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Cardiac Tumours
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
PD-L1 is a key immune checkpoint protein that plays a significant role in sarcomagenesis. Upregulation of PD-L1 is associated with increased tumour aggressiveness. PD-L1+ sarcomas can be targeted with single-agent immunotherapy such as pembrolizumab. MDM2 is a proto-oncogene, which is one of the most frequently mutated genes in cardiac intimal sarcomas. Upregulation of MDM2 results in loss of p53-dependent activities, such as apoptosis and cell-cycle arrest. There are no established guidelines for chemotherapy targeting MDM2. Newer agents such as olaratumab, a monoclonal antibody that targets platelet-derived growth factor receptor (PDGFR)-α, combined with doxorubicin has limited data to show drug efficacy against soft-tissue sarcomas. Pazopanib, which has been used in metastatic non-adipocytic soft-tissue sarcomas, is a multi-kinase inhibitor that targets the tyrosine kinase activity of vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR) and stem-cell factor receptor. Intimal sarcomas can have PDGF and VEGF expression. A case with a moderate to strong expression of PDGFR-α and -β presented a long-term stable disease when treated with pazopanib while a case with weak expression of PDGFR-α and -β did not respond. The level of PDGFR expression in the tumour tissue may therefore be predictive of pazopanib efficacy.28
Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Common side effects for pazopanib include GI (e.g., abdominal distension, diarrhea, dry mouth, dyspepsia, flatulence, and taste disturbance) and skin (e.g., dry skin, flushing, hair discoloration, and nail disorders) disturbances. Other side effects include anorexia, blood disorders, blurred vision, chest pain, dehydration, and hyperbilirubinemia.
UGT1A1 Polymorphisms and Mutations Affect Anticancer Drug Therapy
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Tristan M. Sissung, Roberto Barbier, Lisa M. Cordes, William D. Figg
Since 2006, sunitinib has been the standard of care for metastatic renal cell carcinoma (RCC), while pazopanib has demonstrated non-inferiority and is also a preferred first-line therapy. Furthermore, axitinib is an option in the first-line setting while cabozantinib may be considered first-line in poor- and intermediate-risk groups. Subsequent TKI therapies include cabozantinib, axitinib, pazopanib, lenvatinib, and sunitinib (see NCCN Kidney Cancer version 2.2020). These agents all inhibit angiogenesis in RCC, a disease in which mutations in the Von Hipple-Lindau gene and other genetic aberrations result in dysregulation of the hypoxia-inducible factor (HIF1A and HIF2A) and vascular endothelial growth factor (VEGF) pathways. Pazopanib induces benign hyperbilirubinemia in patients with RCC carrying UGT1A1*28/*28 [126, 127]. Sorafenib-induced hyperbilirubinemia and treatment interruption is also associated with UGT1A1*28/*28 carriers, while for unknown reasons, the odds of having sorafenib AUC above the 93rd percentile were also significantly higher in patients carrying UGT1A1*28/*28 [106, 128]. It is likely that the greater exposure to sorafenib is related to the greater rate of sorafenib-related toxicities in these patients [106, 128]. These data may be relevant to sorafenib treatment in hepatocellular carcinoma as well (https://www.accessdata.fda.gov/drugsatfda_docs/label/2010/021923s008s009lbl.pdf). The UGT1A1*28 polymorphism was not associated with variation in axitinib clearance or volume of distribution [129].
Emerging tyrosine kinase inhibitors for head and neck cancer
Published in Expert Opinion on Emerging Drugs, 2022
Zhen Long, Jennifer R. Grandis, Daniel E. Johnson
Pazopanib (Votrient) is an oral multi-targeted TKI that primarily targets VEGFR1-3, PDGFRα, PDGFβ, and c-KIT [88,89]. The anti-tumor effects of pazopanib occur via inhibition of angiogenesis and inhibition of tumor cell growth [89]. The FDA has approved pazopanib for use in advanced renal cell carcinoma and advanced soft tissue sarcoma. Altered liver function and hypertension are relatively common adverse effects and may result in discontinuation of pazopanib treatment [89]. A Phase I trial of pazopanib in combination with weekly cetuximab in recurrent or metastatic HNSCC did not reach a maximum tolerated dose and administration of 800 mg/day pazopanib with weekly cetuximab was determined to be feasible [90]. Two of 31 evaluable patients achieved a complete response and 9 had a partial response. Moreover, 5/18 patients with platinum-resistant disease and 3/12 with cetuximab-resistant disease exhibited measurable tumor responses. Pazopanib is currently being evaluated in a Phase I trial in HNSCC in combination with cetuximab (NCT01716416) and in a Phase II as monotherapy in salivary gland carcinomas (NCT02393820)(Table 1).
Risks of molecular targeted therapies to fertility and safety during pregnancy: a review of current knowledge and future needs
Published in Expert Opinion on Drug Safety, 2021
Elena Lorenzi, Matteo Simonelli, Pasquale Persico, Angelo Dipasquale, Armando Santoro
To date, the only report on the impact of pazopanib on human female fertility was published in 2019 by De Sanctis et al. [52]. De Sanctis et al. described the case of an 18-year-old woman with a diagnosis of a high-grade angiosarcoma who experienced a transient ovarian insufficiency on pazopanib treatment. Pazopanib was administered at a dose of 800 mg daily for 10 months. Amenorrhea developed within 2 months from the initiation of pazopanib treatment and menses returned regularly after 2 months from pazopanib discontinuation. After 3 months of treatment, the antral follicle count was dramatically decreased with a low anti-Müllerian hormone (AMH) level. However, the normalization of hormone values after treatment discontinuation suggests that the damage caused by pazopanib could be transient [52].
An update on the conquests and perspectives of cardio-oncology in the field of tumor angiogenesis-targeting TKI-based therapy
Published in Expert Opinion on Drug Safety, 2019
Antonio Galvano, Aurelia Guarini, Federica Iacono, Marta Castiglia, Sergio Rizzo, Luigi Tarantini, Stefania Gori, Giuseppina Novo, Viviana Bazan, Antonio Russo
Pazopanib is an oral TKI. It targets VEGF-1, 2 and 3, PDGFRs, and c-KIT. Arterial hypertension represents its most studied side effect. Fundamentally, the drug-induced cardiac effects that involve the use of this drug, remain the same. Cody N et al. described in a review article all the side effects related to Pazopanib and its possible mechanisms. Among the known side effects that have been already mentioned, they reported myocardial ischemia. Particularly, in a phase 3 placebo-controlled trial in patients with metastatic RCC and soft-tissue sarcoma (STS), the incidence of treatment-related myocardial ischemia was about 2% and 1%, respectively [33], while cerebrovascular accidents and transient ischemic attacks occurred in <1% of Pazopanib-treated patients with metastatic RCC. Furthermore, other adverse reactions have been reported, like thrombosis, that developed in <1% of patients receiving Pazopanib for advanced and recurrent cervical cancer [34]. Moreover, venous thromboembolic events were reported in 5% of the patients with STS on Pazopanib [35].