-
Pharmacological boosting of cGAS activation sensitizes chemotherapy by enhancing antitumor immunity.Cell Reports Mar 2023Enhancing chemosensitivity is one of the largest unmet medical needs in cancer therapy. Cyclic GMP-AMP synthase (cGAS) connects genome instability caused by...
Enhancing chemosensitivity is one of the largest unmet medical needs in cancer therapy. Cyclic GMP-AMP synthase (cGAS) connects genome instability caused by platinum-based chemotherapeutics to type I interferon (IFN) response. Here, by using a high-throughput small-molecule microarray-based screening of cGAS interacting compounds, we identify brivanib, known as a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor, as a cGAS modulator. Brivanib markedly enhances cGAS-mediated type I IFN response in tumor cells treated with platinum. Mechanistically, brivanib directly targets cGAS and enhances its DNA binding affinity. Importantly, brivanib synergizes with cisplatin in tumor control by boosting CD8 T cell response in a tumor-intrinsic cGAS-dependent manner, which is further validated by a patient-derived tumor-like cell clusters model. Taken together, our findings identify cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment.
Topics: Humans; High-Throughput Screening Assays; Triazines; Alanine; Nucleotidyltransferases; Interferons; Cisplatin; Antineoplastic Agents; CD8-Positive T-Lymphocytes; Tumor Cells, Cultured; Neoplasms
PubMed: 36943864
DOI: 10.1016/j.celrep.2023.112275 -
European Journal of Cancer (Oxford,... Oct 2019Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Brivanib is a selective inhibitor of vascular endothelial growth factor and fibroblast growth factor (FGF) signalling. We performed a phase II randomised discontinuation trial of brivanib in 7 tumour types (soft-tissue sarcomas [STS], ovarian cancer, breast cancer, pancreatic cancer, non-small-cell lung cancer [NSCLC], gastric/esophageal cancer and transitional cell carcinoma [TCC]).
PATIENTS AND METHODS
During a 12-week open-label lead-in period, patients received brivanib 800 mg daily and were evaluated for FGF2 status by immunohistochemistry. Patients with stable disease at week 12 were randomised to brivanib or placebo. A study steering committee evaluated week 12 response to determine if enrolment in a tumour type would continue. The primary objective was progression-free survival (PFS) for brivanib versus placebo in patients with FGF2-positive tumours.
RESULTS
A total of 595 patients were treated, and stable disease was observed at the week 12 randomisation point in all tumour types. Closure decisions were made for breast cancer, pancreatic cancer, NSCLC, gastric cancer and TCC. Criteria for expansion were met for STS and ovarian cancer. In 53 randomised patients with STS and FGF2-positive tumours, the median PFS was 2.8 months for brivanib and 1.4 months for placebo (hazard ratio [HR]: 0.58, p = 0.08). For all randomised patients with sarcomas, the median PFS was 2.8 months (95% confidence interval [CI]: 1.4-4.0) for those treated with brivanib compared with 1.4 months (95% CI: 1.3-1.6) for placebo (HR = 0.64, 95% CI: 0.38-1.07; p = 0.09). In the 36 randomised patients with ovarian cancer and FGF2-positive tumours, the median PFS was 4.0 (95% CI: 2.6-4.2) months for brivanib and 2.0 months (95% CI: 1.2-2.7) for placebo (HR: 0.56, 95% CI: 0.26-1.22). For all randomised patients with ovarian cancer, the median PFS in those randomised to brivanib was 4.0 months (95% CI: 2.6-4.2) and was 2.0 months (95% CI: 1.2-2.7) in those randomised to placebo (HR = 0.54, 95% CI: 0.25-1.17; p = 0.11).
CONCLUSION
Brivanib demonstrated activity in STS and ovarian cancer with an acceptable safety profile. FGF2 expression, as defined in the protocol, is not a predictive biomarker of the efficacy of brivanib.
Topics: Aged; Alanine; Antineoplastic Agents; Biomarkers, Tumor; Female; Follow-Up Studies; Humans; Male; Middle Aged; Neoplasms; Prognosis; Survival Rate; Triazines; Withholding Treatment
PubMed: 31522033
DOI: 10.1016/j.ejca.2019.07.024 -
PloS One 2023Oral multikinase inhibitors and immune checkpoint inhibitors (ICIs) are effective for treating advanced hepatocellular carcinoma (aHCC) but may increase cost. This study...
BACKGROUND
Oral multikinase inhibitors and immune checkpoint inhibitors (ICIs) are effective for treating advanced hepatocellular carcinoma (aHCC) but may increase cost. This study compared the cost-effectiveness of oral multikinase inhibitors and ICIs in the first-line treatment of patients with aHCC.
METHODS
A three-state Markov model was established to study the cost-effectiveness of drug treatment from the perspective of Chinese payers. The key outcomes in this study were total cost, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER).
RESULTS
The total costs and QALYs of sorafenib, sunitinib, donafenib, lenvatinib, sorafenib plus erlotinib, linifanib, brivanib, sintilimab plus IBI305, and atezolizumab plus bevacizumab were $9070 and 0.25, $9362 and 0.78, $33,814 and 0.45, $49,120 and 0.83, $63,064 and 0.81, $74,814 and 0.82, $81,995 and 0.82, $74083 and 0.85, and $104,188 and 0.84, respectively. The drug regimen with the lowest ICER was sunitinib ($551 per QALY), followed by lenvatinib ($68,869 per QALY). For oral multikinase inhibitors, the ICER of lenvatinib, sorafenib plus erlotinib, linifanib and brivanib compared with sunitinib was $779576, $1534,347, $1768,971, and $1963,064, respectively. For ICIs, sintilimab plus IBI305 is more cost effective than atezolizumab plus bevacizumab. The model was most sensitive to the price of sorafenib, the utility of PD, and the price of second-line drugs.
CONCLUSION
For oral multikinase inhibitors, the order of possible treatment options is sunitinib > lenvatinib > sorafenib plus erlotinib > linifanib > brivanib > donafenib. For ICIs, the order of possible treatment options is sintilimab plus IBI305 > atezolizumab plus bevacizumab.
Topics: Humans; Carcinoma, Hepatocellular; Sorafenib; Bevacizumab; Sunitinib; Cost-Effectiveness Analysis; Erlotinib Hydrochloride; Liver Neoplasms; Cost-Benefit Analysis; Quality-Adjusted Life Years
PubMed: 37053300
DOI: 10.1371/journal.pone.0279786 -
Gastrointestinal Tumors Jun 2014Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. The outcome of HCC therapy depends on the stage of HCC. Early-stage HCC... (Review)
Review
BACKGROUND
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. The outcome of HCC therapy depends on the stage of HCC. Early-stage HCC patients can be cured with radical treatment approaches, whereas no standard treatment regimens can be recommended for patients with advanced disease.
SUMMARY
In-depth basic research into the molecular mechanisms of HCC has contributed to the development of novel therapeutic agents. This article reviews several key classes of novel therapeutic agents that are under development, including molecular-targeted therapies, cancer stem cell (CSC)-based therapy and differentiation therapy.
KEY MESSAGE
A greater understanding of the molecular pathogenesis of HCC has contributed to the development of novel therapeutic agents. This article reviews several key classes of novel therapeutic agents that are under development, including molecular-targeted therapies, CSC-based therapy and differentiation therapy.
PRACTICAL IMPLICATIONS
Molecular-targeted therapies based on signaling pathways involved in hepatocarcinogenesis and progression are being evaluated in several clinical trials. There are three main categories of targeted agents: tyrosine kinase inhibitors (TKIs), monoclonal antibodies and enzyme inhibitors. The best-established agent is sorafenib, a non-specific TKI that is accepted as first-line therapy for specific patients. Other similar agents under investigation include erlotinib, linifanib and brivanib. CSC-based therapies are still in the earlier stages of development and include a neutralizing anti-CD44 antibody, small interfering RNA to suppress epithelial cell adhesion molecular levels, a neutralizing anti-CD13 antibody and a CD13 inhibitor. An important point is that CSC-targeted therapy should be combined with conventional therapies to achieve complete tumor regression. Differentiation therapy is defined as a strategy that induces malignant reversion of tumor cells. Hepatocyte nuclear factor 4α or 1α, important transcriptional factors for hepatocyte differentiation and phenotype maintenance, have shown significant antitumor effects by inducing differentiation of both non-CSCs and CSCs in HCC towards a hepatocyte-like phenotype.
PubMed: 26675991
DOI: 10.1159/000362579 -
Drug Discoveries & Therapeutics Oct 2015Hepatocellular carcinoma (HCC) is a common cancer with high incidence and mortality worldwide. The main treatments for HCC include radical hepatectomy, liver transplant,... (Review)
Review
Hepatocellular carcinoma (HCC) is a common cancer with high incidence and mortality worldwide. The main treatments for HCC include radical hepatectomy, liver transplant, locoregional therapies, and systemic therapies. Systemic treatments include targeted agent treatment, chemotherapies, antiviral therapies, and nutritional treatments. According to the results of SHARP and ORIENTAL study, sorafenib became the standard first-line therapy since 2008 because of nearly three months of survival improvement in patients with advanced HCC. Subsequent studies on targeted agents found that neither sunitinib nor brivanib were superior to sorafenib as first-line therapy. After progression or intolerance of sorafenib, brivanib did not improve the overall survival (OS) compared with placebo as second-line therapy. Randomized controlled EACH study and retrospective AGEO study for systemic chemotherapy showed that oxaliplatin-based or gemcitabine-based regimen was effective for advanced HCC patients. Randomized controlled trial for adjuvant chemotherapy in China showed that capecitabine could reduce the risk of recurrence and improve postoperative survival of HCC. Comparing sorafenib with other treatments, several retrospective studies found that other treatments were not inferior to sorafenib in terms of OS. In the systemic treatment of HCC, antiviral treatment can decrease the recurrence of HBV-related HCC postoperation and prolong the survival of patients. Based on the etiology, symptoms, complications, and treatment-related side effects, nutritional treatment is also very important for HCC patients. Systemic chemotherapy, newer targeted agents, and immune therapy are the new directions in future research.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Antiviral Agents; Carcinoma, Hepatocellular; Disease Progression; Disease-Free Survival; Humans; Liver Neoplasms; Molecular Targeted Therapy; Nutritional Support; Risk Factors; Treatment Outcome
PubMed: 26632544
DOI: 10.5582/ddt.2015.01047 -
Chinese Clinical Oncology Feb 2021Therapeutic options for advanced, unresectable hepatocellular carcinoma (HCC) have changed dramatically over the last 3 years. While surgical resection, orthotropic...
Therapeutic options for advanced, unresectable hepatocellular carcinoma (HCC) have changed dramatically over the last 3 years. While surgical resection, orthotropic liver transplantation, and localized therapeutic options such as ablation, radiation therapy, and embolization remain therapeutics of choice in localized disease, systemic therapy is the only option in advanced, metastatic HCC. Since the United States Food and Drug Administration (US FDA) approval of sorafenib in 2008, targeted therapies such as sunitinib, tivantinib, brivanib, erlotinib, and linifanib; monoclonal antibody- bevacizumab showed no meaningful improvement in treatment of HCC. However, with improved understanding on the molecular pathophysiology and tumor heterogeneity of HCC, we have made progress in expanding the therapeutic options in advanced HCC. Targeted therapy with lenvatinib, cabozantinib, and regorafenib; monoclonal antibody ramucirumab; immunotherapies nivolumab and pembrolizumab have demonstrated promising results in the clinical trials. The current work outlines the molecular mechanisms and tumorigenesis of HCC, a detailed discussion of the trial results of the approved therapies in HCC, future perspectives and potential options to overcome the challenges of systemic therapy in HCC.
Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Immunotherapy; Liver Neoplasms; Sorafenib
PubMed: 32434345
DOI: 10.21037/cco-20-117 -
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 -
Medicine Dec 2016A variety of targeted drug therapies in clinical trials have been proven to be effective for the treatment of hepatocellular carcinoma (HCC). Our study aims to compare... (Comparative Study)
Comparative Study Meta-Analysis Review
Short-term and long-term efficacy of 7 targeted therapies for the treatment of advanced hepatocellular carcinoma: a network meta-analysis: Efficacy of 7 targeted therapies for AHCC.
BACKGROUND
A variety of targeted drug therapies in clinical trials have been proven to be effective for the treatment of hepatocellular carcinoma (HCC). Our study aims to compare the short-term and long-term efficacies of different targeted drugs in advanced hepatocellular carcinoma (AHCC) treatment using a network meta-analysis approach.
METHODS
PubMed, Embase, Ovid, EBSCO, and Cochrane central register of controlled trials were searched for randomized controlled trials (RCTs) of different targeted therapies implemented to patients with AHCC. And the retrieval resulted in 7 targeted drugs, namely, sorafenib, ramucirumab, everolimus, brivanib, tivantinib, sunitinib, and sorafenib+erlotinib. Direct and indirect evidence were combined to evaluate stable disease (SD), progressive disease (PD), complete response (CR), partial response (PR), disease control rate (DCR), overall response ratio (ORR), overall survival (OS), and surface under the cumulative ranking curve (SUCRA) of patients with AHCC.
RESULTS
A total of 11 RCTs were incorporated into our analysis, including 6594 patients with AHCC, among which 1619 patients received placebo treatment and 4975 cases had targeted therapies. The results revealed that in comparison with placebo, sorafenib, and ramucirumab displayed better short-term efficacy in terms of PR and ORR, and brivanib was better in ORR. Regarding long-term efficacy, sorafenib and sorafenib+erlotinib treatments exhibited longer OS. The data of cluster analysis showed that ramucirumab or sorafenib+erlotinib presented relatively better short-term efficacy for the treatment of AHCC.
CONCLUSION
This network meta-analysis shows that ramucirumab and sorafenib+erlotinib may be the better targeted drugs for AHCC patients, and sorafenib+erlotinib achieved a better long-term efficacy.
Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Carcinoma, Hepatocellular; Disease-Free Survival; Erlotinib Hydrochloride; Female; Humans; Liver Neoplasms; Male; Molecular Targeted Therapy; Neoplasm Invasiveness; Neoplasm Staging; Niacinamide; Phenylurea Compounds; Prognosis; Randomized Controlled Trials as Topic; Risk Assessment; Sorafenib; Survival Analysis; Treatment Outcome; Ramucirumab
PubMed: 27930578
DOI: 10.1097/MD.0000000000005591 -
Cancer Medicine Aug 2023Trials of tyrosine kinase inhibitors (TKI) have not demonstrated dramatic benefits in advanced colorectal cancer (CRC), and this may be a function of poor patient... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Trials of tyrosine kinase inhibitors (TKI) have not demonstrated dramatic benefits in advanced colorectal cancer (CRC), and this may be a function of poor patient selection. TKI-induced hypertension is reportedly a surrogate marker for treatment benefit for some tumor types. Our objective was to determine whether hypertension was associated with benefit in the context of CRC treatment, and also to gain insight on the pathogenesis of TKI-induced hypertension by monitoring associated changes in the circulating metabolome.
PATIENTS AND METHODS
Clinical data were acquired from clinical trial patients with metastatic CRC randomized to cetuximab ± the TKI brivanib (N = 750). Outcomes were evaluated as a function of treatment-induced hypertension. For metabolomic studies, plasma samples were taken at baseline, as well as at 1, 4, and 12 weeks after treatment initiation. Samples were submitted to gas chromatography-mass spectrometry to identify treatment-related metabolomic changes associated with TKI-induced hypertension, compared to pre-treatment baseline. A model based on changes in metabolite concentrations was generated using orthogonal partial least squares discriminant analysis (OPLS-DA).
RESULTS
In the brivanib treated group, 95 patients had treatment-related hypertension within 12 weeks of initiating treatment. TKI-induced hypertension was not associated with a significantly higher response rate, nor was it associated with improved progression-free or overall survival. In metabolomic studies, 386 metabolites were identified. There were 29 metabolites that changed with treatment and distinguished patients with and without TKI-induced hypertension. The OPLS-DA model for brivanib-induced hypertension was significant and robust (R Y score = 0.89, Q Y score = 0.70, CV-ANOVA = 2.01 e-7). Notable metabolomic features previously reported in pre-eclampsia and associated with vasoconstriction were found.
CONCLUSION
TKI-induced hypertension was not associated with clinical benefit in metastatic CRC. We have identified changes in the metabolome that are associated with the development of worsening brivanib-induced hypertension that may be useful in future efforts of characterizing this toxicity.
Topics: Humans; Metabolomics; Colorectal Neoplasms; Metabolome; Triazines; Colonic Neoplasms; Rectal Neoplasms
PubMed: 37329221
DOI: 10.1002/cam4.6248 -
Gynecologic Oncology Sep 2017Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy...
BACKGROUND
Brivanib is an oral, tyrosine kinase inhibitor against vascular endothelial growth factor (VEGF) and fibroblast growth factor receptor (FGFR). We studied its efficacy and tolerability in persistent or recurrent cervical cancer patients.
METHODS
Eligible patients had at least one prior cytotoxic regimen for recurrence and with measurable disease. Brivanib 800mg was administered orally every day (1cycle=28days) until disease progression or prohibitive toxicity. Primary endpoints were progression-free survival (PFS) >6months and objective tumor response.
RESULTS
Of 28 eligible and evaluable women enrolled, 11 (39%) had primary surgery and 25 (89%) had prior radiation. Eighteen (64%) received one prior cytotoxic treatment and 10 (36%) had 2 prior regimens. Twelve (43%) had >2cycles of brivanib with 4 (14%) receiving >10cycles (range: 1-20). Seven (25%) patients had PFS >6months (90% CI: 7.3%-33.9%). Two (7%) (90% CI: 1.3%-20.8%) patients had partial tumor response with duration of 8 and 22months and 12 (43%) had stable disease. The median PFS was 3.2months (90% CI: 2.1-4.4). The median overall survival was 7.9months (90% CI: 6.1-11.7). More common grade 3 adverse events were hypertension, anemia, hyponatremia, hyperglycemia, elevated liver enzymes, nausea, headache, and colon hemorrhage. Grade 4 adverse events included sepsis and hypertension.
CONCLUSIONS
Based on early results of this phase II trial, brivanib was well tolerated and demonstrated sufficient activity after first stage but trial was stopped due to lack of drug availability.
Topics: Adult; Aged; Aged, 80 and over; Alanine; Antineoplastic Agents; Carcinoma; Disease Progression; Disease-Free Survival; Early Termination of Clinical Trials; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Response Evaluation Criteria in Solid Tumors; Retreatment; Survival Rate; Triazines; Uterine Cervical Neoplasms
PubMed: 28728751
DOI: 10.1016/j.ygyno.2017.05.033