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Journal of Gastrointestinal Cancer Jun 2018To date, sorafenib, a multiple tyrosine kinase inhibitor, is the only systemic agent approved by the FDA in the first-line treatment of patients with unresectable... (Review)
Review
To date, sorafenib, a multiple tyrosine kinase inhibitor, is the only systemic agent approved by the FDA in the first-line treatment of patients with unresectable hepatocellular carcinoma (HCC). Several other tyrosine kinase-inhibiting agents have been investigated in the first-line setting, either alone (sunitinib, brivanib, linifanib, and lenvatinib) or in combination with sorafenib (erlotinib and doxorubicin) in phase 3 trials. However, none of these studies demonstrated an improvement in survival over sorafenib. Many agents have also been tested in patients with HCC whose disease has progressed on sorafenib, but regorafenib is the only one to have demonstrated efficacy in this setting in a randomized, phase 3 trial. There were no clear survival benefits shown with everolimus, brivanib, or ramucirumab as second-line therapy. Nivolumab has also shown promising efficacy in patients with HCC who progressed on sorafenib, which was recently granted approval by the FDA, although larger confirmative trials may be considered. The treatment landscape for patients with advanced unresectable hepatocellular tumors has remained fairly static for the past 10 years, with multiple failed trials yield little change in the way these patients might be treated. However, recent findings for regorafenib, lenvatinib, and nivolumab have led to the most significant changes in the treatment paradigm in years.
Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Treatment Outcome
PubMed: 29453759
DOI: 10.1007/s12029-018-0065-8 -
Pharmaceuticals (Basel, Switzerland) Sep 2021Non-alcoholic fatty liver disease is the most common liver disorder worldwide, and its progressive form non-alcoholic steatohepatitis (NASH) is a growing cause of liver... (Review)
Review
Non-alcoholic fatty liver disease is the most common liver disorder worldwide, and its progressive form non-alcoholic steatohepatitis (NASH) is a growing cause of liver cirrhosis and hepatocellular carcinoma (HCC). Lifestyle changes, which are capable of improving the prognosis, are hard to achieve, whereas a pharmacologic therapy able to combine efficacy and safety is still lacking. Looking at the pathophysiology of various liver diseases, such as NASH, fibrosis, cirrhosis, and HCC, the process of angiogenesis is a key mechanism influencing the disease progression. The relationship between the worsening of chronic liver disease and angiogenesis may suggest a possible use of drugs with antiangiogenic activity as a tool to stop or slow the progression of the disorder. In this review, we highlight the available preclinical data supporting a role of known antiangiogenic drugs (e.g., sorafenib), or phytotherapeutic compounds with multiple mechanism of actions, including also antiangiogenic activities (e.g., berberine), in the treatment of NASH.
PubMed: 34681219
DOI: 10.3390/ph14100995 -
Digestive Diseases (Basel, Switzerland) 2011Hepatocellular carcinoma (HCC), one of the most common cancers worldwide, is particularly prevalent in the Asia-Pacific region. Guidelines on the treatment of HCC in... (Review)
Review
Hepatocellular carcinoma (HCC), one of the most common cancers worldwide, is particularly prevalent in the Asia-Pacific region. Guidelines on the treatment of HCC in Japan come from both consensus-based and evidence-based treatment algorithms. However, patients with extensive liver damage and/or more advanced disease (major vascular invasion and/or extrahepatic spread) are currently ineligible for any treatment. Recent knowledge of hepatocarcinogenesis has led to the targeting of new pathways, particularly the angiogenic pathway, with a specific focus on the vascular endothelial growth factor receptor (VEGFR). Apparently the most studied systemic antiangiogenic agent for HCC is sorafenib. An updated version of the aforementioned treatment algorithms recommends sorafenib therapy for advanced HCC patients with Child-Pugh A liver function and extrahepatic spread or major vascular invasion. Moreover, sorafenib is recommended for use in HCC patients who are refractory or intolerant to transarterial chemoembolization (TACE) with well-preserved liver function (Child-Pugh A). However, one of the unresolved issues is anti-VEGF resistance. It is speculated that novel antiangiogenic agents that combine inhibition of other pathways such as fibroblast growth factor receptor signaling in addition to VEGFR signaling might provide a potential mechanism to overcome anti-VEGF resistance in HCC. Brivanib inhibits both VEGF and fibroblast growth factor receptor signaling. To further investigate the benefits of brivanib for advanced HCC, a broad-spectrum, global, phase III development plan, the Brivanib studies in HCC patients at RISK (BRISK) clinical program, has been initiated. Clinical benefits seen with brivanib in the first-line setting, and following the failure of sorafenib therapy, highlight the potential to improve the clinical course of patients with advanced HCC, and this agent may provide a novel therapeutic option for the growing population of patients for whom no other treatment choice exists.
Topics: Alanine; Carcinoma, Hepatocellular; Clinical Trials as Topic; Humans; Liver Neoplasms; Molecular Targeted Therapy; Triazines; Vascular Endothelial Growth Factor A
PubMed: 21829023
DOI: 10.1159/000327568 -
Liver Cancer Oct 2014Assessing treatment responses in hepatocellular carcinoma (HCC) is challenging, and alternative radiologic methods of measuring treatment response are required. Modified... (Review)
Review
BACKGROUND AND AIMS
Assessing treatment responses in hepatocellular carcinoma (HCC) is challenging, and alternative radiologic methods of measuring treatment response are required. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for HCC and alpha-fetoprotein (AFP) levels were assessed in a post hoc analysis of a phase II study of brivanib, a selective dual inhibitor of fibroblast growth factor and vascular endothelial growth factor signaling.
METHODS
HCC patients were treated with first-line (cohort A; n = 55) or second-line (cohort B; n = 46) brivanib alaninate 800 mg once daily. Outcomes were compared between World Health Organization (WHO) criteria and (retrospectively by) mRECIST by independent review. The relationship between on-study AFP changes and outcome was analyzed in patients with elevated AFP at baseline.
RESULTS
Response rates were higher with mRECIST versus WHO criteria in cohorts A (25.5% vs. 7.3%) and B (10.9% vs. 4.3%). Progressive disease (PD) as assessed by mRECIST was associated with a very short median overall survival (OS; cohort A, 2.8 months; cohort B, 5.3 months); PD as assessed by WHO criteria reflected a mixed population of patients with better outcomes. mRECIST responders tended to have a>50% AFP decrease during therapy. In cohorts A and B pooled, an early AFP response (>20%or >50% decline from baseline within the first 4 weeks) was not associated with longer median OS.
CONCLUSIONS
Tumor response as assessed by mRECIST differed from that by WHO criteria, with mRECIST possibly identifying true nonresponders with a poor prognosis. Many patients had AFP decreases correlating with tumor shrinkage, yet an association with long-term benefit was unclear. mRECIST and on-treatment AFP levels are being explored further with brivanib in HCC.
PubMed: 26280005
DOI: 10.1159/000343872 -
Medicine Mar 2019Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related death worldwide. Its poor prognosis is due to the high invasiveness of the disease...
RATIONALE
Hepatocellular carcinoma (HCC) is one of the most frequent causes of cancer-related death worldwide. Its poor prognosis is due to the high invasiveness of the disease and limited efficacy of available treatments.
PATIENT CONCERNS
We reported an HCC patient who developed lung metastases 1 year after HCC resection. Sorafenib was then initiated; however, disease progression was noted 3 months later. Sorafenib therapy was initially maintained due to lack of effective alternatives, but disease progression continued.
DIAGNOSES
HCC patient with lung metastases, and pulmonary portal, and mediastinal lymph node metastases (stage IVB).
INTERVENTIONS
Brivanib alaninate was used alone as second-line therapy.
OUTCOMES
All metastases showed increased size on radiographic imaging approximately 3 months after brivanib alaninate was initiated. However, 2.5 months later, the lung metastases significantly decreased in size or disappeared. The pulmonary portal, and mediastinal lymph node metastases also significantly decreased in size. At 9.5 months after brivanib alaninate initiation, the pulmonary portal, and mediastinal lymph node metastases nearly disappeared, and the lung metastases continued to decrease in size. Alpha fetoprotein (AFP) level showed the same change pattern as the tumor-response observed on radiographic imaging. The total duration of brivanib alaninate treatment was 11 months, which was stopped due to repeated grade 2 thrombocytopenia. The other side effects were tolerable. Fifteen months after initiation of brivanib alaninate, the patient remained in very good condition without evidence of disease progression.
LESSONS
Brivanib alaninate alone as second-line therapy showed excellent antitumor efficacy for an HCC patient with numerous lung and lymph node metastases. It may exert its antitumor effects in a delayed-onset fashion. We suggest that patients receive brivanib alaninate for a long duration to fully determine its efficacy.
Topics: Alanine; Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Male; Middle Aged; Retreatment; Sorafenib; Treatment Failure; Triazines
PubMed: 30855507
DOI: 10.1097/MD.0000000000014823 -
World Journal of Gastroenterology Feb 2012Hepatocellular carcinoma (HCC) is a lethal disease in most patients, due to its aggressive course and a lack of effective systemic therapies for advanced disease.... (Review)
Review
Hepatocellular carcinoma (HCC) is a lethal disease in most patients, due to its aggressive course and a lack of effective systemic therapies for advanced disease. Surgical resection and liver transplantation remain the only curative options for a small subset of patients. Few patients with HCC are diagnosed early enough to be eligible for curative treatment. Angiogenesis inhibition is a natural therapeutic target for all solid tumors, but particularly for the highly vascularized HCC tumors. With the approval of the targeted agent sorafenib, there are now additional options for patients with HCC. Although sorafenib does produce some improvement in survival in HCC patients, the responses are not durable. In addition, there are significant dermatologic, gastrointestinal, and metabolic toxicities, and, as importantly, there is still limited knowledge of its usefulness in special subpopulations with HCC. Other angiogenesis inhibitors are in development to treat HCC both in the first-line setting and for use following sorafenib failure; the furthest in development is brivanib, a dual fibroblast growth factor pathway and vascular endothelial growth factor receptor inhibitor. Additional agents with antiangiogenic properties also in phase II and III development for the treatment of patients with HCC include bevacizumab, ramucirumab, ABT-869, everolimus and ARQ 197.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Hepatocellular; Clinical Trials as Topic; Humans; Liver Neoplasms; Neovascularization, Pathologic; Treatment Outcome
PubMed: 22363115
DOI: 10.3748/wjg.v18.i6.498 -
Gynecologic Oncology Oct 2014Brivanib, an oral, multi-targeted tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR)...
PURPOSE
Brivanib, an oral, multi-targeted tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR) was investigated as a single agent in a phase II trial to assess the activity and tolerability in recurrent or persistent endometrial cancer (EMC).
PATIENTS AND METHODS
Eligible patients had persistent or recurrent EMC after receiving one to two prior cytotoxic regimens, measurable disease, and performance status of ≤2. Treatment consisted of brivanib 800 mg orally every day until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) at six months and objective tumor response. Expression of multiple angiogenic proteins and FGFR2 mutation status was assessed.
RESULTS
Forty-five patients were enrolled. Forty-three patients were eligible and evaluable. Median age was 64 years. Twenty-four patients (55.8%) received prior radiation. Median number of cycles was two (range 1-24). No GI perforations but one rectal fistula were seen. Nine patients had grade 3 hypertension, with one experiencing grade 4 confusion. Eight patients (18.6%; 90% CI 9.6%-31.7%) had responses (one CR and seven PRs), and 13 patients (30.2%; 90% CI 18.9%-43.9%) were PFS at six months. Median PFS and overall survival (OS) were 3.3 and 10.7 months, respectively. When modeled jointly, VEGF and angiopoietin-2 expression may diametrically predict PFS. Estrogen receptor-α (ER) expression was positively correlated with OS.
CONCLUSION
Brivanib is reasonably well tolerated and worthy of further investigation based on PFS at six months in recurrent or persistent EMC.
Topics: Adult; Aged; Aged, 80 and over; Alanine; Disease-Free Survival; Endometrial Neoplasms; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Receptor, Fibroblast Growth Factor, Type 2; Triazines; Vascular Endothelial Growth Factor A
PubMed: 25019571
DOI: 10.1016/j.ygyno.2014.07.083 -
British Journal of Cancer Mar 2019Sorafenib is the first targeted agent proven to improve survival of patients with advanced hepatocellular carcinoma (HCC) and it has been used in first line treatments...
BACKGROUND
Sorafenib is the first targeted agent proven to improve survival of patients with advanced hepatocellular carcinoma (HCC) and it has been used in first line treatments with heterogeneous response across patients. Most of the promising agents evaluated in first-line or second-line phase III trials for HCC failed to improve patient survival. The absence of molecular characterisation, including the identification of pathways driving resistance might be responsible for these disappointing results.
METHODS
2D DIGE and MS analyses were used to reveal proteomic signatures resulting from Notch3 inhibition in HepG2 cells, combined with brivanib treatment. The therapeutic potential of Notch3 inhibition combined with brivanib treatment was also demonstrated in a rat model of HCC and in cell lines derived from different human cancers.
RESULTS
Using a proteomic approach, we have shown that Notch3 is strongly involved in brivanib resistance through a p53-dependent regulation of enzymes of the tricarboxylic acid (TCA), both in vitro and in vivo.
CONCLUSION
We have demonstrated that regulation of the TCA cycle is a common mechanism in different human cancers, suggesting that Notch3 inhibitors combined with brivanib treatment may represent a strong formulation for the treatment of HCC as well as Notch3-driven cancers.
Topics: Alanine; Animals; Carcinoma, Hepatocellular; Cell Line, Tumor; Drug Resistance, Neoplasm; Electrophoresis, Polyacrylamide Gel; Gene Knockdown Techniques; Hep G2 Cells; Humans; Liver Neoplasms; Liver Neoplasms, Experimental; MCF-7 Cells; Molecular Targeted Therapy; Proteomics; RNA, Small Interfering; Rats; Rats, Wistar; Receptor, Notch3; Triazines; Two-Dimensional Difference Gel Electrophoresis
PubMed: 30765875
DOI: 10.1038/s41416-018-0375-4 -
PloS One 2016Hyponatraemia has been reported with targeted therapies in cancer patients. Aim of the study was to perform an up-to-date meta-analysis in order to determine the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hyponatraemia has been reported with targeted therapies in cancer patients. Aim of the study was to perform an up-to-date meta-analysis in order to determine the incidence and relative risk (RR) in cancer patients treated with these agents.
MATERIALS AND METHODS
The scientific literature regarding hyponatraemia was extensively reviewed using MEDLINE, PubMed, Embase and Cochrane databases. Eligible studies were selected according to PRISMA statement. Summary incidence, RR, and 95% Confidence Intervals were calculated using random-effects or fixed-effects models based on the heterogeneity of selected studies.
RESULTS
4803 potentially relevant trials were identified: of them, 13 randomized phase III studies were included in this meta-analysis. 6670 patients treated with 8 targeted agents were included: 2574 patients had hepatocellular carcinoma, whilst 4096 had other malignancies. The highest incidences of all-grade hyponatraemia were observed with the combination of brivanib and cetuximab (63.4) and pazopanib (31.7), while the lowest incidence was reported by afatinib (1.7). The highest incidence of high-grade hyponatraemia was reported by cetuximab (34.8), while the lowest incidences were reported by gefitinib (1.0). Summary RR of developing all-grade and high-grade hyponatraemia with targeted agents was 1.36 and 1.52, respectively. The highest RRs of all-grade and high-grade hyponatraemia were associated with brivanib (6.5 and 5.2, respectively). Grouping by drug category, the RR of high-grade hyponatraemia with angiogenesis inhibitors was 2.69 compared to anti-Epidermal Growth Factor Receptors agents (1.12).
CONCLUSION
Treatment with biological therapy in cancer patients is associated with a significant increased risk of hyponatraemia, therefore frequent clinical monitoring should be emphasized when managing targeted agents.
Topics: Clinical Trials, Phase III as Topic; Humans; Hyponatremia; Incidence; Neoplasms; Randomized Controlled Trials as Topic; Risk Factors
PubMed: 27167519
DOI: 10.1371/journal.pone.0152079 -
Frontiers in Bioengineering and... 2022Vascular-disrupting agents are an interesting class of anticancer compounds because of their combined mode of action in preventing new blood vessel formation and...
Vascular-disrupting agents are an interesting class of anticancer compounds because of their combined mode of action in preventing new blood vessel formation and disruption of already existing vasculature in the immediate microenvironment of solid tumors. The validation of vascular disruption properties of these drugs is rarely addressed due to the lack of proper angiogenesis models comprising mature and long-lived vascular-like networks. We herein report an indirect coculture model of human umbilical vein endothelial cells (HUVECs) and human dermal fibroblasts (HDFs) to form three-dimensional profuse vascular-like networks. HUVECs embedded and sandwiched in the collagen scaffold were cocultured with HDFs located outside the scaffold. The indirect coculture approach with the vascular endothelial growth factor (VEGF) producing HDFs triggered the formation of progressively maturing lumenized vascular-like networks of endothelial cells within less than 7 days, which have proven to be viably maintained in culture beyond day 21. Molecular weight-dependent Texas red-dextran permeability studies indicated high vascular barrier function of the generated networks. Their longevity allowed us to study the dose-dependent response upon treatment with the three known antiangiogenic and/or vascular disrupting agents brivanib, combretastatin A4 phosphate (CA4P), and 6´-sialylgalactose (SG) semi-quantitative brightfield and qualitative confocal laser scanning microscopic (CLSM) image analysis. Compared to the reported data on efficacy of these drugs in terms of antiangiogenic and vascular disrupting effects, we observed similar trends with our 3D model, which are not reflected in conventional angiogenesis assays. High-vascular disruption under continuous treatment of the matured vascular-like network was observed at concentrations ≥3.5 ng·ml for CA4P and ≥300 nM for brivanib. In contrast, SG failed to induce any significant vascular disruption . This advanced model of a 3D vascular-like network allows for testing single and combinational antiangiogenic and vascular disrupting effects with optimized dosing and may thus bridge the gap between the and experiments in validating hits from high-throughput screening. Moreover, the physiological 3D environment mimicking assay is not only highly relevant to studies linked to cancer but also to the field of tissue regeneration.
PubMed: 35769106
DOI: 10.3389/fbioe.2022.888492