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Pazopanib

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https://www.readbyqxmd.com/read/29788981/safety-of-pazopanib-and-sunitinib-in-treatment-naive-patients-with-metastatic-renal-cell-carcinoma-asian-versus-non-asian-subgroup-analysis-of-the-comparz-trial
#1
Jun Guo, Jie Jin, Mototsugu Oya, Hirotsugu Uemura, Shunji Takahashi, Katsunori Tatsugami, Sun Young Rha, Jae-Lyun Lee, Jinsoo Chung, Ho Yeong Lim, Hsi Chin Wu, Yen Hwa Chang, Arun Azad, Ian D Davis, Marlene J Carrasco-Alfonso, Bhupinder Nanua, Jackie Han, Qasim Ahmad, Robert Motzer
BACKGROUND: The international, phase 3 COMPARZ study demonstrated that pazopanib and sunitinib have comparable efficacy as first-line therapy in patients with advanced renal cell carcinoma, but that safety and quality-of-life profiles favor pazopanib. Our report analyzed pazopanib and sunitinib safety in Asian and non-Asian subpopulations. METHODS: Patients were randomized 1:1 to receive pazopanib 800 mg once daily (continuous dosing) or sunitinib 50 mg once daily in 6-week cycles (4 weeks on, 2 weeks off)...
May 22, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29787262/discovery-of-novel-pazopanib-based-hdac-and-vegfr-dual-inhibitors-targeting-cancer-epigenetics-and-angiogenesis-simultaneously
#2
Jie Zang, Xuewu Liang, Yongxue Huang, Yuping Jia, Xiaoyang Li, Wenfang Xu, C James Chou, Yingjie Zhang
Herein a novel series of pazopanib hybrids as polypharmacological antitumor agents were developed based on the crosstalk between histone deacetylases (HDACs) and vascular endothelial growth factor (VEGF) pathway. Among them, one ortho-aminoanilide 6d and one hydroxamic acid 13f exhibited considerable total HDACs and VEGFR-2 inhibitory activities. The HDAC inhibitory activities endowed 6d and 13f with potent antiproliferative activities, which was not observed in the approved VEGFR inhibitor pazopanib. Compounds 6d and 13f possessed comparable HDAC isoform selectivity profiles to the clinical class I HDAC inhibitor MS-275 and the approved pan-HDAC inhibitor SAHA, respectively...
May 22, 2018: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/29786782/preclinical-impact-of-high-dose-intermittent-antiangiogenic-tyrosine-kinase-inhibitor-pazopanib-in-intrinsically-resistant-tumor-models
#3
Elaine Reguera-Nuñez, Shan Man, Ping Xu, Robert S Kerbel
Antiangiogenic tyrosine kinase inhibitors (TKIs) target vascular endothelial growth factor receptors and other receptor tyrosine kinases. As a result of toxicity, the clinical failures or the modest benefits associated with antiangiogenic TKI therapy may be related in some cases to suboptimal drug dosing and scheduling, thereby facilitating resistance. Most antiangiogenic TKIs, including pazopanib, are administered on a continuous daily basis. Here, instead, we evaluated the impact of increasing the dose and administering the drug intermittently...
May 21, 2018: Angiogenesis
https://www.readbyqxmd.com/read/29784193/adjuvant-vascular-endothelial-growth-factor-targeted-therapy-in-renal-cell-carcinoma-a-systematic-review-and-pooled-analysis
#4
REVIEW
Maxine Sun, Lorenzo Marconi, Tim Eisen, Bernard Escudier, Rachel H Giles, Naomi B Haas, Lauren C Harshman, David I Quinn, James Larkin, Sumanta K Pal, Thomas Powles, Christopher W Ryan, Cora N Sternberg, Robert Uzzo, Toni K Choueiri, Axel Bex
CONTEXT: Contradictory data exist with regard to adjuvant vascular endothelial growth factor receptor (VEGFR)-targeted therapy in surgically managed patients for localized renal cell carcinoma (RCC). OBJECTIVE: To systematically evaluate the current evidence regarding the therapeutic benefit (disease-free survival [DFS] and overall survival [OS]) and grade 3-4 adverse events (AEs) for adjuvant VEGFR-targeted therapy for resected localized RCC. EVIDENCE ACQUISITION: A critical review of PubMed/Medline, Embase, and the Cochrane Library in January 2018 according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement was performed...
May 18, 2018: European Urology
https://www.readbyqxmd.com/read/29783587/re-randomized-phase-iii-trial-of-adjuvant-pazopanib-versus-placebo-after-nephrectomy-in-patients-with-localized-or-locally-advanced-renal-cell-carcinoma
#5
https://www.readbyqxmd.com/read/29780156/the-successful-treatment-of-metastatic-extraosseous-ewing-sarcoma-with-pazopanib
#6
Yoshinori Mori, Shiori Kinoshita, Takashi Kanamori, Hiromi Kataoka, Takashi Joh, Shinsuke Iida, Masashi Takemoto, Masahiro Kondo, Junko Kuroda, Hirokazu Komatsu
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...
May 18, 2018: Internal Medicine
https://www.readbyqxmd.com/read/29774795/prospective-evaluation-of-hypogonadism-in-male-metastatic-renal-cell-carcinoma-patients-treated-with-targeted-therapies
#7
Julie Bastin, Emilie Werbrouck, Annelies Verbiest, Kevin Punie, Oliver Bechter, Sherida Feng Woei-A-Jin, Pascal Wolter, Hans Wildiers, Evelyne Lerut, Herlinde Dumez, Brigitte Decallonne, Paul Clement, Dirk Vanderschueren, Maarten Albersen, Raymond Oyen, Patrick Schöffski, Benoit Beuselinck
Objectives To study the prevalence of hypogonadism in male patients with metastatic renal cell carcinoma (mRCC) starting with targeted therapies and the impact of the vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) sunitinib and pazopanib on the luteinizing hormone (LH)/testosterone (TT)-axis. Methods Male mRCC patients starting with targeted therapies were prospectively included in this study. TT- and LH-levels were sampled at start as well as during systemic therapy. Endpoints of the study were gonadal status (TT- and LH-levels) at start of targeted therapy and TT- and LH-evolution during targeted therapy...
May 18, 2018: Acta Clinica Belgica
https://www.readbyqxmd.com/read/29769293/emerging-multitarget-tyrosine-kinase-inhibitors-in-the-treatment-of-neuroendocrine-neoplasms
#8
Federica Grillo, Tullio Florio, Francesco Ferraù, Elda Kara, Giuseppe Fanciulli, Antongiulio Faggiano, Annamaria A L Colao
In the last few years, the therapeutic approach for neuroendocrine neoplasms (NENs) has changed dramatically following the approval of several novel targeted treatments. The multi-target tyrosine kinase inhibitor (MTKI), sunitinib malate, has been approved by regulatory agencies in pancreatic NENs. The MTKI class, however, includes several other molecules (approved for other conditions), which are currently being studied in NENs. An in depth review on the studies published on the following MTKIs in neuroendocrine tumours: axitinib, cabozantinib, famitinib, lenvatinib, nintedanib, pazopanib, sorafenib and sulfatinib was performed...
May 16, 2018: Endocrine-related Cancer
https://www.readbyqxmd.com/read/29768050/getting-up-to-date-in-the-management-of-soft-tissue-sarcoma
#9
Jean-Yves Blay
Surgery (+ radiation therapy in selected cases) is standard treatment for adult-type localized soft tissue sarcoma (STS). Accumulating randomized clinical evidence also supports adjuvant chemotherapy as a treatment option, although this remains contentious. Doxorubicin (± ifosfamide) is the standard first-line systemic treatment for advanced STS; however, newer chemotherapeutic agents may improve outcomes achieved with single-agent doxorubicin. In a Phase II study, adding olaratumab to doxorubicin markedly improved overall survival...
May 2018: Future Oncology
https://www.readbyqxmd.com/read/29708353/-treatment-of-metastatic-renal-cell-carcinoma
#10
Igor Richter, Josef Dvořák
INTRODUCTION: Renal cell cancer accounts for approximately 2-3% of all cases of malignancy. The incidence of kidney cancer in the Czech Republic is the highest in the world. Approximately 70% of renal cell carcinomas are clear-cell renal cancer. Various treatment options for metastatic renal cell cancer (mRCC) have been developed. Treatment regimens comprise antiangiogenic drugs in combination with vascular endothelial growth factor receptor inhibitors, mTOR inhibitors, and immunotherapy...
2018: Klinická Onkologie: Casopis Ceské a Slovenské Onkologické Spolecnosti
https://www.readbyqxmd.com/read/29706615/clinical-benefit-from-tyrosine-kinase-inhibitors-in-metastatic-merkel-cell-carcinoma-a-case-series-of-5-patients
#11
Erica S Tarabadkar, Hannah Thomas, Astrid Blom, Upendra Parvathaneni, Thomas Olencki, Paul Nghiem, Shailender Bhatia
BACKGROUND Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer. The estimated 5-year survival of patients with metastatic disease is approximately 14%. Cytotoxic chemotherapy is associated with a modest median progression-free survival (PFS) of only 3 months. In recent studies, immunotherapy with anti-PD-1/anti-PD-L1 antibodies has demonstrated a high response rate in immunocompetent patients (>50% in chemotherapy-naïve patients) and responses are typically durable. However, approximately 50% of immunocompetent patients do not respond to immunotherapy...
April 30, 2018: American Journal of Case Reports
https://www.readbyqxmd.com/read/29706503/nomogram-to-assess-the-survival-benefit-of-new-salvage-agents-for-metastatic-urothelial-carcinoma-in-the-era-of-immunotherapy
#12
Guru Sonpavde, Gregory Russell Pond, Jonathan E Rosenberg, Toni K Choueiri, Joaquim Bellmunt, Ashley Marie Regazzi, Stephanie A Mullane, Andrea Necchi, Daniele Raggi, Jae-Lyun Lee, Soonil Lee, Joe Simpson, Christina Louise Derleth, Shih-Wen Lin, Dean F Bajorin
INTRODUCTION: Optimal end points in phase 2 trials evaluating salvage therapy for metastatic urothelial carcinoma are necessary to identify promising drugs, particularly immunotherapeutics, where response and progression-free survival may be unreliable. We developed a nomogram using data from phase 2 trials of historical agents to estimate the 12-month overall survival (OS) for patients to which observed survival of nonrandomized data sets receiving immunotherapies could be compared. PATIENTS AND METHODS: Survival and data for major prognostic factors were obtained from phase 2 trials: hemoglobin, performance status, liver metastasis, treatment-free interval, and albumin...
April 6, 2018: Clinical Genitourinary Cancer
https://www.readbyqxmd.com/read/29706106/the-impact-of-pazopanib-on-the-cardiovascular-system
#13
Cody N Justice, Mohamed H Derbala, Tesla M Baich, Amber N Kempton, Aaron S Guo, Thai H Ho, Sakima A Smith
Pazopanib is an approved treatment for renal cell carcinoma and a second-line treatment for nonadipocytic soft-tissue sarcoma. However, its clinical efficacy is limited by its cardiovascular side effects. Pazopanib and other vascular endothelial growth factor receptor tyrosine kinase inhibitors have been associated with the development of hypertension, QT interval prolongation, and other cardiovascular events; however, these mechanisms are largely unknown. Gaining a deeper understanding of these mechanisms is essential for the development of appropriate surveillance strategies and possible diagnostic biomarkers to allow us to monitor patients and modulate therapy prior to significant cardiac insult...
January 1, 2018: Journal of Cardiovascular Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/29700673/pazopanib-efficacy-in-recurrent-central-nervous-system-hemangiopericytomas
#14
Caroline Apra, Agusti Alentorn, Karima Mokhtari, Michel Kalamarides, Marc Sanson
INTRODUCTION: There is currently no treatment for solitary fibrous tumors/hemangiopericytomas (SFT/H) of the central nervous system recurring after multiple surgeries and radiotherapies. The NAB2-STAT6 gene fusion is the hallmark of these tumors, and upregulates Early Growth Factor, activating several growth pathways. METHODS: We treated two patients presenting pluri-recurrent meningeal SFT/H with Pazopanib, a broad-spectrum tyrosine kinase inhibitor. We analyzed the exome and RNA sequencing data of one of them and, in addition to another meningeal SFT/H, compared it to the transcriptomic profiling of 5 systemic SFT/H...
April 26, 2018: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/29700053/tk-inhibitor-pazopanib-primes-dcs-by-downregulation-of-the-%C3%AE-catenin-pathway
#15
Ilaria Grazia Zizzari, Chiara Napoletano, Andrea Botticelli, Salvatore Caponnetto, Fabio Calabrò, Alain Gelibter, Aurelia Rughetti, Ilary Ruscito, Hassan Rahimi, Ernesto Rossi, Giovanni Schinzari, Paolo Marchetti, Marianna Nuti
Tyrosine kinase inhibitors (TKIs) target angiogenesis by affecting, for example, the VEGF receptors in tumors and have improved outcomes for patients with metastatic renal cell carcinoma (mRCC). Immune checkpoint inhibitors (ICIs) have also been proposed for treatment of mRCC with encouraging results. A better understanding of the activity of immune cells in mRCC, the immuneomodulatory effects of TKIs, and the characteristics defining patients most likely to benefit from various therapies will help optimize immunotherapeutic approaches...
April 26, 2018: Cancer Immunology Research
https://www.readbyqxmd.com/read/29692506/efficacy-and-safety-of-third-and-fourth-line-targeted-therapy-in-japanese-patients-with-metastatic-renal-cell-carcinoma-a-retrospective-analysis
#16
Negishi Takahito, Nagase Kei, Iwai Hidenori, Furubayashi Nobuki, Taguchi Kenichi, Nakamura Motonobu
Introduction: There is limited data on the efficacy of sequential targeted therapy for metastatic renal cell carcinoma (mRCC) beyond the second line, especially for Asian patients. We evaluated the efficacy and side effects of targeted therapy beyond the second line. Materials and Methods: We retrospectively reviewed 69 patients who were administered targeted therapy for mRCC at our institution between 2008 and 2016. Sunitinib, pazopanib, sorafenib, axitinib, everolimus, and temsirolimus were available in Japan in 2016, and treatment had been conducted with those six agents...
April 2018: Indian Journal of Urology: IJU: Journal of the Urological Society of India
https://www.readbyqxmd.com/read/29684209/drug-review-pazopanib
#17
Shingo Miyamoto, Shigenori Kakutani, Yujiro Sato, Akira Hanashi, Yoshitaka Kinoshita, Akira Ishikawa
Pazopanib (Votrient®) is an oral small-molecule multi-kinase inhibitor that primarily inhibits vascular endothelial growth factor receptor-1, -2 and -3, platelet endothelial growth factor receptor-α, and -β, and the stem-cell factor receptor c-kit. In preliminary experiments using angiogenesis models with mice and rabbits, pazopanib inhibited angiogenesis caused by combined vascular endothelial growth factor and basic fibroblast growth factor. Although pazopanib was developed as a therapeutic agent against various tumors, it is currently approved in many countries for advanced soft-tissue sarcoma and renal cell carcinoma...
April 19, 2018: Japanese Journal of Clinical Oncology
https://www.readbyqxmd.com/read/29680279/solubility-and-bioavailability-improvement-of-pazopanib-hydrochloride
#18
Maikel Herbrink, Stefanie L Groenland, Alwin D R Huitema, Jan H M Schellens, Jos H Beijnen, Neeltje Steeghs, Bastiaan Nuijen
The anti-cancer drug pazopanib hydrochloride (PZH) has a very low aqueous solubility and a variable oral bioavailability. A new pharmaceutical formulation with an improved solubility may enhance the bioavailability and reduce the variability. A broad selection of polymer excipients was tested for their compatibility and solubilizing properties by conventional microscopic, thermal and spectrometric techniques. A wet milling and mixing technique was used to produce homogenous powder mixtures. The dissolution properties of the formulation were tested by a pH-switch dissolution model...
April 19, 2018: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/29677483/design-synthesis-and-biological-evaluation-of-pyrimidine-based-derivatives-as-vegfr-2-tyrosine-kinase-inhibitors
#19
Wuji Sun, Shengquan Hu, Shubiao Fang, Hong Yan
Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a crucial role in tumor angiogenesis, and inhibition of the VEGFR-2 signaling pathway has already become an attractive approach for cancer therapy. In this study, a novel pyrimidine-based derivative 7j was designed as lead compound, and three series of potent VEGFR-2 inhibitors were synthesized and biologically evaluated against A549 and HepG2 cell lines. Compounds 7d, 9s and 13n exhibited superior inhibitory activities against A549 cell with IC50 ranged from 9...
April 13, 2018: Bioorganic Chemistry
https://www.readbyqxmd.com/read/29670046/resistance-to-anti-angiogenic-therapy-in-cancer-alterations-to-anti-vegf-pathway
#20
REVIEW
Yoshiro Itatani, Kenji Kawada, Takamasa Yamamoto, Yoshiharu Sakai
Anti-angiogenic therapy is one of the promising strategies for many types of solid cancers. Bevacizumab (Avastin), a recombinant humanized monoclonal antibody of vascular endothelial growth factor (VEGF) A, was approved for the first time as an anti-angiogenic drug for the treatment of metastatic colorectal cancer (CRC) by the Food and Drug Administration (FDA) in 2004. In addition, the other VEGF pathway inhibitors including small molecule tyrosine kinase inhibitors (sunitinib, sorafenib, and pazopanib), a soluble VEGF decoy receptor (aflibercept), and a humanized monoclonal antibody of VEGF receptor 2 (VEGFR2) (ramucirumab) have been approved for cancer therapy...
April 18, 2018: International Journal of Molecular Sciences
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