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Current Treatment Options in Oncology Oct 2021New molecular insights are being achieved in synovial sarcoma (SS) that can provide new potential diagnostic and prognostic markers as well as therapeutic targets. In... (Review)
Review
New molecular insights are being achieved in synovial sarcoma (SS) that can provide new potential diagnostic and prognostic markers as well as therapeutic targets. In particular, the advancement of research on epigenomics and gene regulation is promising. The concrete hypothesis that the pathogenesis of SS might mainly depend on the disruption of the balance of the complex interaction between epigenomic regulatory complexes and the consequences on gene expression opens interesting new perspectives. The standard of care for primary SS is wide surgical resection combined with radiation in selected cases. The role of chemotherapy is still under refinement and can be considered in patients at high risk of metastasis or in those with advanced disease. Cytotoxic chemotherapy (anthracyclines, ifosfamide, trabectedin, and pazopanib) is the treatment of choice, despite several possible side effects. Many possible drug-able targets have been identified. However, the impact of these strategies in improving SS outcome is still limited, thus making current and future research strongly needed to improve the survival of patients with SS.
Topics: Anthracyclines; Antineoplastic Agents; Chemotherapy, Adjuvant; Epigenomics; Gene Expression Regulation, Neoplastic; Genomics; Humans; Ifosfamide; Indazoles; Molecular Targeted Therapy; Pyrimidines; Radiotherapy, Adjuvant; Sarcoma, Synovial; Soft Tissue Neoplasms; Sulfonamides; Surgical Procedures, Operative; Trabectedin
PubMed: 34687366
DOI: 10.1007/s11864-021-00914-4 -
Ecancermedicalscience 2021Uncommon histopathological subtypes account for less than 5% cases of soft tissue sarcoma (STS) and unclassified STSs comprise another 16%, these are often...
BACKGROUND
Uncommon histopathological subtypes account for less than 5% cases of soft tissue sarcoma (STS) and unclassified STSs comprise another 16%, these are often chemotherapy-resistant, with a dismal outcome in unresectable/metastatic disease. Prospective studies on the use of pazopanib in this cohort of patients are lacking in the literature. Here, we describe the safety and efficacy of pazopanib in rare histologies of advanced STS.
MATERIALS AND METHODS
We conducted a retrospective study at two tertiary cancer centres in India, evaluating 33 cases of rare subtypes of STS, who received pazopanib as per institutional protocol between January 2013 and December 2019. Patients who received pazopanib for unresectable/metastatic disease were enrolled in this study for clinicopathologic features, treatment outcome and evaluation of prognostic factors.
RESULTS
Out of 33 patients, there were seven cases of undifferentiated pleomorphic sarcoma, four cases each of myxofibrosarcoma, epithelioid sarcoma and malignant peripheral nerve sheath tumour, three cases each of haemangiopericytoma and spindle cell sarcoma, two cases of haemangioendothelioma and a case each of clear cell sarcoma, retroperitoneal sarcoma, angiosarcoma and pleomorphic rhabdomyosarcoma-adult type. The objective response rate was 27%. Most of the patients (67%) received pazopanib in second or subsequent lines of therapy. The majority (70%) were started at a lower dose of 400/600 mg and only 43% of these (10/23) could be escalated to a full dose of 800 mg based on tolerance. On univariate analysis, pazopanib's starting dose didn't predict progression-free survival (PFS)/overall survival (OS)/response rate. At a median duration of follow-up of 18.8 months (range 1.9-150.4 months), the median PFS and median OS were 10.3 months (95% confidence interval (CI): 5.9-14.8) and 17.8 months (95% CI: 10.7-29.3), respectively. 27% of the patients experienced grade ¾ toxicities, 12% required dose modification of pazopanib and 21% needed permanent discontinuation due to toxicity.
CONCLUSION
Our study shows that pazopanib is active in rare subtypes of STS.
PubMed: 34824604
DOI: 10.3332/ecancer.2021.1281 -
The Journal of Pharmacology and... Feb 2022Drug-induced liver injury (DILI) is the leading cause of acute liver failure and a major concern in drug development. Altered bile acid homeostasis via inhibition of the...
Drug-induced liver injury (DILI) is the leading cause of acute liver failure and a major concern in drug development. Altered bile acid homeostasis via inhibition of the bile salt export pump (BSEP) is one mechanism of DILI. Dasatinib, pazopanib, and sorafenib are tyrosine kinase inhibitors (TKIs) that competitively inhibit BSEP and increase serum biomarkers for hepatotoxicity in ∼25-50% of patients. However, the mechanism(s) of hepatotoxicity beyond competitive inhibition of BSEP are poorly understood. This study examined mechanisms of TKI-mediated hepatotoxicity associated with altered bile acid homeostasis. Dasatinib, pazopanib, and sorafenib showed bile acid-dependent toxicity at clinically relevant concentrations, based on the C-DILI assay using sandwich-cultured human hepatocytes (SCHH). Among several bile acid-relevant genes, cytochrome P450 (CYP) 7A1 mRNA was specifically upregulated by 6.2- to 7.8-fold (dasatinib) and 5.7- to 9.3-fold (pazopanib), compared with control, within 8 hours. This was consistent with increased total bile acid concentrations in culture medium up to 2.3-fold, and in SCHH up to 1.4-fold, compared with control, within 24 hours. Additionally, protein abundance of sodium taurocholate co-transporting polypeptide (NTCP) was increased up to 2.0-fold by these three TKIs. The increase in NTCP protein abundance correlated with increased function; dasatinib and pazopanib increased hepatocyte uptake clearance (CL) of taurocholic acid, a probe bile acid substrate, up to 1.4-fold. In conclusion, upregulation of and NTCP in SCHH constitute novel mechanisms of TKI-associated hepatotoxicity. SIGNIFICANCE STATEMENT: Understanding the mechanisms of hepatotoxicity associated with tyrosine kinase inhibitors (TKIs) is fundamental to development of effective and safe intervention therapies for various cancers. Data generated in sandwich-cultured human hepatocytes, an model of drug-induced hepatotoxicity, revealed that TKIs upregulate bile acid synthesis and alter bile acid uptake and excretion. These findings provide novel insights into additional mechanisms of bile acid-mediated drug-induced liver injury, an adverse effect that limits the use and effectiveness of TKI treatment in some cancer patients.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 11; Antineoplastic Agents; Bile Acids and Salts; Cells, Cultured; Chemical and Drug Induced Liver Injury; Cholesterol 7-alpha-Hydroxylase; Dasatinib; Hepatocytes; Humans; Indazoles; Organic Anion Transporters, Sodium-Dependent; Protein Kinase Inhibitors; Pyrimidines; Sorafenib; Sulfonamides; Symporters
PubMed: 34794962
DOI: 10.1124/jpet.121.000828 -
European Journal of Cancer (Oxford,... Jul 2024Sorafenib and pazopanib, two tyrosine kinase inhibitors (TKI), are widely used in patients with progressive symptomatic desmoid tumors (DT). Limited real-word data is...
BACKGROUND
Sorafenib and pazopanib, two tyrosine kinase inhibitors (TKI), are widely used in patients with progressive symptomatic desmoid tumors (DT). Limited real-word data is available on long-term outcomes of patients who progressed on, stopped, or continued TKIs.
METHODS
Patients diagnosed with DTs and treated with sorafenib or pazopanib between 2011 and 2022 at 11 institutions were reviewed. Patient history, response to therapy and toxicity were recorded. Statistical analyses utilized Kaplan-Meier and log-rank tests.
RESULTS
142 patients with DT treated with sorafenib (n = 126, 88.7 %) or pazopanib (n = 16, 11.3 %) were analyzed. The median treatment duration was 10.8 months (range: 0.07- 73.9). The overall response rate and the disease control rate were 26.0 % and 95.1 %, respectively. The median tumor shrinkage was - 8.5 % (range -100.0 %- +72.5 %). Among responders, the median time to an objective response was 15.2 months (range: 1.1 to 33.1). The 1-year and 2-year progression-free survival rates were 82 % and 80 %. Dose reductions were necessary in 34 (23.9 %) patients. Grade 3 or higher adverse events were reported in 36 (25.4 %) patients. On the last follow-up, 55 (38.7 %) patients continued treatment. Treatment discontinuation (n = 85, 59.9 %) was mainly for toxicity (n = 35, 45.9 %) or radiological or clinical progression (n = 30, 35.3 %). For the entire cohort, 36 (25.4 %) patients required subsequent treatment. In the 32 responders, only 1 (3.1 %) patient required a subsequent treatment. In patients who discontinued TKI, 25 (44.6 %) with stable disease received subsequent treatment compared to 0 (0.0 %) of responders.
CONCLUSION
This retrospective study represents the largest cohort of DT patients treated with sorafenib or pazopanib to date. Discontinuation of treatment in responders is safe. The optimal treatment duration in patients with stable disease remains to be defined.
Topics: Humans; Indazoles; Sorafenib; Sulfonamides; Male; Female; Pyrimidines; Middle Aged; Adult; Aged; Young Adult; Fibromatosis, Aggressive; Adolescent; Retrospective Studies; Aged, 80 and over; Progression-Free Survival; Protein Kinase Inhibitors; Antineoplastic Combined Chemotherapy Protocols; Treatment Outcome
PubMed: 38759389
DOI: 10.1016/j.ejca.2024.114119 -
Thoracic Cancer Nov 2014Angiogenesis is an indispensible process for tumor growth and metastasis. Anti-angiogenesis based therapy is one of the most promising treatments for inhibiting cancer... (Review)
Review
Angiogenesis is an indispensible process for tumor growth and metastasis. Anti-angiogenesis based therapy is one of the most promising treatments for inhibiting cancer progression. Through the exploration of inhibitors of vascular endothelial growth factor receptor (VEGFR)-2, deemed as the major angiogenesis pathway, pazopanib was found as a small molecular pan-VEGFR and pan-platelet-derived growth factor receptor (PDGFR) inhibitor, with suitable pharmacodynamic and pharmacokinetic parameters to be an oral drug. In an vitro study, pazopanib exerted anti-tumor effect through mechanisms including the Raf-MAPK/ERK (MEK)-extracellular signal-regulated kinase (ERK) pathway, and directly targeted on v-raf murine sarcoma viral oncogene homolog B (B-raf) as well. It inhibited the proliferation of cell lines, such as DU-145 and HRC-45 in hepatocellular carcinoma, through mechanisms like "cell cycle arrest." In vivo xenograft studies and phase I/II clinical trials revealed a series of plasma cytokine and angiogenic factors, such as interleukin (IL)-6, IL-12, hepatocyte growth factor (HGF), and soluble VEGFR2, which have significant association with clinical curative effect. Pazopanib has been shown to be effective in solid tumors and some hematological malignancies. Future studies should focus on the exploration of biomarkers to screen sensitive patients and concomitant or metronomic dosage with other kinds of medicines.
PubMed: 26767042
DOI: 10.1111/1759-7714.12136 -
Acta Medica Indonesiana Oct 2016In the past 10 years, recent development of targeted therapy in metastatic renal cell carcinoma (mRCC) has provided a new hope and significantly enhanced the prognosis... (Review)
Review
In the past 10 years, recent development of targeted therapy in metastatic renal cell carcinoma (mRCC) has provided a new hope and significantly enhanced the prognosis of the disease. Three class of targeted therapy were developed, including multi-targeted tyrosine kinase inhibitors (TKI), the mammalian target of rapamycin (mTOR) complex-1 kinase inhibitors, and the humanized antivascular endothelial growth factor (VEGF) monoclonal antibody. Hence, the objective of this article was to critically examine the current evidence of targeted therapy treatment for patients with mRCC. In the majority of trials evaluating targeted therapy, patients were stratified according to Memorial Sloan Kattering Cancer Center (MSKCC) risk model and the recommendation of targeted treatment based on risk features. In first-line setting (no previous treatment), sunitinib, pazopanib, or bevacizumab plus IFN-α were recommended as treatment options for patient with favorable- or intermediate- risk features and clear cell histology. Patients who progressed after previous cytokine therapy would have sorafenib or axitinib as treatment options. Clear-cell mRCC with favorable- or intermediate- risk features and failure with first-line TKI therapy might be treated with sorafenib, everolimus, temsirolimus or axitinib. However, the current evidence did not show the best treatment sequencing after first-line TKI failure. In patients with poor-risk clear-cell and non-clear cell mRCC, temsirolimus was the treatment option supported by phase III clinical trial. In addition, several new drugs, nowadays, are still being investigated and waiting for the result of phase II or III clinical trial, and this might change the standard therapy for mRCC in the future.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Axitinib; Bevacizumab; Carcinoma, Renal Cell; Everolimus; Humans; Imidazoles; Immunologic Factors; Indazoles; Indoles; Interferon-alpha; Kidney Neoplasms; Niacinamide; Phenylurea Compounds; Prognosis; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Sirolimus; Sorafenib; Sulfonamides; Sunitinib
PubMed: 28143997
DOI: No ID Found -
Frontiers in Oncology 2015Pazopanib and sunitinib are treatment options for metastatic renal cell cancer (mRCC), with similar efficacy, and minor differences in their toxicity profile. Our...
Pazopanib and sunitinib are treatment options for metastatic renal cell cancer (mRCC), with similar efficacy, and minor differences in their toxicity profile. Our experience has suggested that pazopanib-induced alopecia may be a potentially significant but previously under-reported toxicity. For this reason, we performed a retrospective review of the clinical records of all patients with mRCC treated with pazopanib at the Royal Marsden Hospital from European licensing until June 2013, and all patients treated with sunitinib over the same period. We found that 36 patients with mRCC were treated with pazopanib and 85 patients with sunitinib. Four of the 36 (11%) patients treated with pazopanib developed alopecia severe enough to warrant a wig versus none of 85 patients treated with sunitinib (p = 0.007). In conclusion, grade 2 pazopanib-induced alopecia was reported at significantly higher rates when compared to sunitinib-induced alopecia. Hence, in our view, patients should be informed about this potential toxicity when discussing the treatment options for mRCC.
PubMed: 26029668
DOI: 10.3389/fonc.2015.00112 -
BMC Urology Jul 2016The currently recommended treatment algorithm for patients with advanced renal cell carcinoma who fail the first-line targeted therapy does not normally include... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
The currently recommended treatment algorithm for patients with advanced renal cell carcinoma who fail the first-line targeted therapy does not normally include pazopanib as a second-line treatment option. It would therefore be of interest to determine the efficiency of pazopanib in this setting in terms of the partial response rate (PRR), disease control rate (DCR), and progression-free survival (PFS).
METHODS
Peer-reviewed clinical reports without language restriction, both full papers and conference abstracts, which assessed the second-line use of pazopanib following failure of first-line non-cytokine-targeted therapy, were included. After the literature retrieval, we conducted a Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA)-compliant systematic review of the literature and meta-analysis of the size of the effect of each outcome measure (PRR, DCR, and PFS). The effect size and 95 % confidence interval (CI) were calculated using fixed-effect or random-effects models based on the heterogeneity represented by I(2) of selected studies. Meta-analysis forest plots with a fixed-effect model showing the PRR and DCR were created.
RESULTS
Our results show that there are no available comparative studies on pazopanib second-line treatment. Only phase II trials or retrospective analysis reports were retrievable. Six studies (comprising 217 patients) were included in the qualitative and quantitative analysis. Pazopanib as a second-line treatment resulted in a PRR of 23 % (95 % CI, 17-31 %; I(2) = 52.6 %) and a DCR of 73 % (95 % CI, 65-80 %; I(2) = 0.00 %). The meta-analysis with fixed-effect model revealed that PFS was 6.5 months (95 % CI, 5.6-7.5 months; I(2) = 86.2 %).
CONCLUSIONS
In conclusion, the effectiveness and indication of pazopanib for use in the second-line setting has not yet been examined in-depth; however, this meta-analysis has shown that the treatment effects in terms of PRR, DCR, and PFS may be similar to other well-studied second-line targeted therapies. Rigorous comparative phase III trials testing this hypothesis are required.
Topics: Angiogenesis Inhibitors; Antineoplastic Agents; Carcinoma, Renal Cell; Disease-Free Survival; Humans; Indazoles; Kidney Neoplasms; Pyrimidines; Sulfonamides; Treatment Outcome
PubMed: 27377922
DOI: 10.1186/s12894-016-0156-4 -
Journal of Thoracic Disease Apr 2024Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease with a high mortality rate and limited treatment efficacy. Nintedanib, a...
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease with a high mortality rate and limited treatment efficacy. Nintedanib, a tyrosine kinase inhibitor, is clinically used to treat pulmonary fibrosis. At present, only nintedanib is on the market for the treatment of pulmonary fibrosis. Pazopanib is a drug for the treatment of renal cell carcinoma and advanced soft tissue sarcoma.
METHODS
In this study, we explored whether pazopanib can attenuate bleomycin (BLM)-induced pulmonary fibrosis and explored its antifibrotic mechanism. and investigations were carried out to investigate the efficacy and mechanism of action of pazopanib in pulmonary fibrosis.
RESULTS
experiments showed that pazopanib can alleviate pulmonary fibrosis caused by BLM, reduce the degree of collagen deposition and improve lung function. experiments showed that pazopanib suppressed transforming growth factor-β1 (TGF-β1)-induced myofibroblast activation and promoted apoptosis and autophagy in myofibroblasts. Further mechanistic studies demonstrated that pazopanib inhibited the TGF-β1/Smad and non-Smad signaling pathways during fibroblast activation.
CONCLUSIONS
In conclusion, pazopanib attenuated BLM-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway. Pazopanib inhibits myofibroblast activation, migration, autophagy, apoptosis, and extracellular matrix (ECM) buildup by downregulating the TGF-β1/Smad signal route and the TGF-β1/non-Smad signal pathway. It has the same target as nintedanib and is a tyrosine kinase inhibitor.
PubMed: 38738240
DOI: 10.21037/jtd-23-1349 -
Therapeutic Advances in Urology Feb 2016Pazopanib is an orally available multitargeted tyrosine kinase inhibitor (a class of targeted therapies) that inhibits tumor angiogenesis and cell proliferation. The... (Review)
Review
Pazopanib is an orally available multitargeted tyrosine kinase inhibitor (a class of targeted therapies) that inhibits tumor angiogenesis and cell proliferation. The safety and efficacy of pazopanib (noninferior to sunitinib for progression-free survival) in patients with advanced or metastatic renal cell carcinoma (mRCC) have been demonstrated in several clinical trials. However, in addition to therapeutic efficacy, treatment choices should also take into account health-related quality of life (HRQoL) aspects of cancer therapy. Here, we summarize the HRQoL findings related to pazopanib use, based on patient-reported outcome measures; pazopanib has been shown to be superior to sunitinib on several HRQoL domains (including patient preference). A further consideration for treatment choice is how well the findings from clinical trials correlate with evidence from general clinical practice. This review therefore includes descriptions of real-world experience of pazopanib use in the treatment of patients with mRCC, following its approval by medical regulatory authorities in a number of countries. Naturalistic observational studies demonstrate that the efficacy of pazopanib in patients with mRCC is consistent with clinical trial findings. Similarly, consistent results were observed for the safety profile of pazopanib between observational studies and clinical trials, with most treatment-associated adverse events being mild to moderate in severity, and manageable.
PubMed: 26834841
DOI: 10.1177/1756287215614236