits anti-apoptotic cell growth through suppressing the autocrine VEGF signaling, supporting a potential role for using Apatinib in the treatment of ICC.

Topics: Animals; Antineoplastic Agents; Apoptosis; Bile Duct Neoplasms; Cholangiocarcinoma; Humans; Mice; Mice, Inbred NOD; Mice, SCID; Pyridines; Signal Transduction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays