pazopanib and Lung-Neoplasms

Vascular endothelial growth factor signaling pathway plays a crucial role in angiogenesis and has become a promising target for cancer drug development. We aimed to quantify the overall efficacy and safety of angiogenesis inhibitors in advanced non-small cell lung cancer (NSCLC).. Electronic databases were searched for randomized controlled trials (RCTs) comparing angiogenesis inhibitors with non-angiogenesis inhibitors for NSCLC patients. The extracted data on objective response rates (ORRs), disease control rates (DCRs), progression-free survival (PFS) and overall survival (OS) were pooled. Common adverse events (AEs) were also studied.. A total of 33 RCTs involving 17,396 patients were included. Compared with non-angiogenesis inhibitors, angiogenesis inhibitors resulted in significant improvement in PFS (HR, 0.81; 95 % CI 0.76-0.85; p < 0.001), OS (HR, 0.95; 95 % CI 0.92-0.98; p = 0.004), ORR (RR, 1.54; 95 % CI 1.37-1.73; p < 0.001) and DCR (RR, 1.18; 95 % CI 1.10-1.27; p < 0.001). The AEs associated with angiogenesis inhibitors were generally predictable and manageable.. Angiogenesis inhibitors were superior to non-angiogenesis inhibitors in terms of ORR, DCR, PFS and OS in advanced NSCLC patients. Further studies are warranted to explore the predictive biomarkers to pick up those who may gain utmost benefit from anti-angiogenic therapy.

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Hemorrhage; Humans; Indazoles; Indoles; Lung Neoplasms; Niacinamide; Odds Ratio; Phenylurea Compounds; Piperidines; Pyrimidines; Pyrroles; Quinazolines; Ramucirumab; Randomized Controlled Trials as Topic; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sorafenib; Sulfonamides; Sunitinib; Thrombocytopenia; Treatment Outcome; Vascular Endothelial Growth Factor A

Epithelioid hemangioendothelioma is a rare vascular tumor of borderline or low-grade malignancy. The lungs and liver are the two common primary organs affected. Metastatic disease was reported in more than 100 cases in the literature. However, no firm conclusions can be determined for recommended treatment options.. The current case presents a patient with metastatic pulmonary epithelioid hemangioendothelioma to the cervical and mediastinal lymph nodes, lungs and liver that has been treated with pazopanib for more than two years with PET avid complete metabolic response in the mediastinum and lungs, and long-lasting stable disease. Target therapies that block VEGFR have a logical base in this rare malignancy.. The current case is the first to report objective, long-lasting response to pazopanib.

Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Female; Hemangioendothelioma, Epithelioid; Humans; Immunohistochemistry; Indazoles; Lung Neoplasms; Middle Aged; Neoplasm Metastasis; Positron-Emission Tomography; Protein Kinase Inhibitors; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Tomography, X-Ray Computed; Treatment Outcome

Angiogenesis is essential for tumor growth and metastasis. The main regulators of the process are the signaling cascades of VEGF-, PDGF- and FGF receptors. Inhibition of these pathways holds potential therapeutic benefit not only for cancer patients, but also for the treatment of other diseases. This paper summarizes the experimental and clinical results of studies available so far on the multi-target tyrosine kinase inhibitor nintedanib (BIBF 1120). According to these studies, nintedanib effectively inhibits VEGFR-, PDGFR- and FGFR signalization and thus the proliferation and survival of cell types which highly express these receptors (i.e. endothelial and smooth muscle cells and pericytes). In vitro studies and in vivo xenograft experiments have provided promising results. In the clinical setting, BIBF 1120 seems to be effective and well tolerated in various tumor types, such as lung, prostate, colorectal and hepatocellular carcinoma, as well as in gynecological tumors. The main adverse events are gastrointestinal toxicities and the reversible elevation of liver enzyme levels. Nintedanib might also be combined with paclitaxel, carboplatin, pemetrexed and docetaxel. There are several ongoing clinical trials testing the efficacy of BIBF 1120.

Topics: Animals; Antineoplastic Agents; Axitinib; Benzenesulfonates; Carcinoma, Hepatocellular; Clinical Trials as Topic; Colorectal Neoplasms; Digestive System; Enzyme Inhibitors; Female; Genital Neoplasms, Female; Humans; Imidazoles; Indazoles; Indoles; Liver Neoplasms; Lung Neoplasms; Male; Neoplasms; Niacinamide; Oligonucleotides; Phenylurea Compounds; Phthalazines; Piperidines; Prostatic Neoplasms; Protein-Tyrosine Kinases; Pyridines; Pyrimidines; Quinazolines; Receptors, Fibroblast Growth Factor; Receptors, Platelet-Derived Growth Factor; Receptors, Vascular Endothelial Growth Factor; Signal Transduction; Sorafenib; Sulfonamides; Xenograft Model Antitumor Assays

We investigated whether pazopanib maintenance following first-line chemotherapy would improve survival in patients with extensive disease small-cell lung cancer (ED-SCLC).. This study is a randomised, placebo-controlled, phase II study that enroled ED-SCLC patients who had not progressed after four cycles of etoposide plus platinum therapy. Eligible patients were randomly assigned (1 : 1 ratio) to either placebo or pazopanib 800 mg per day until progression or unacceptable toxicity. The primary end point was progression-free survival (PFS).. 97 patients were enroled and randomly assigned; 2 patients did not receive study drugs. In total, 95 patients received maintenance therapy (pazopanib, n=48; placebo, n=47) and were included in the analyses. Grade 3 toxicities for pazopanib maintenance were thrombocytopenia (10.4%, including one case with grade 4 toxicity), liver enzyme elevation (10.4%), fatigue (6.3%), and hypertension (6.3%). Median PFS was 3.7 months for pazopanib maintenance and 1.8 months for placebo (hazard ratio 0.44, 95% confidence interval: 0.29-0.69, P<0.0001).. Pazopanib maintenance significantly prolonged PFS in patients with ED-SCLC. Given the toxicity profiles, however, relevant biomarkers to select patients for benefit from pazopanib should be further investigated.

Topics: Aged; Aged, 80 and over; Double-Blind Method; Drug Administration Schedule; Etoposide; Female; Humans; Indazoles; Lung Neoplasms; Maintenance Chemotherapy; Male; Middle Aged; Platinum; Progression-Free Survival; Pyrimidines; Small Cell Lung Carcinoma; Sulfonamides; Survival Analysis; Treatment Outcome

This study compared the efficacy and safety of treatment with erlotinib plus pazopanib versus erlotinib plus placebo in patients with previously treated advanced non-small cell lung cancer (NSCLC).. Patients with progressive-stage IV NSCLC after either 1 or 2 previous chemotherapy regimens were randomized to receive erlotinib (150 mg by mouth daily) with either pazopanib (600 mg by mouth daily) or placebo. During treatment, patients were evaluated every 8 weeks until disease progression or unacceptable toxicity. After a study amendment, pretreatment serum specimens for the VeriStrat assay were collected. The predictive value of the VeriStrat score (good vs poor) for progression-free survival (PFS) and overall survival (OS) was assessed in the overall population and in each treatment group.. One hundred ninety-two eligible patients were randomized between February 2010 and February 2011. PFS was prolonged with erlotinib plus pazopanib versus erlotinib plus placebo (median, 2.6 vs 1.8 months; hazard ratio, 0.58; P = .001). There was no difference in the OS of the 2 groups. A good VeriStrat score predicted longer PFS and OS in the entire group and predicted longer PFS in the subgroup receiving erlotinib plus pazopanib. The addition of pazopanib increased toxicity, and this was consistent with the known toxicity profile.. The addition of pazopanib to erlotinib in an unselected group of patients with previously treated NSCLC improved PFS and increased treatment-related toxicity, but it had no influence on OS. The efficacy of both regimens was modest. Patients receiving erlotinib plus pazopanib had longer PFS if they had a good VeriStrat score versus a poor one. Cancer 2018;124:2355-64. © 2018 American Cancer Society.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Dose-Response Relationship, Drug; Erlotinib Hydrochloride; Female; Humans; Indazoles; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Placebos; Progression-Free Survival; Proteomics; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides

Pazopanib is a tyrosine kinase inhibitor with antiangiogenic activity. Vascular endothelial growth factor expression is increased in SCLC and is correlated with poor prognosis. The efficacy and tolerance of second-line pazopanib in SCLC was evaluated.. Patients with platinum-sensitive (cohort A; n=39) and -resistant/refractory (cohort B; n=19) SCLC were enrolled in a multicentre phase II study. The primary end point was the progression-free survival rate (PFS-R) at week 8 in each cohort. Pazopanib (800 mg per day per os) was administered until progressive disease (PD). Circulating tumour cells (CTCs) were enumerated using the Cellsearch assay.. All patients were evaluable for response and toxicity. In the intention-to-treat analysis, eight (13.8%) patients achieved partial response (PR) (95% confidence interval (CI): 5.0-22.7), 20 (34.5%) stable disease (SD) and 30 (51.7%) PD. Accrual in cohort B was halted because the hard-stop rule was met; in cohort A, the PFS-R was 59% (95% CI: 43.5-74.4; PR=7, SD=16). Nine (23.1%) patients received pazopanib for >6 months and 3 of them for >12 months. One pazopanib cycle resulted to a significant decrease to the number of patients with ⩾5 CTCs/7.5 ml of blood (20%) compared with baseline (50%). The median PFS and OS for all patients was 2.5 months (95% CI: 1.9-3.1 months) and 6.0 months (95% CI: 3.8-8.2 months), respectively (cohort A: PFS=3.7 months and OS=8.0 months). No unexpected toxicity was observed.. Second-line treatment with pazopanib in platinum-sensitive SCLC is well tolerated and resulted in promising objective responses and disease control; CTC enumeration might serve as a reliable surrogate biomarker of response.

Topics: Adult; Aged; Aged, 80 and over; Angiogenesis Inhibitors; Antineoplastic Agents; Carboplatin; Cisplatin; Disease-Free Survival; Drug Resistance, Neoplasm; Female; Humans; Indazoles; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplastic Cells, Circulating; Pyrimidines; Small Cell Lung Carcinoma; Sulfonamides; Treatment Outcome

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Carcinoma, Non-Small-Cell Lung; Combined Modality Therapy; Diagnosis, Differential; Femoral Neoplasms; Fracture Fixation, Intramedullary; Fractures, Spontaneous; Humans; Imidazoles; Indazoles; Lung Neoplasms; Male; Middle Aged; Oximes; Pyrimidines; Radiodermatitis; Radiotherapy, Adjuvant; Sulfonamides

Switch maintenance is an effective strategy in the treatment of advanced Non-Small Cell Lung Cancer (NSCLC). Pazopanib is an oral, multi-targeted tyrosine kinase inhibitor (TKI). EORTC 08092 evaluated pazopanib given as maintenance treatment following standard first line platinum-based chemotherapy in patients with advanced NSCLC.. Patients with non-progressive disease after 4-6 cycles of chemotherapy were randomised to receive either pazopanib 800mg/day or matched placebo until progression or unacceptable toxicity. The primary end-point was overall survival and secondary end-points were progression-free survival (PFS) and safety.. A total of 600 patients were planned to be randomised. The trial was prematurely stopped following an early interim analysis, after 102 patients were randomised to pazopanib (n=50) or placebo (n=52). Median age was 64years in both arms. Median overall survival was 17.4 months for pazopanib and 12.3 months for placebo (adjusted hazard ratio (HR) 0.72 [95% confidence interval (CI) 0.40-1.28]; p=0.257). Median PFS was 4.3 months versus 3.2 months (HR 0.67, [95% CI 0.43-1.03], p=0.068). PFS rates at 4 months were 56% and 45% respectively. The majority of treatment-related adverse events (AEs) were grade 1-2. Grade 3-4 AEs (pazopanib versus placebo) were hypertension (38% versus 8%), neutropenia (8% versus 0%), and elevated SGPT (6% versus 0%). Of the patients randomised to pazopanib, 22% withdrew due to a treatment-related AE.. Switch maintenance with pazopanib following platinum-based chemotherapy in advanced NSCLC patients had limited side-effects. This study was stopped due to lack of efficacy by stringent criteria for PFS at a futility interim analysis.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Disease Progression; Disease-Free Survival; Double-Blind Method; Female; Humans; Indazoles; Kaplan-Meier Estimate; Lung Neoplasms; Maintenance Chemotherapy; Male; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Sulfonamides

We assessed the maximum tolerated regimen (MTR) and dose-limiting toxicities of pazopanib and lapatinib in combination with weekly paclitaxel, and the effect of pazopanib and lapatinib on paclitaxel pharmacokinetics.. Patients received intravenous paclitaxel on days 1, 8, and 15 of a 28-day cycle concurrently with daily pazopanib and lapatinib. Dose levels of paclitaxel (mg m(-2))/pazopanib(mg)/lapatinib(mg) were 50/400/1000, 50/800/1000, 80/800/1000, and 80/400/1000. At the MTR, additional patients were enrolled to further evaluate tolerability, and the potential effects of pazopanib and lapatinib, inhibitors of cytochrome P450 (CYP)3A4, on the pharmacokinetics of paclitaxel, a CYP2C8 and CYP3A4 substrate.. Twenty-six patients were enrolled. Dose-limiting toxicities at the MTR (80/400/1000) included grade 4 thrombosis and grade 3 aspartate aminotransferase elevation. Other toxicities included diarrhoea, neutropenia, fatigue, and liver enzyme elevations. Coadministration of pazopanib 400 mg and lapatinib 1000 mg increased paclitaxel maximum plasma concentration (38%) and area under the curve (37%) relative to paclitaxel alone. One patient with a salivary gland tumour had a partial response; three patients had stable disease (⩾6 months).. Pazopanib 400 mg per day and lapatinib 1000 mg per day can be combined with paclitaxel 80 mg m(-2) in 28-day cycles. Coadministration of pazopanib and lapatinib, weak inhibitors of CYP2C8 and CYP3A4, had an inhibitory effect on paclitaxel clearance.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biliary Tract Neoplasms; Carcinoma, Non-Small-Cell Lung; Drug Administration Schedule; Female; Humans; Indazoles; Lapatinib; Lung Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Paclitaxel; Pyrimidines; Quinazolines; Salivary Gland Neoplasms; Sulfonamides; Treatment Outcome

Platinum-based chemotherapy with bevacizumab is a standard therapy for patients with stage IIIB/IV non-small cell lung cancer (NSCLC) with non-squamous (NS) histology. Mechanisms of resistance to bevacizumab include increased VEGF signaling or activation of VEGF receptors. Pazopanib is a multi-targeted VEGF receptor tyrosine kinase with single agent activity in NSCLC.. Stage IIIB/IV patients with adequate organ function, who progressed on a bevacizumab containing therapy were eligible if it had been ≤8 weeks since the last bevacizumab treatment. The primary end-point was disease control rate (DCR), defined as partial or complete response, or stable disease for ≥12 weeks. Patients were assessed radiographically every 2 cycles (6 weeks). A Simon 2-stage design was used, and if in the first stage ≤4 of 17 patients experienced disease control the trial was to have been stopped for futility. An unplanned analysis was performed after 15 patients were evaluable secondary to slow accrual.. Between December 2010 and November 2013, 15 patients were treated on trial. The median age was 61 years (range 39-74), and all patients had stage IV disease. Of the 15 patients, 4 discontinued therapy prior to cycle 2 evaluation due to adverse events (n=3) and medical illness (n=1), 5 patients had progressive disease, 4 patients had stable disease for <12 weeks, and 2 patients had stable disease for ≥12 weeks. No responses were observed. The DCR observed was 13% (2/15), and the trial did not meet the criteria to proceed to the second stage. Episodes of grade 3 treatment related toxicities observed included: increased ALT (n=2), increased AST (n=1), anorexia (n=3), fatigue (n=3), hypertension (n=1), infection (n=1), mucositis (n=2), nausea (n=3), pericardial effusion (n=1), and vomiting (n=1).. Pazopanib has limited activity in NSCLC-NS in patients who have experienced disease progression on bevacizumab.

Topics: Adult; Aged; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Carcinoma, Non-Small-Cell Lung; Disease Progression; Female; Humans; Indazoles; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Pyrimidines; Sulfonamides; Treatment Outcome

This randomized open-label phase II study evaluated the efficacy, safety, and tolerability of pazopanib in combination with pemetrexed compared with the standard cisplatin/pemetrexed doublet in patients with previously untreated, advanced, nonsquamous non-small-cell lung cancer.. Patients were randomized (2:1 ratio) to receive pemetrexed 500 mg/m(2) intravenously once every 3 weeks plus either oral pazopanib 800 mg daily or cisplatin 75 mg/m(2) intravenously once every 3 weeks up to six cycles. All patients received folic acid, vitamin B12, and steroid prophylaxis. The primary endpoint was progression-free survival (PFS).. The study was terminated after 106 of 150 patients were randomized due to a higher incidence of adverse events leading to withdrawal from the study and severe and fatal adverse events in the pazopanib/pemetrexed arm than in the cisplatin/pemetrexed arm. At the time enrolment was discontinued, there were three fatal adverse events in the pazopanib/pemetrexed arm, including ileus, tumor embolism, and bronchopneumonia/sepsis. Treatment with pazopanib/pemetrexed was discontinued resulting in more PFS data censored for patients in the pazopanib/pemetrexed arm than those in the cisplatin/pemetrexed arm. There was no statistically significant difference between the pazopanib/pemetrexed and cisplatin/pemetrexed arms for PFS (median PFS, 25.0 versus 22.9 weeks, respectively; hazard ratio = 0.75; 95% confidence interval, 0.43%-1.28%; p = 0.26) or objective response rate (23% versus 34%, respectively; 95% confidence interval, -30.6% to 7.2%; p = 0.21).. The combination of pazopanib/pemetrexed in first-line treatment of non-small-cell lung cancer showed some antitumor activity but had unacceptable levels of toxicity.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Large Cell; Carcinoma, Non-Small-Cell Lung; Cisplatin; Female; Follow-Up Studies; Glutamates; Guanine; Humans; Indazoles; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Pemetrexed; Prognosis; Pyrimidines; Sulfonamides; Survival Rate

PURPOSE Pazopanib is an oral angiogenesis inhibitor targeting vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit. This randomized, double-blind, placebo-controlled phase III study evaluated efficacy and safety of pazopanib monotherapy in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). PATIENTS AND METHODS Adult patients with measurable, locally advanced, and/or metastatic RCC were randomly assigned 2:1 to receive oral pazopanib or placebo. The primary end point was progression-free survival (PFS). Secondary end points included overall survival, tumor response rate (Response Evaluation Criteria in Solid Tumors), and safety. Radiographic assessments of tumors were independently reviewed. Results Of 435 patients enrolled, 233 were treatment naive (54%) and 202 were cytokine pretreated (46%). PFS was significantly prolonged with pazopanib compared with placebo in the overall study population (median, PFS 9.2 v 4.2 months; hazard ratio [HR], 0.46; 95% CI, 0.34 to 0.62; P < .0001), the treatment-naive subpopulation (median PFS 11.1 v 2.8 months; HR, 0.40; 95% CI, 0.27 to 0.60; P < .0001), and the cytokine-pretreated subpopulation (median PFS, 7.4 v 4.2 months; HR, 0.54; 95% CI, 0.35 to 0.84; P < .001). The objective response rate was 30% with pazopanib compared with 3% with placebo (P < .001). The median duration of response was longer than 1 year. The most common adverse events were diarrhea, hypertension, hair color changes, nausea, anorexia, and vomiting. There was no evidence of clinically important differences in quality of life for pazopanib versus placebo. CONCLUSION Pazopanib demonstrated significant improvement in PFS and tumor response compared with placebo in treatment-naive and cytokine-pretreated patients with advanced and/or metastatic RCC.

Topics: Adult; Aged; Aged, 80 and over; Bone Neoplasms; Carcinoma, Renal Cell; Double-Blind Method; Female; Humans; Indazoles; International Agencies; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Placebos; Prognosis; Pyrimidines; Sulfonamides; Survival Rate; Treatment Outcome; Young Adult

There is an unmet need for pharmacodynamic and predictive biomarkers for antiangiogenic agents. Recent studies have shown that soluble vascular endothelial growth factor receptor 2 (sVEGFR2), VEGF, and several other soluble factors may be modulated by VEGF pathway inhibitors. We conducted a broad profiling of cytokine and angiogenic factors (CAF) to investigate the relationship between baseline CAF levels, CAF changes during treatment, and tumor shrinkage in early-stage non-small cell lung cancer (NSCLC) patients treated with pazopanib, an oral angiogenesis inhibitor targeting VEGFR, platelet-derived growth factor receptor, and c-kit. Plasma samples were collected before treatment and on the last day of therapy from 33 patients with early-stage NSCLC participating in a single-arm phase II trial. Levels of 31 CAFs were measured by suspension bead multiplex assays or ELISA and correlated with change in tumor volume. Pazopanib therapy was associated with significant changes of eight CAFs; sVEGFR2 showed the largest decrease, whereas placental growth factor underwent the largest increase. Increases were also observed in stromal cell-derived factor-1alpha, IP-10, cutaneous T-cell-attracting chemokine, monokine induced by IFN-gamma, tumor necrosis factor-related apoptosis-inducing ligand, and IFN-alpha. Posttreatment changes in plasma sVEGFR2 and interleukin (IL)-4 significantly correlated with tumor shrinkage. Baseline levels of 11 CAFs significantly correlated with tumor shrinkage, with IL-12 showing the strongest association. Using multivariate classification, a baseline CAF signature consisting of hepatocyte growth factor and IL-12 was associated with tumor response to pazopanib and identified responding patients with 81% accuracy. These data suggest that CAF profiling may be useful for identifying patients likely to benefit from pazopanib, and merit further investigation in clinical trials.

Topics: Aged; Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Cluster Analysis; Cytokines; Female; Humans; Indazoles; Lung Neoplasms; Male; Middle Aged; Neovascularization, Pathologic; Pyrimidines; Sulfonamides

Patients with early-stage, resectable, non-small-cell lung cancer (NSCLC) are at risk for recurrent disease, and 5-year survival rates do not exceed 75%. Angiogenesis inhibitors have shown clinical activity in patients with late-stage NSCLC, raising the possibility that targeting the vascular endothelial growth factor pathway in earlier-stage disease may be beneficial. This proof-of-concept study examined safety and efficacy of short-term, preoperative pazopanib monotherapy in patients with operable stage I/II NSCLC.. Patients scheduled for resection received oral pazopanib 800 mg/d for 2 to 6 weeks preoperatively. Tumor response was measured by high-resolution computed tomography, permitting estimation of change in tumor volume and diameter. Gene-expression profiling was performed on 77 pre- and post-treatment lung samples from 34 patients.. Of 35 patients enrolled, 33 (94%) had clinical stage I NSCLC and two (6%) had clinical stage II NSCLC. Median treatment duration was 16 days (range, 3 to 29 days). Thirty patients (86%) achieved tumor-volume reduction after pazopanib treatment. Two patients achieved tumor-volume reduction > or = 50%, and three patients had partial response according to Response Evaluation Criteria in Solid Tumors. Pazopanib was generally well tolerated. The most common adverse events included grade 2 hypertension, diarrhea, and fatigue. One patient developed pulmonary embolism 11 days after surgery. Several pazopanib target genes and other angiogenic factors were dysregulated post-treatment.. Short-duration pazopanib was generally well tolerated and demonstrated single-agent activity in patients with early-stage NSCLC. Several target genes were dysregulated after pazopanib treatment, validating target-specific response and indicating a persistent pazopanib effect on lung cancer tissue. Further clinical evaluation of pazopanib in NSCLC is planned.

Topics: Administration, Oral; Aged; Aged, 80 and over; Carcinoma, Non-Small-Cell Lung; Diarrhea; Drug Administration Schedule; Fatigue; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Hypertension; Indazoles; Lung Neoplasms; Male; Middle Aged; Neoplasm Staging; Pyrimidines; Sulfonamides; Treatment Outcome

Pazopanib is an approved multitarget anticancer agent for soft tissue sarcoma (STS) and renal cell carcinoma (RCC), which is also under clinical investigation for other malignancies, including small cell lung cancer (SCLC). However, the potential anti-SCLC mechanisms of pazopanib remain unclear.. Cell viability was evaluated by CCK-8, apoptotic cell detection was conducted using annexin V/PI staining followed by flow cytometry, and Western blot analysis was used to detect the apoptotic-related molecules and ER-stress pathway effectors. The intracellular reactive oxygen species (ROS) level was determined by DCFH-HA staining followed by flow cytometry. An NCI-H446 xenograft model was established to evaluate pazopanib on tumor suppression in vivo. Immunohistochemistry (IHC) was used to assess the proliferative activity of xenograft in NCI-H446 cell-bearing NOD-SCID mice.. Pazopanib dose- and time-dependently inhibited SCLC cell proliferation induced significant apoptosis in SCLC cell lines, increased cleaved-caspase3 and Bax, and decreased Bcl-2. Moreover, the PERK-related ER-stress pathway was potently activated by pazopanib treatment, inhibiting ER-stress by salubrinal significantly reversing pazopanib-mediated apoptosis in SCLC cell lines. Furthermore, pazopanib-induced intracellular ROS levels increased, while inhibiting ROS by NAC significantly reversed pazopanib-induced apoptosis in SCLC cells. In addition, pazopanib significantly suppressed NCI-H446 xenograft growth and decreased Ki67 positive cells in the tumor.. Our findings indicate that pazopanib induces SCLC cell apoptosis through the ER-stress process via upregulation of ROS levels. Further investigation of relevant biomarkers to accurately select patients for benefit from pazopanib should be further investigated.

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Proliferation; Endoplasmic Reticulum Stress; Humans; Indazoles; Lung Neoplasms; Mice; Mice, Inbred NOD; Mice, SCID; Pyrimidines; Reactive Oxygen Species; Small Cell Lung Carcinoma; Sulfonamides

The present investigation deals with the pazopanib-loaded solid lipid nanoparticles (Pazo-SLNs) and their in-vitro and in-vivo assessments. Quality by design approach employing the Plackett-Burman and central composite design was used to identify the formulation variables, including drug/lipid ratio, organic/aqueous phase ratio, and surfactant concentration with a significant impact on the process and to fabricate a safe and efficacious novel oral dosage form of pazopanib. Particle size, drug loading, entrapment efficiency, and zeta potential of optimal Pazo-SLNs formulation were 210.03 ± 7.68 nm, 13.35 ± 0.95 %, 79.05 ± 2.55 % and -18.29 ± 1.89 mV (n = 3) respectively. FTIR study affirmed the absence of incompatibilities between the drug and the excipients. DSC and XRD measurements substantiated the amorphous form of pazopanib entrapped within the SLNs. Pazo-SLNs demonstrated high cellular uptake, showed substantial cytotoxicity to A-549 lung cancer cells due to apoptotic mode and inhibited tyrosine kinase in-vitro. Pazo-SLNs were found to be stable for three months. SLNs greatly ameliorated the pharmacokinetic behavior and bioavailability (9.5 folds) of pazopanib with a sustained-release pattern (92.67 ± 4.68 % within 24 h). A biodistribution study corroborated the lung targeting potential of Pazo-SLNs. Thus, SLNs could potentially boost the oral route efficacy of pazopanib against cancer cells.

Topics: Biological Availability; Carcinoma, Non-Small-Cell Lung; Drug Carriers; Excipients; Humans; Lipids; Lung Neoplasms; Nanoparticles; Particle Size; Tissue Distribution

In order to identify more effective therapy for recalcitrant osteosarcoma, we evaluated the efficacy of an mTOR-VEGFR inhibitor combination on tumor growth in a unique osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model derived from the lung metastasis of an osteosarcoma patient who failed doxorubicin therapy. We also determined the efficacy of this inhibitor combination on angiogenesis using an in vivo Gelfoam fluorescence angiogenesis mouse model implanted with osteosarcoma patient-derived cells (OS-PDCs). PDOX models were randomly divided into five groups of seven nude mice. Group 1, control; Group 2, doxorubicin (DOX); Group 3, everolimus (EVE, an mTOR and VEGF inhibitor); Group 4, pazopanib (PAZ, a VEGFR inhibitor); Group 5, EVE-PAZ combination. Tumor volume and body weight were monitored 2 times a week. The in vivo Gelfoam fluorescence angiogenesis assay was performed with implanted OS-PDCs. The nude mice with implanted Gelfoam and OSPDCs also were divided into the four therapeutic groups and vessel length was monitored once a week. The EVE-PAZ combination suppressed tumor growth in the osteosarcoma PDOX model and decreased the vessel length ratio in the in vivo Gelfoam fluorescent angiogenesis model, compared with all other groups (p < 0.05). There was no significant body-weight loss in any group. Only the EVE-PAZ combination caused tumor necrosis. The present study demonstrates that a combination of an mTOR-VEGF inhibitor and a VEGFR inhibitor was effective for a DOX-resistant lung-metastatic osteosarcoma PDOX mouse model, at least in part due to strong anti-angiogenesis efficacy of the combination.

Topics: Adolescent; Animals; Antibiotics, Antineoplastic; Bone Neoplasms; Disease Models, Animal; Doxorubicin; Drug Resistance, Neoplasm; Drug Therapy, Combination; Everolimus; Female; Humans; Indazoles; Lung Neoplasms; Mice; Mice, Nude; Neoplasm Transplantation; Neovascularization, Pathologic; Osteosarcoma; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; TOR Serine-Threonine Kinases

To investigate pneumothorax patterns in pazopanib treatment by focusing on the positional relationship between the visceral pleura and metastatic lung tumor, we examined 20 patients with advanced soft tissue tumors who developed lung metastases and underwent pazopanib treatment between 2012 and 2019. Pneumothorax was classified into two types based on the location of the metastatic lesion around the visceral pleural area before pazopanib treatment: subpleural type, within 5 mm from the pleura; and central type, >5 mm from the pleura. We investigated the rates of pneumothorax and the associated risk factors. Five patients experienced pneumothorax (three subpleural and two central types). Cavitation preceded pneumothorax in 83% of patients and led to connection of the cavitated cyst of the metastatic lesion to the chest cavity in the shorter term in patients with the subpleural type. Conversely, a more gradual increase in the cavity size and sudden cyst rupture were observed in the central type. The risk factors for pneumothorax were cavitation after initiating pazopanib and intervention before pazopanib, either ablation or surgery. The location of the metastatic lesions was not a risk factor for the occurrence of pneumothorax. In conclusion, pneumothorax is an adverse event associated with pazopanib treatment. Therefore, attention must be paid to predisposing factors such as the formation of cavitation after pazopanib initiation and previous interventions to the lungs. Moreover, because subpleural pneumothorax tends to occur earlier than the central type, a different time course can be anticipated based on the positional relationships of the metastatic lesions to the visceral pleura.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Incidence; Indazoles; Lung; Lung Neoplasms; Male; Middle Aged; Pleura; Pneumothorax; Pyrimidines; Retrospective Studies; Risk Assessment; Risk Factors; Soft Tissue Neoplasms; Sulfonamides; Time Factors

Pazopanib is a multitarget tyrosine kinase inhibitor used in the treatment of renal cancer and soft tissue sarcoma. Its use is commonly associated with a number of side effects, such as hemorrhagic diathesis, neutropenia, leukopenia, thrombocytopenia, nausea, vomiting, abdominal pain, increased serum aspartate aminotransferase, increased serum alanine aminotransferase, decreased serum glucose, increased serum bilirubin, decreased serum phosphate and magnesium, fatigue, hypertension, diarrhea, anorexia, proteinuria, and hypothyroidism. Abscesses of metastases caused by pazopanib administration are rarely reported in the literature.. We report a case of abscesses of lung metastases related to pazopanib in a patient with metastatic renal cancer. The patient was a 53-year-old Caucasian man who developed abscesses of lung metastases during the first 3 months of treatment with pazopanib. The abscesses resolved after 1 month by stopping pazopanib and administering adequate antibiotic therapy.. We conclude that abscesses of metastases could be a rare side effect occurring during treatment with pazopanib in patients with renal cancer.

Topics: Humans; Indazoles; Kidney Neoplasms; Lung Abscess; Lung Neoplasms; Male; Middle Aged; Pyrimidines; Sulfonamides

Topics: Aged; Angiogenesis Inhibitors; Duodenal Ulcer; Fatal Outcome; Female; Gastrointestinal Hemorrhage; Hemangiosarcoma; Humans; Indazoles; Lung Neoplasms; Lymphangiosarcoma; Pyrimidines; Stomach Ulcer; Sulfonamides

Renal cell carcinoma (RCC) metastasis to the bladder is rare. We report two cases that occurred metachronously during pazopanib treatment for other metastases. To our knowledge, this is the first report to demonstrate bladder metastasis from RCC during molecular targeted therapy with pazopanib. (Case 1) A woman in her 60s was referred to our department for evaluation of an incidental right renal tumor. Dynamic CT showed a 6 cm renal cell carcinoma. In February 201X she underwent laparoscopic right radical nephrectomy, revealing clear cell carcinoma (grade 1>2), stage pT3aN0M0. In February 201X+1 she complained of left pelvic pain. She was found to have metastasis to two iliac bones and an occipital bone. She received pazopanib, in addition to a bone modifying agent and radiotherapy for the iliac bones. After 8 months, she complained of asymptomatic gross hematuria in spite of having stable disease for bone metastasis. Cystoscopy showed a 1 cm solitary sessile nonpapillary tumor on the posterior wall. She underwent transurethral resection of bladder tumor (TUR-BT). Histological examination showed metastatic RCC. Thereafter she received sequential therapies (axitinib, sunitinib, nivolumab). She remains alive without recurrence in the bladder 51 months after TUR-BT. (Case 2) A woman in her 60s presented to our department with a complaint of painless gross hematuria. A dynamic CT showed an 8.5 cm renal cell carcinoma and multiple lung metastases. In March 201Y she underwent right radical nephrectomy, revealing clear cell carcinoma (grade 2>3), stage pT2aN0M1. In June 201Y she started pazopanib. After 9 months CT showed a bladder tumor in addition to progression of lung metastases. Cystoscopy showed a 1 cm solitary sessile nonpapillary tumor at dome. She underwent TUR-BT. Histological examination showed metastatic RCC. She had no recurrence in the bladder during follow-up although she died of RCC.

Topics: Aged; Carcinoma, Renal Cell; Combined Modality Therapy; Cystectomy; Fatal Outcome; Female; Humans; Indazoles; Kidney Neoplasms; Lung Neoplasms; Molecular Targeted Therapy; Neoplasm Staging; Nephrectomy; Pyrimidines; Sulfonamides; Treatment Outcome; Urinary Bladder Neoplasms

Drug-induced nephrotic syndrome (NS) can be resolved by eliminating the causative agents. However, patients with metastatic cancer have not been previously reported to achieve complete recovery from anticancer drug-induced NS after discontinuation of treatment, because many patients die of cancer progression before NS is restored.. A 67-year-old man presented with edema of both lower extremities. He received pazopanib therapy for recurrent metastatic renal cell carcinoma (mRCC) for 17 months. Laboratory examinations revealed 7484.58 mg/day of 24-h urine protein, 434 mg/dL of serum cholesterol, and 2.9 g/dL of serum albumin. He was diagnosed with NS, and pazopanib treatment was discontinued. Four months later, he completely recovered from NS. He was then treated with temsirolimus and nivolumab sequentially for > 26 months. Pazopanib was re-introduced following disease progression, and demonstrated antitumor effects for 7 months without NS recurrence.. Pazopanib-induced NS can occur late in patients with mRCC, and its subsequent discontinuation can enable patients to completely recover from its adverse effects. Moreover, pazopanib treatment may be re-introduced without the recurrence of NS.

Topics: Aged; Amlodipine; Angiogenesis Inhibitors; Antihypertensive Agents; Antineoplastic Agents; Carcinoma, Renal Cell; Combined Modality Therapy; Diabetic Nephropathies; Dihydropyridines; Drug Substitution; Edema; Everolimus; Humans; Hypertension; Indazoles; Kidney Failure, Chronic; Lung Neoplasms; Male; Nephrotic Syndrome; Nivolumab; Pancreatic Neoplasms; Pancreaticoduodenectomy; Pneumonectomy; Protein Kinase Inhibitors; Pyrimidines; Sirolimus; Sulfonamides; Sunitinib

Ewing's sarcoma (ES)/primitive neuroectodermal tumors (PNETs) are highly malignant neoplasms that usually affect the bones and soft tissues in children and young adults. ES/PNET of the lung is very rare and is associated with a poor prognosis. We herein report a case of ES/PNET of the left lung in a 45-year-old man. He was treated with neoadjuvant chemotherapy and pneumonectomy, but unfortunately his disease recurred 1.5 months after surgery. He was started on pazopanib, which resulted in a five-month progression-free survival. To our knowledge, this is the first demonstration of pazopanib efficacy in ES/PNET of the lung.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Fatal Outcome; Humans; Indazoles; Lung Neoplasms; Male; Middle Aged; Neoplasm Recurrence, Local; Neuroectodermal Tumors, Primitive; Pneumonectomy; Progression-Free Survival; Pyrimidines; Sarcoma, Ewing; Sulfonamides; Treatment Outcome

Non-small cell lung cancer (NSCLC) constitutes more than 85% of lung cancer case. Pemetrexed is used to treat types of NSCLC, and pazopanib is used for some types of soft tissue sarcoma. The aim of the study was development of pemetrexed and pazopanib carrying nanobubble system with magnetic responsiveness and ultrasound sensitivity properties for targeted NSCLC therapy. Drugs were linked to newly designed peptide, and peptide drug conjugates were attached to amine-modified magnetite. Resulting nanoparticles were encapsulated into liposomes, and liposomes were extruded, then nanobubble system was prepared. Moreover, nanobubble biodistribution was monitored by in vivo imaging system. As a result, based on high-performance liquid chromatography data, magnetite and peptide-pemetrexed were conjugated with 54.02% yield, and magnetite and peptide-pazopanib were bound with 63.53% yield. Hydrodynamic size of nanobubbles, prepared from liposomes filtered through 800 nm and 400 nm, was determined as 491.1 ± 130.2 and 275.8 ± 117.8 nm, respectively. Carrier system was accumulated into tumor area with 80.22% yield of the injected carrier system. It was found that nanobubbles were magnetic responsive for accumulation via magnetic field and could be disrupted by ultrasound via focused acoustic pressure, which lead to targeted drug delivery. These nanobubble systems could be investigated for intravenous and inhaler administration in further studies.

Topics: A549 Cells; Administration, Inhalation; Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Chromatography, High Pressure Liquid; Drug Compounding; Drug Delivery Systems; Ferrosoferric Oxide; Humans; Indazoles; Injections, Intralesional; Liposomes; Lung Neoplasms; Magnetic Phenomena; Mice; Nanoparticles; Nebulizers and Vaporizers; Pemetrexed; Pyrimidines; Sulfonamides; Tissue Distribution; Tumor Burden; Ultrasonic Waves; Xenograft Model Antitumor Assays

To test the hypothesis that cytoreductive nephrectomy (CN) improves overall survival (OS) of patients with synchronous metastatic renal cell carcinoma (mRCC), who subsequently receive targeted therapies (TT).. We identified 261 patients who received TT for synchronous mRCC with or without prior CN. To achieve balance in baseline characteristics between groups, we used the inverse probability of treatment weighting (IPTW) method. We conducted OS analyses, including IPTW-adjusted Kaplan-Meier curves, Cox regression models, interaction term, and landmark and sensitivity analyses.. Of the 261 patients, 97 (37.2%) received CN and 164 (62.8%) did not. IPTW-adjusted analyses showed a statistically significant OS benefit for patients treated with CN (HR 0.63, 95% CI 0.46-0.83, P = 0.0015). While there was no statistically significant difference in OS at 3 months (P = 0.97), 6 months (P = 0.67), and 12 months (P = 0.11) from diagnosis, a benefit for the CN group was noted at 18 months (P = 0.005) and 24 months (P = 0.004). On interaction term analyses, the beneficial effect of CN increased with better performance status (P = 0.06), in women (P = 0.03), and in patients with thrombocytosis (P = 0.01).. IPTW-adjusted analysis of our patient cohort suggests that CN improves OS of patients with synchronous mRCC treated with TT. On the whole, the survival difference appears after 12 months. Specific subgroups may particularly benefit from CN, and these subgroups warrant further investigation in prospective trials.

Topics: Aged; Anilides; Antibodies, Monoclonal; Antineoplastic Agents; Carcinoma, Renal Cell; Cohort Studies; Combined Modality Therapy; Cytoreduction Surgical Procedures; Female; Humans; Indazoles; Indoles; Kaplan-Meier Estimate; Kidney Neoplasms; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Molecular Targeted Therapy; Neoplasm Metastasis; Nephrectomy; Nivolumab; Probability; Prognosis; Proportional Hazards Models; Pyridines; Pyrimidines; Pyrroles; Retrospective Studies; Sex Factors; Sulfonamides; Sunitinib; Survival Rate; Thrombocytosis

Topics: Carcinoma, Non-Small-Cell Lung; ErbB Receptors; Erlotinib Hydrochloride; Humans; Indazoles; Lung Neoplasms; Proteomics; Pyrimidines; Sulfonamides

The clinical efficacy and outcomes of pazopanib treatment for metastatic extraosseous Ewing sarcoma remain unclear. We herein report a case of heavily pre-treated metastatic extraosseous Ewing sarcoma in which pazopanib treatment achieved a significant improvement. A 17-year-old girl was referred to our hospital due to metastatic extraosseous Ewing sarcoma. The initial cytotoxic chemotherapy was temporarily effective, however, her disease eventually progressed, and she was subsequently treated with pazopanib. The recurrent tumor showed a marked response to pazopanib therapy; the therapeutic effect has lasted for more than 26 months. The present case suggests that pazopanib may be a therapeutic option for extraosseous Ewing sarcoma.

Topics: Adolescent; Angiogenesis Inhibitors; Antineoplastic Agents; Bone Neoplasms; Female; Humans; Indazoles; Lung Neoplasms; Pyrimidines; Sarcoma, Ewing; Sulfonamides; Vaginal Neoplasms

The tyrosine kinase inhibitor pazopanib is used for treatment of sarcoma. Recent studies have suggested that the use of pazopanib may lead to the development of pneumothorax, an unexpected adverse effect in patients with sarcoma metastatic to the chest.. We conducted a retrospective case control study of patients with sarcoma with metastases to the chest with pneumothorax (cases) and without pneumothorax (controls). The control population was selected from tumor registry in a 1:4 (cases to controls) ratio. The primary outcome of interest was the association between pazopanib and pneumothorax risk in patients with sarcoma metastatic to the chest. Secondary objective was to evaluate risk factors for pneumothorax.. We identified 41 cases and 164 controls. Using purposeful selection method the odds of developing pneumothorax while being on pazopanib was not significant in univariate (p = .06) and multivariable analysis (p = .342). On univariate analysis risk factors of pneumothorax in patients with sarcoma were age, male sex, African American race, the presence of cavitary lung nodules/masses, and the presence of pleural-based nodules/masses. On multivariate analysis, only the presence of cavitary lung nodules/masses (P < .001) and the presence of pleural-based nodules/masses (P < .001) remained as risk factors for developing pneumothorax.. Pazopanib does not increase the risk of pneumothorax in patients with sarcoma and evidence of metastatic disease to the chest. Presence of cavitary lung nodules/masses and the presence of pleural-based nodules/masses were found to be risk factors for pneumothorax.

Topics: Adult; Aged; Case-Control Studies; Female; Humans; Indazoles; Logistic Models; Lung Neoplasms; Male; Middle Aged; Pneumothorax; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Risk Factors; Sarcoma; Sulfonamides

Pulmonary carcinosarcoma (PCS) is a rare primary lung malignancy and has a poor prognosis among lung tumor histological subtypes. However, an appropriate treatment strategy has not been developed for unresectable PCS.. A 65-year-old man who was diagnosed with PCS was treated by surgical removal of the primary lung lesion, followed by six cycles of adjuvant chemotherapy with cisplatin plus irinotecan. Following the chemotherapy, he experienced a relapse with brain metastasis, which induced the rapid onset of left leg paralysis. Radical surgical resection and stereotactic radiosurgery to the resection cavity were performed. However, meningeal dissemination and new lung metastases occurred after a year and half. To control these multiple metastatic lesions, the patient was treated with the multiple kinase inhibitor pazopanib. No change was observed in the meningeal dissemination, while the metastatic lung lesions were prominently reduced in size following treatment with pazopanib. Consequently, the patient showed a partial response to pazopanib treatment, although the dose of pazopanib was reduced by half as a result of thrombocytopenia.. This is the first report of metastatic PCS showing an evident therapeutic response to tumor-targeted therapy. We suggest that pazopanib may be a therapeutic option for patients with metastatic PCS.

Topics: Aged; Angiogenesis Inhibitors; Antineoplastic Agents; Brain Neoplasms; Carcinosarcoma; Chemotherapy, Adjuvant; Dose-Response Relationship, Drug; Humans; Indazoles; Lung Neoplasms; Male; Meningeal Neoplasms; Neoplasm Staging; Pneumonectomy; Pyrimidines; Radiosurgery; Sulfonamides; Thrombocytopenia; Treatment Outcome

Kinase inhibitors are important cancer therapeutics. Polypharmacology is commonly observed, requiring thorough target deconvolution to understand drug mechanism of action. Using chemical proteomics, we analyzed the target spectrum of 243 clinically evaluated kinase drugs. The data revealed previously unknown targets for established drugs, offered a perspective on the "druggable" kinome, highlighted (non)kinase off-targets, and suggested potential therapeutic applications. Integration of phosphoproteomic data refined drug-affected pathways, identified response markers, and strengthened rationale for combination treatments. We exemplify translational value by discovering SIK2 (salt-inducible kinase 2) inhibitors that modulate cytokine production in primary cells, by identifying drugs against the lung cancer survival marker MELK (maternal embryonic leucine zipper kinase), and by repurposing cabozantinib to treat FLT3-ITD-positive acute myeloid leukemia. This resource, available via the ProteomicsDB database, should facilitate basic, clinical, and drug discovery research and aid clinical decision-making.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cytokines; Drug Discovery; fms-Like Tyrosine Kinase 3; Humans; Leukemia, Myeloid, Acute; Lung Neoplasms; Mice; Molecular Targeted Therapy; Protein Kinase Inhibitors; Protein Serine-Threonine Kinases; Proteomics; Xenograft Model Antitumor Assays

Topics: Adolescent; Angiogenesis Inhibitors; Bone Neoplasms; Child; Female; Humans; Indazoles; Liver Neoplasms; Lung Neoplasms; Male; Osteosarcoma; Pyrimidines; Sulfonamides

A named patient program (NPP) was designed to provide patients with advanced soft-tissue sarcoma (aSTS) access to pazopanib, a multitargeted tyrosine kinase inhibitor. The SPIRE study was a retrospective chart review of participating patients.. Eligibility criteria for the NPP and SPIRE mirrored those of the pivotal phase-III study, PALETTE, which compared pazopanib with placebo in patients ≥18 years with aSTS and whose disease had progressed during or following prior chemotherapy or were otherwise unsuitable for chemotherapy. Outcomes of interest included treatment patterns, treatment duration, relative dose intensity, progression-free survival (PFS), overall survival (OS), clinical benefit rate, adverse events (AEs) and reasons for treatment discontinuation.. A total of 211 patients were enrolled (median age 56 years; 60% female). Most patients received pazopanib in second- and third-line therapy (28.0% and 28.4%, respectively), followed by fourth line (19.0%) and ≥ fifth line (18.5%). The median duration of pazopanib treatment was 3.1 months (95% CI: 2.8-3.8), with a mean daily dose of 715 mg equating to 92% of recommended dose. Median OS was 11.1 months and clinical benefit rate was 46%. There was evidence of some clinical benefit across most histological subtypes. At study end, 40% of patients were alive and of these, 18% remained on pazopanib. Thirteen percent (13%) of patients discontinued pazopanib due to AEs.. The SPIRE study demonstrated activity of pazopanib in heavily pretreated aSTS patients in a compassionate use setting. No new safety concerns were noted. Reassuringly, the relative dose intensity of pazopanib was 92%.

Topics: Angiogenesis Inhibitors; Compassionate Use Trials; Disease-Free Survival; Female; Hemangiosarcoma; Humans; Indazoles; Leiomyosarcoma; Lung Neoplasms; Male; Middle Aged; Pyrimidines; Retrospective Studies; Sarcoma; Sarcoma, Synovial; Solitary Fibrous Tumors; Sulfonamides; Survival Rate; Time Factors; Uterine Neoplasms

Chondrosarcoma is the most common bone sarcoma in adults. Conventional chondrosarcoma, the commonest histological subtype, is largely resistant to anthracycline-based chemotherapy. There have been anecdotal reports of durable clinical benefit with antiangiogenic agents in this disease. A retrospective search of patients treated at three sarcoma referral centers was performed to identify patients with advanced chondrosarcoma treated with antiangiogenic agents. The aim of this study was to evaluate the efficacy and safety of antiangiogenic agents in advanced chondrosarcoma. Ten patients were identified; seven with conventional, one each with clear cell, extraskeletal mesenchymal chondrosarcoma and extraskeletal myxoid chondrosarcoma. The median progression-free survival for patients with conventional and clear cell sarcoma was 22.6 months. Median overall survival has not been met. Antiangiogenic therapy was well tolerated in this series of patients. Our retrospective data suggest that antiangiogenic therapy can provide prolonged clinical benefit in advanced chondrosarcoma patients. Further prospective trials are required to precisely define the role of this class of agent in advanced chondrosarcoma.

Topics: Adult; Aged; Angiogenesis Inhibitors; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Chondrosarcoma; Disease-Free Survival; Female; Humans; Indazoles; Lung Neoplasms; Male; Middle Aged; Neoplasms, Connective and Soft Tissue; Pyrimidines; Ramucirumab; Retrospective Studies; Sulfonamides; Treatment Outcome

Topics: Angiogenesis Inhibitors; Bronchial Fistula; Female; Humans; Indazoles; Lung Neoplasms; Middle Aged; Pleural Diseases; Pyrimidines; Sarcoma; Sulfonamides

We herein report the case of a patient presenting with myxofibrosarcoma (MFS) who underwent treatment with surgery, proton beam therapy (PBT), and pazopanib. A 64-year-old male was diagnosed with MFS, which ranged from the posterior neck to the shoulder. Surgery was performed as an initial treatment; however, the primary tumor recurred 83 months after the initial treatment. We, therefore, administered PBT. Although most of the recurrent tumor disappeared after PBT, multiple lung metastases were identified 3 months after the completion of PBT. We initiated antiangiogenic treatment with pazopanib. Although long-term survival was achieved with the treatments, the patient suffered from a skin ulcer and soft tissue necrosis and eventually died of general prostration caused by infection, and complicated by pneumonia. Although PBT and pazopanib were effective for treating the local recurrence and lung metastases of MFS, respectively, clinicians must be cognizant of the fact that the combination of high-dose irradiation and angiogenesis inhibitors, even in nonconcurrent cases, can result in a severe skin ulcer and soft tissue necrosis.

Topics: Angiogenesis Inhibitors; Debridement; Fatal Outcome; Fibrosarcoma; Head and Neck Neoplasms; Humans; Indazoles; Lung Neoplasms; Male; Middle Aged; Myxoma; Necrosis; Proton Therapy; Pyrimidines; Skin Ulcer; Soft Tissue Infections; Sulfonamides; Tomography, X-Ray Computed

Topics: Child; Female; Humans; Indazoles; Lung Neoplasms; Pyrimidines; Sarcoma, Alveolar Soft Part; Sulfonamides; Treatment Outcome

Pazopanib is a potent multitargeted tyrosine kinase inhibitor that has been shown to have good efficacy in patients with renal cell carcinoma. A previous phase II trial demonstrated that short-term pazopanib administration was generally well tolerated and showed antitumor activity in patients with early-stage non-small cell lung cancer. Herein, we report on the case of a 66-year-old man with simultaneous metastatic squamous cell carcinoma of the lung and renal cell carcinoma who was treated with pazopanib. The patient showed an unexpected partial response and experienced a 10-month progression-free survival without significant toxicity. To the best of the authors' knowledge, this is the first report of pazopanib treatment in a non-small cell lung cancer patient in Korea. The results in this patient suggest that pazopanib may be a valid treatment option for advanced non-small cell lung cancer.

Topics: Aged; Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; Disease-Free Survival; Humans; Indazoles; Kidney Neoplasms; Lung Neoplasms; Male; Protein-Tyrosine Kinases; Pyrimidines; Republic of Korea; Sulfonamides; Treatment Outcome

Cancer cells with high metastatic potential and stem cell-like characteristics express the cell surface marker CD44. CD44 isoforms that include the v6 exon are co-receptors for the receptor tyrosine kinases MET and Vascular Endothelial Growth factor Receptor-2 (VEGFR-2). We studied CD44v6 signaling in several pancreatic cancer cell lines, and its role in tumor growth and metastasis in several models of pancreatic cancer.. We analyzed the effects of v6 peptides that interfere with the co-receptor functions of CD44v6 for MET and VEGFR-2 in tumors and metastases grown from cells that express different CD44 isoforms, including CD44v6. The peptides were injected into rats with syngeneic tumors and mice with orthotopic or xenograft tumors. We also tested the effects of the peptides in mice with xenograft tumors grown from patient tumor samples and mice that express an oncogenic form of RAS and develop spontaneous pancreatic cancer (KPC mice). We measured levels of CD44v6 messenger RNA (mRNA) in pancreatic cancer tissues from 136 patients.. Xenograft tumors grown from human cancer cells injected with v6 peptides were smaller and formed fewer metastases in mice. The v6 peptide was more efficient than the MET inhibitor crizotinib and/or the VEGFR-2 inhibitor pazopanib in reducing xenograft tumor growth and metastasis. Injection of KPC mice with the v6 peptide increased their survival time. Injection of mice and rats bearing metastases with the v6 peptide induced regression of metastases. Higher levels of CD44v6 mRNA in human pancreatic tumor tissues were associated with increased expression of MET, tumor metastasis, and shorter patient survival times.. Peptide inhibitors of CD44v6 isoforms block tumor growth and metastasis in several independent models of pancreatic cancer. The v6 peptides induced regression of metastases. Levels of CD44v6 mRNA are increased, along with those of MET mRNA, in patients with metastatic pancreatic tumors, compared with nonmetastatic tumors; the increased levels correlated with shorter patient survival time.

Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Movement; Crizotinib; Gene Expression Regulation, Neoplastic; Genes, ras; Humans; Hyaluronan Receptors; Indazoles; Kaplan-Meier Estimate; Lung Neoplasms; Male; Mice, Nude; Mice, Transgenic; Mutation; Neoplasm Metastasis; Pancreatic Neoplasms; Peptides; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-met; Pyrazoles; Pyridines; Pyrimidines; Rats; RNA, Messenger; Signal Transduction; Sulfonamides; Time Factors; Transfection; Tumor Burden; Vascular Endothelial Growth Factor Receptor-2; Xenograft Model Antitumor Assays

Topics: Angiogenesis Inhibitors; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Axitinib; Bevacizumab; Brain Edema; Brain Neoplasms; Carcinoma, Renal Cell; Female; Humans; Imidazoles; Indazoles; Lung Neoplasms; Middle Aged; Programmed Cell Death 1 Receptor; Protein Kinase Inhibitors; Pyrimidines; Radiation Injuries; Sulfonamides

It is currently not known whether treatment with anti-vascular endothelial growth factor agents for metastatic renal cell carcinoma (mRCC) can be safely discontinued in patients achieving a complete response (CR).. To assess outcomes for patients with mRCC achieving CR on targeted therapy (TT) and the survival of patients discontinuing TT after CR.. A national registry was used to identify patients achieving CR during first-line TT using bevacizumab, sunitinib, sorafenib, or pazopanib.. Relationships with outcomes were analysed using a log-rank test.. A total of 100 patients achieving CR were identified out of 2803 patients. The median time to CR was 10.1 mo. Median progression-free survival (PFS) from TT initiation was 3.8 yr (95% confidence interval [CI] 2.9-4.6 yr) and the 5-yr overall survival (OS) was 80% (95% CI 70-91%). Patients discontinuing TT within 1 mo after achieving CR and those continuing TT beyond CR had similar OS (CI for difference in 2-yr post-CR OS -13% to 19%; p=0.3) and PFS (CI for difference in 2-yr post-CR PFS -29% to 17%; p=0.7). The limitations include the retrospective, registry-based data analysis.. Achievement of CR on TT for mRCC was associated with excellent long-term prognosis. No significant differences in post-CR survival were observed between patients discontinuing TT after the date of CR and those who continued on TT, although the wide CIs cannot exclude important differences between the groups.. According to this registry-based analysis, patients with metastatic renal cancer with no signs of disease (complete response) after treatment with targeted agents experience excellent long-term survival even if the treatment does not continue beyond the date of complete response.

Topics: Aged; Antineoplastic Agents; Bevacizumab; Carcinoma, Renal Cell; Disease-Free Survival; Female; Humans; Indazoles; Indoles; Kidney Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Molecular Targeted Therapy; Niacinamide; Phenylurea Compounds; Pyrimidines; Pyrroles; Receptors, Vascular Endothelial Growth Factor; Registries; Response Evaluation Criteria in Solid Tumors; Sorafenib; Sulfonamides; Sunitinib; Survival Rate; Treatment Outcome; Withholding Treatment

Soft tissue sarcomas are rare malignant tumors with a great variety of histological types and different response to multimodality treatment. Pazopanib has been recently introduced for the treatment of non-adipocytic metastatic soft tissue sarcomas which are resistant to conventional chemotherapy. Spontaneous pneumothorax is a rare but well recognized complication of this molecule and its treatment is quite challenging. The case reported herein describes the surgical management of a simultaneous bilateral spontaneous pneumothorax in a patient with pulmonary metastases treated with pazopanib. It underlines the fact that the main objective should be the maintenance of the treatment in patients who benefit from it. Close oncologic and surgical collaboration is crucial in order to deal with adverse effects due to the anti-angiogenic action of pazopanib.

Topics: Humans; Indazoles; Lung Neoplasms; Male; Middle Aged; Muscle Neoplasms; Pneumonectomy; Pneumothorax; Pyrimidines; Sarcoma; Sulfonamides

Uterine leiomyosarcoma (ULMS) is an aggressive tumor associated with high rates of progression, recurrence, and mortality. Pazopanib is the only approved molecular targeted drug for advanced soft tissue sarcoma, and it has been proven to prolong progression-free survival relative to placebo. We herein report a case of ULMS with multiple lung metastases treated with pazopanib, which led to sustained disease control for 44 weeks. A 53-year-old woman was referred to our hospital due to massive uterine bleeding from a uterine corpus tumor mass. Total abdominal hysterectomy with bilateral salpingo-oophorectomy was performed as emergency surgery. The final histopathological diagnosis was uterine leiomyosarcoma, and computed tomography revealed multiple lung metastases. After chemotherapy with 17 cycles of gemcitabine and docetaxel and two cycles of doxorubicin, the lung metastases had increased in size and new lesions had appeared. Pazopanib administration at 800 mg/day was started as third-line therapy. Ten weeks later, the dose of pazopanib was reduced to 600 mg/day because of hepatic impairment and hypertension. However, lung metastases of ULMS were stabilized by pazopanib administration for about 44 weeks without a decline in the patient's quality of life. After 44 weeks of therapy, pazopanib administration was discontinued because of progressive disease and worsening of the patient's respiratory status. Pazopanib is an oral multityrosine kinase inhibitor of vascular endothelial growth factor receptor-1, -2, and -3; platelet-derived growth factor-α and -β; and c-Kit receptor. The role of pazopanib may be clinically significant in the treatment of advanced ULMS.

Topics: Antineoplastic Agents; Female; Humans; Indazoles; Leiomyosarcoma; Lung Neoplasms; Middle Aged; Protein Kinase Inhibitors; Pyrimidines; Salvage Therapy; Sulfonamides; Tomography, X-Ray Computed; Uterine Neoplasms

Topics: Aged; Angiogenesis Inhibitors; Carcinoma, Transitional Cell; Female; Gene Amplification; Humans; Indazoles; Lung Neoplasms; Mutation; Pyrimidines; Receptor, Fibroblast Growth Factor, Type 3; Sulfonamides; Urinary Bladder Neoplasms

Antiangiogenic agents have been widely investigated in combination with standard chemotherapy or targeted cancer agents for better management of advanced cancers. Therapeutic agents that concurrently inhibit epidermal growth factor receptor and other angiokinases could be useful alternatives to combination therapies for epidermal growth factor receptor-dependent cancers. Here, we report the synthesis of an indole derivative of pazopanib using a bioisosteric replacement strategy, which was designated MKP101. MKP101 inhibited not only the epidermal growth factor receptor with an IC50 value of 43 nM but also inhibited angiokinases as potently as pazopanib. In addition, MKP101 effectively inhibited vascular endothelial growth factor-induced endothelial proliferation, tube formation, migration of human umbilical vein endothelial cells and proliferation of HCC827, an epidermal growth factor receptor-addicted cancer cell line. A docking model of MKP101 and the kinase domain of the epidermal growth factor receptor was generated to predict its binding mode, and validated by synthesizing and evaluating MKP101 derivatives. Additionally, a study of structure-activity relationships of indolylamino or indolyloxy pyrimidine analogues derived from MKP101 demonstrated that selectivity for epidermal growth factor receptor and other angiokinases, especially vascular endothelial growth factor receptor 2 depends on the position of substituents on pyrimidine and the type of link between pyrimidine and the indole moiety. We believe that this study could provide a basis for developing angiokinase inhibitors having high affinity for the epidermal growth factor receptor, from the pyrimidine scaffold.

Topics: Angiogenesis Inhibitors; Carcinoma, Non-Small-Cell Lung; Cell Proliferation; ErbB Receptors; Human Umbilical Vein Endothelial Cells; Humans; Indazoles; Indoles; Inhibitory Concentration 50; Lung Neoplasms; Molecular Docking Simulation; Neovascularization, Pathologic; Protein Kinase Inhibitors; Protein Kinases; Pyrimidines; Structure-Activity Relationship; Sulfonamides; Vascular Endothelial Growth Factor A

Topics: Angiogenesis Inhibitors; Humans; Indazoles; Lung Neoplasms; Male; Middle Aged; Pyrimidines; Sarcoma; Sulfonamides; Tomography, X-Ray Computed

Topics: Aged; Female; Granular Cell Tumor; Humans; Indazoles; Lung Neoplasms; Lymphatic Metastasis; Pyrimidines; Receptors, Vascular Endothelial Growth Factor; Sulfonamides; Treatment Outcome

Assess interaction of pazopanib, an oral antivascular endothelial growth factor inhibitor, with radiation in tumor xenograft models.. Flank xenografts in female athymic nude mice of human lung cancer cell line, A549, and head and neck cancer cell line, UM-SCC-6, were allowed to grow to ∼5×5 mm. Groups were then treated with pazopanib and/or escalating doses of radiation and tumor measurements over time compared with untreated tumor-bearing controls. Pazopanib (100 mg/kg) began 7 days before radiation and continued for 28 days. Daily radiation was 0.5, 1, 2, or 3 Gy ×5 days.. Tumors in the A549 control group reached >4× the original size by day 36 postradiation. All treatment groups had less robust tumor growth (p<0.05) and the group receiving pazopanib+3 Gy radiation/day had tumor regression to less than baseline. In the UM-SCC-6-tumor-bearing animals, tumors in all treatment groups had less robust growth than untreated controls after day 23 post-treatment.. The combination of pazopanib and radiation resulted in a trend of superior tumor growth inhibition compared with either agent alone. All treatment groups had impaired tumor progression compared with untreated controls.

Topics: Angiogenesis Inhibitors; Animals; Cell Line, Tumor; Combined Modality Therapy; Female; Head and Neck Neoplasms; Humans; Indazoles; Lung Neoplasms; Mice; Mice, Nude; Pyrimidines; Sulfonamides; Xenograft Model Antitumor Assays

Topics: Adolescent; Angiogenesis Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Female; Humans; Humerus; Indazoles; Lung Neoplasms; Male; Neoplasms, Radiation-Induced; Osteosarcoma; Pyrimidines; Skull Neoplasms; Sulfonamides; Young Adult

Topics: Aged; Angiogenesis Inhibitors; Axitinib; Carcinoma, Renal Cell; Female; Humans; Imidazoles; Indazoles; Kidney Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Neoplasm Recurrence, Local; Prognosis; Pyrimidines; Radiography; Spinal Neoplasms; Sulfonamides

Increasing studies implicate cancer stem cells (CSCs) as the source of resistance and relapse following conventional cytotoxic therapies. Few studies have examined the response of CSCs to targeted therapies, such as tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs would have differential effects on CSC populations depending on their mechanism of action (anti-proliferative vs. anti-angiogenic).. We exposed human sarcoma cell lines to sorafenib, regorafenib, and pazopanib and assessed cell viability and expression of CSC markers (ALDH, CD24, CD44, and CD133). We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy. We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.. After functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P < 0.05), with a corresponding 1.4 - 2.8 fold increase in ALDHbright cells from baseline (P < 0.05). In contrast, we observed negligible effects on viability and CSC sub-populations with pazopanib. At low doses, there was progressive CSC enrichment in vitro after longer term exposure to sorafenib although the anti-proliferative effects were attenuated. In vivo, sorafenib improved median survival by 11 days (P < 0.05), but enriched ALDHbright cells 2.5 - 2.8 fold (P < 0.05). Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells (P < 0.05). Again, negligible effects from pazopanib were observed. TMA analysis of archived specimens from sarcoma patients treated with sorafenib demonstrated significant enrichment for ALDHbright cells in the post-treatment resection specimen (P < 0.05), whereas clinical specimens obtained longitudinally from a patient treated with pazopanib showed no enrichment for ALDHbright cells (P > 0.05).. Anti-proliferative TKIs appear to enrich for sarcoma CSCs while anti-angiogenic TKIs do not. The rational selection of targeted therapies for sarcoma patients may benefit from an awareness of the differential impact of TKIs on CSC populations.

Topics: Aldehyde Dehydrogenase 1 Family; Angiogenesis Inhibitors; Animals; Antigens, CD; Cell Line, Tumor; Cell Proliferation; Cell Survival; Female; Humans; Indazoles; Isoenzymes; Liver Neoplasms; Lung Neoplasms; Mice, Inbred NOD; Neoadjuvant Therapy; Neoplastic Stem Cells; Niacinamide; Phenylurea Compounds; Protein Kinase Inhibitors; Pyrimidines; Retinal Dehydrogenase; Sarcoma; Sorafenib; Sulfonamides; Tissue Array Analysis; Xenograft Model Antitumor Assays

Topics: Adamantinoma; Adult; Antineoplastic Agents; Female; Humans; Indazoles; Lung Neoplasms; Pyrimidines; Sulfonamides

A comprehensive description of genomic alterations in lung squamous cell carcinoma (lung SCC) has recently been reported, enabling the identification of genomic events that contribute to the oncogenesis of this disease. In lung SCC, one of the most frequently altered receptor tyrosine kinase families is the fibroblast growth factor receptor (FGFR) family, with amplification or mutation observed in all four family members. Here, we describe the oncogenic nature of mutations observed in FGFR2 and FGFR3, each of which are observed in 3% of samples, for a mutation rate of 6% across both genes. Using cell culture and xenograft models, we show that several of these mutations drive cellular transformation. Transformation can be reversed by small-molecule FGFR inhibitors currently being developed for clinical use. We also show that mutations in the extracellular domains of FGFR2 lead to constitutive FGFR dimerization. In addition, we report a patient with an FGFR2-mutated oral SCC who responded to the multitargeted tyrosine kinase inhibitor pazopanib. These findings provide new insights into driving oncogenic events in a subset of lung squamous cancers, and recommend future clinical studies with FGFR inhibitors in patients with lung and head and neck SCC.

Topics: Animals; Carcinogenesis; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Dimerization; Humans; Indazoles; Interleukin-3; Ligands; Lung Neoplasms; Mice; Mice, Nude; Mutation; NIH 3T3 Cells; Protein Kinase Inhibitors; Pyrimidines; Receptor, Fibroblast Growth Factor, Type 2; Receptor, Fibroblast Growth Factor, Type 3; Sulfonamides

Predictive biomarkers to guide therapy for cancer patients are a cornerstone of precision medicine. Discussed herein are considerations regarding the design and interpretation of such predictive biomarker studies. These considerations are important for both planning and interpreting prospective studies and for using specimens collected from completed randomized clinical trials. Specific issues addressed are differentiation between qualitative and quantitative predictive effects, challenges due to sample size requirements for predictive biomarker assessment, and consideration of additional factors relevant to clinical utility assessment, such as toxicity and cost of new therapies as well as costs and potential morbidities associated with routine use of biomarker-based tests.

Topics: Antineoplastic Agents; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Renal Cell; Dacarbazine; DNA Modification Methylases; DNA Repair Enzymes; ErbB Receptors; Gefitinib; Glioblastoma; Humans; Indazoles; Interleukin-6; Kidney Neoplasms; Lung Neoplasms; Methylation; Molecular Targeted Therapy; Mutation; Neoplasms; Precision Medicine; Predictive Value of Tests; Pyrimidines; Quinazolines; Radiotherapy, Adjuvant; Randomized Controlled Trials as Topic; Sample Size; Sulfonamides; Temozolomide; Tumor Suppressor Proteins

Osteosarcoma (OS) is the most common malignant bone tumor and the prognosis depends on pulmonary metastases, which arise from multi-step progression of malignant tumors. We herein aimed to clarify the critical step of pulmonary metastasis using the syngeneic mouse spontaneous highly metastatic OS LM8 and parental Dunn cell lines, to identify new candidate molecules to suppress pulmonary metastasis. We first investigated the chronological detection of circulating tumor cells (CTCs) from mice with either cell line. LM8 CTCs appeared faster, at a higher rate and with a greater number compared to Dunn CTCs. Cultured cells from CTCs of LM8 showed higher proliferative ability than cells from the primary site in suspension culture, which mimicked the environment of the bloodstream for CTCs. The proliferative ability of LM8 cells was also higher than that of Dunn cells in 3D collagen culture with low stiffness (-150 Pa; close to conditions in the lung). We next focused on the extravasation step. LM8 showed higher migration ability compared to Dunn with transendothelial migration assay. We also found a disruption in endothelial barrier function throughout co-culture with LM8 using time-lapse imaging. In addition, LM8 secreted high levels of vascular endothelial growth factor (VEGF), while VEGF signal inhibition with a small molecule tyrosine kinase inhibitor (pazopanib) decreased disruption of the vascular barrier and transendothelial migration of LM8. Finally, daily oral administration of pazopanib reduced the rate and size of pulmonary metastasis in vivo. Collectively, these results show anti-VEGF therapy as a candidate for pulmonary metastasis of OS.

Topics: Angiogenesis Inhibitors; Animals; Apoptosis; Blotting, Western; Bone Neoplasms; Cell Movement; Cell Proliferation; Coculture Techniques; Immunoenzyme Techniques; Indazoles; Lung Neoplasms; Mice; Mice, Inbred C3H; Osteosarcoma; Pyrimidines; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sulfonamides; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Burkitt Lymphoma; Carcinoma, Non-Small-Cell Lung; Humans; Indazoles; Lung Neoplasms; Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Neoplasms; Pyrimidines; Randomized Controlled Trials as Topic; Rituximab; Sulfonamides; Treatment Outcome