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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 -
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 -
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 -
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 -
British Journal of Cancer Jun 2011The objectives of this phase I study were to determine the safety, pharmacokinetics (PK), pharmacodynamics and efficacy of brivanib combined with full-dose cetuximab in...
Phase I dose-escalation study to determine the safety, pharmacokinetics and pharmacodynamics of brivanib alaninate in combination with full-dose cetuximab in patients with advanced gastrointestinal malignancies who have failed prior therapy.
BACKGROUND
The objectives of this phase I study were to determine the safety, pharmacokinetics (PK), pharmacodynamics and efficacy of brivanib combined with full-dose cetuximab in patients with advanced gastrointestinal malignancies.
METHODS
Patients with advanced gastrointestinal malignancies who had failed prior therapies received brivanib (320, 600 or 800 mg daily) plus cetuximab (400 mg m(-2) loading dose then 250 mg m(-2) weekly). Assessments included adverse events, PK, tumour response, 2[18F]fluoro-2-deoxyglucose positron-emitting tomography and K-Ras mutation analyses.
RESULTS
Toxicities observed were manageable; the most common treatment-related toxicities (>10% of patients) were fatigue, diarrhoea, anorexia, increase in aspartate aminotransferase and alanine aminotransferase, acneiform dermatitis, headache, mucosal inflammation, nausea, dry skin, vomiting, hypertension, pruritus, proteinuria and weight loss. Of 62 patients, 6 (9.7%) had objective radiographic partial responses, with an overall response rate of 10%. Median duration of response was 9.2 months; median progression-free survival was 3.9 months.
CONCLUSIONS
The acceptable toxicity profile and efficacy of brivanib observed in this study were promising. These findings are being further evaluated in a phase III study of brivanib plus cetuximab vs cetuximab alone in patients previously treated with combination chemotherapy for K-Ras wild-type advanced metastatic colorectal cancer.
Topics: Adult; Aged; Alanine; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cetuximab; Drug Therapy, Combination; Female; Gastrointestinal Neoplasms; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Salvage Therapy; Survival Rate; Tissue Distribution; Treatment Outcome; Triazines; Vascular Endothelial Growth Factor Receptor-2
PubMed: 21629245
DOI: 10.1038/bjc.2011.182 -
Clinical Cancer Research : An Official... Aug 2011Preclinical trials of a mouse model of pancreatic neuroendocrine tumors (PNET) were conducted to determine whether dual FGF/VEGF pathway inhibition with brivanib can...
Brivanib, a dual FGF/VEGF inhibitor, is active both first and second line against mouse pancreatic neuroendocrine tumors developing adaptive/evasive resistance to VEGF inhibition.
PURPOSE
Preclinical trials of a mouse model of pancreatic neuroendocrine tumors (PNET) were conducted to determine whether dual FGF/VEGF pathway inhibition with brivanib can improve first-line efficacy in comparison with VEGF inhibitors lacking fibroblast growth factor (FGF)-inhibitory activity and to characterize second-line brivanib activity before and after the onset of evasive resistance to VEGF-selective therapy.
EXPERIMENTAL DESIGN
An anti-VEGFR2 monoclonal antibody (DC101), an inhibitor of FGF signaling (FGF ligand trap), sorafenib, and brivanib were comparatively evaluated in first-line monotherapy in short and longer term fixed endpoint intervention trials in the RIP-Tag2 mouse model of PNET. Brivanib was also tested second line aiming to block adaptive resistance to selective VEGF therapies, assessing tumor growth, vascularity, hypoxia, invasion, and metastasis. The effects of initiating second-line brivanib therapy prior to or following overt relapse on sorafenib therapy were compared in overall survival trials to first-line therapies.
RESULTS
Brivanib produced enduring tumor stasis and angiogenic blockade, both first and second line following the failure of DC101 or sorafenib. Overall survival was significantly extended by brivanib versus sorafenib, both first-line and when second-line therapy was initiated prior to sorafenib failure; second-line brivanib was less beneficial when initiated later, after the initiation of revascularization and incipient tumor progression.
CONCLUSIONS
Brivanib holds promise and deserves consideration for clinical evaluation as an antiangiogenic therapy, both in the context of impending failures of VEGF-selective therapy and in a first-line setting aiming to limit the adaptive response to VEGF inhibitors that results in evasive resistance.
Topics: Alanine; Animals; Antibodies, Monoclonal; Antineoplastic Combined Chemotherapy Protocols; Benzenesulfonates; Blotting, Western; Drug Resistance, Neoplasm; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Mice; Mice, Knockout; Mice, Transgenic; Neuroendocrine Tumors; Niacinamide; Pancreatic Neoplasms; Phenylurea Compounds; Protein Kinase Inhibitors; Pyridines; Receptors, Fibroblast Growth Factor; Sorafenib; Treatment Outcome; Triazines; Tumor Burden; Vascular Endothelial Growth Factor Receptor-2
PubMed: 21622725
DOI: 10.1158/1078-0432.CCR-10-2847 -
Drug Metabolism and Disposition: the... Nov 2010The goal of this study was to evaluate the pharmacokinetics, mass balance, metabolism, routes and extent of elimination, and safety of a single oral dose of... (Clinical Trial)
Clinical Trial
The goal of this study was to evaluate the pharmacokinetics, mass balance, metabolism, routes and extent of elimination, and safety of a single oral dose of (14)C-labeled brivanib alaninate and the safety and tolerability of brivanib after multiple doses in patients with advanced or metastatic solid tumors. This was a two-part, single-center, open-label, single oral-dose (part A) followed by multiple-dose (part B) study in patients with advanced or metastatic solid tumors. In part A, patients received a single dose of [(14)C]brivanib alaninate and in part B patients received 800 mg of nonradiolabeled brivanib alaninate every day. Four patients (two white, two black: two with non-small-cell lung cancer, one with ovarian cancer, and one with renal cell carcinoma) were treated in both parts. The median time to reach the maximal plasma concentration of brivanib was 1 h, geometric mean maximal plasma concentration was 6146 ng/ml, mean terminal half-life was 13.8 h, and geometric mean apparent oral clearance was 14.7 l/h. After a single oral dose of [(14)C]brivanib alaninate, 12.2 and 81.5% of administered radioactivity was recovered in urine and feces, respectively. Brivanib alaninate was completely converted to the active moiety, brivanib, and the predominant route of elimination was fecal. Renal excretion of unchanged brivanib was minimal. Brivanib was well tolerated; fatigue was the most frequent adverse event occurring in all patients and the most frequent treatment-related adverse event in three (75%). The best clinical response in one patient was stable disease; the other three had progressive disease. Brivanib alaninate was rapidly absorbed and extensively metabolized after a single 800-mg oral dose; the majority of drug-related radioactivity was excreted in feces.
Topics: Administration, Oral; Aged; Alanine; Antineoplastic Agents; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Feces; Female; Humans; Male; Metabolic Clearance Rate; Middle Aged; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Pyrroles; Triazines
PubMed: 20671097
DOI: 10.1124/dmd.110.033951 -
PloS One 2014Brivanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR) tyrosine kinases, which are both...
BACKGROUND AND AIMS
Brivanib is a selective inhibitor of vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR) tyrosine kinases, which are both involved in mechanisms of liver fibrosis. We hypothesized that inhibition of VEGFR and FGFR by brivanib would inhibit liver fibrosis. We therefore examined the effect of brivanib on liver fibrosis in three mouse models of fibrosis.
METHODS
In vivo, we induced liver fibrosis by bile duct ligation (BDL), chronic carbon tetrachloride (CCl4), and chronic thioacetamide (TAA) administration. Liver fibrosis was examined by immunohistochemistry and Western immunoblotting. In vitro, we used LX-2 human hepatic stellate cells (HSCs) to assess the effect of brivanib on stellate cell proliferation and activation.
RESULTS
After in vivo induction with BDL, CCl4, and TAA, mice treated with brivanib showed reduced liver fibrosis and decreased expression of collagen Iα1 and α-smooth muscle actin in the liver. In vitro, brivanib decreased proliferation of HSCs induced by platelet-derived growth factor (PDGF), VEGF, and FGF. Brivanib also decreased stellate cell viability and inhibited PDGFBB-induced phosphorylation of its cognate receptor.
CONCLUSION
Brivanib reduces liver fibrosis in three different animal models and decreases human hepatic stellate cell activation. Brivanib may represent a novel therapeutic approach to treatment of liver fibrosis and prevention of liver cancer.
Topics: Alanine; Animals; Carbon Tetrachloride Poisoning; Cell Line; Cell Proliferation; Cell Survival; Collagen Type I; Collagen Type I, alpha 1 Chain; Fibroblast Growth Factors; Hepatic Stellate Cells; Humans; Immunohistochemistry; Liver Cirrhosis; Liver Neoplasms; Mice; Platelet-Derived Growth Factor; Protein Kinase Inhibitors; Signal Transduction; Triazines; Vascular Endothelial Growth Factor A
PubMed: 24710173
DOI: 10.1371/journal.pone.0092273 -
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 -
Gastroenterology May 2011Unlike most solid tumors, the incidence and mortality of hepatocellular carcinoma (HCC) have increased in the United States and Europe in the past decade. Most patients... (Review)
Review
Unlike most solid tumors, the incidence and mortality of hepatocellular carcinoma (HCC) have increased in the United States and Europe in the past decade. Most patients are diagnosed at advanced stages, so there is an urgent need for new systemic therapies. Sorafenib, a tyrosine kinase inhibitor (TKI), has shown clinical efficacy in patients with HCC. Studies in patients with lung, breast, or colorectal cancers have indicated that the genetic heterogeneity of cancer cells within a tumor affect its response to therapeutics designed to target specific molecules. When tumor progression requires alterations in specific oncogenes (oncogene addiction), drugs that selectively block their products might slow tumor growth. However, no specific oncogene addictions are yet known to be implicated in HCC progression, so it is important to improve our understanding of its molecular pathogenesis. There are currently many clinical trials evaluating TKIs for HCC, including those tested in combination with (eg, erlotinib) or compared with (eg, linifanib) sorafenib as a first-line therapy. For patients who do not respond or are intolerant to sorafenib, TKIs such as brivanib, everolimus, and monoclonal antibodies (eg, ramucirumab) are being tested as second-line therapies. There are early stage trials investigating the efficacy for up to 60 reagents for HCC. Together, these studies might change the management strategy for HCC, and combination therapies might be developed for patients with advanced HCC. Identification of oncogenes that mediate tumor progression, and trials that monitor their products as biomarkers, might lead to personalized therapy; reagents that interfere with signaling pathways required for HCC progression might be used to treat selected populations, and thereby maximize the efficacy and cost benefit.
Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Neovascularization, Pathologic; Treatment Outcome
PubMed: 21406195
DOI: 10.1053/j.gastro.2011.03.006