Worsening membranous nephropathy in a patient with GIST treated with sunitinib

2021 ◽  
Vol 14 (8) ◽  
pp. e243567
Author(s):  
Shahrzad Zonoozi ◽  
Matthew Palmer ◽  
Teitelbaum Ursina ◽  
Abdallah Geara
Keyword(s):  
Nephrotic Syndrome ◽  
Adverse Events ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Membranous Nephropathy ◽  
Systematic Approach ◽  
Kinase Inhibitors ◽  
Kidney Biopsy ◽  
Gastrointestinal Stromal Tumours ◽  
Metastatic Gist

Tyrosine kinase inhibitors (TKI) are anticancer agents widely used for a variety of malignancies including gastrointestinal stromal tumours (GIST). Although generally well-tolerated, TKIs have been associated with a number of adverse events including hypertension, proteinuria and nephrotic syndrome. We present the case of a 70-year-old patient with metastatic GIST on long-standing sunitinib who developed hypertension, oedema and hypoalbuminemia with a rising serum creatinine and was found to have nephrotic syndrome. Workup revealed elevated antiphospholipase A2 receptor (PLA2R) antibody IgG titres and a kidney biopsy confirmed PLA2R-positive membranous nephropathy without findings of thrombotic microangiopathy. Cessation of sunitinib led to reduction in anti-PLA2R antibody IgG titres while resumption, due to concern for cancer progression, led to worsening symptoms. Treatment with rituximab led to undetectable anti-PLA2R IgG titres. We highlight the importance of maintaining a systematic approach for evaluating nephrotic syndrome and provide a case showing that TKIs can exacerbate underlying nephrotic syndrome.

Linking kinases to adverse events through kinase inhibitors.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e13524-e13524
Author(s):  
Afsheen Iqbal ◽  
Shan Zhao ◽  
Sonia Evelyn Reichert ◽  
Robert G. Maki
Keyword(s):  
Adverse Events ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Attributable Risk ◽  
Unequal Variance ◽  
Prevalence Data ◽  
Hand Foot Syndrome ◽  
Average Probability ◽  
The Difference ◽  
Grade 3

e13524 Background: Small molecule oral kinase inhibitors (SMOKIs) are anticancer agents with unique activity and toxicity. We sought to determine if specific kinases blocked by SMOKIs could be linked to specific adverse events (AEs). Methods: We identified studies in which cancer indications for SMOKIs were compared to placebo or other therapy, and collected prevalence data of grade 3, 4, and 5 AEs for each study arm. Targets of each SMOKI were screened from existing data on kinase specificity, selecting Kd<500nM. Each SMOKI was mapped to its respective kinases. We compared the frequency of AEs from all studies when the kinase of interest was involved to AE frequency when the kinase was not involved, and computed the probabilities for attributed risk for each kinase and the significance of association between AE and drug of interest via t-test. We evaluated the significance in a pair-wise manner, computing the difference in probability for a single AE for each study independently, and then evaluating the significance of the average probability, assuming unequal variance across studies. Results: 67 trials fit our criteria, and led to the identification of AEs associated with varying number of kinases, e.g. diarrhea (45 kinases), asthenia (43), hypertension (30), rash (30), thrombocytopenia (plts, 29), and neutropenia (21). Most associations, while statistically significant, had low attributable risk (≤5%), except diarrhea (24 kinases), hand-foot syndrome (19), and plts (13). BRAF (5.4% attributable risk) and VEGFR1 (4.9%) inhibition were most strongly associated with hypertension; AXL (5.3%), FGFR3 (5.3%), MAP4K5 (5%), and YES1 (5%) were associated with neutropenia; and TNIK (5.4%), PLK4 (5.3%), STK16 (5.3%), RPS6KA1 (5.1%), and FGFR3 (5%) were associated with asthenia. Conclusions: Certain AEs are common to many SMOKIs and thus many kinases. Other AEs such as neutropenia and asthenia were more tightly linked to specific kinases. By developing SMOKIs that block the target of interest but not kinases identified from these data, it may be possible to decrease the toxicity burden of future generations of SMOKIs.

Alkaloids as Anticancer Agents: A Review of Chinese Patents in Recent 5 Years

2020 ◽  
Vol 15 (1) ◽  
pp. 2-13 ◽  
Author(s):  
Hongyu Tao ◽  
Ling Zuo ◽  
Huanli Xu ◽  
Cong Li ◽  
Gan Qiao ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Cdk Inhibitors ◽  
Comprehensive Overview ◽  
P53 Expression ◽  
Study Results

Background: In recent years, many novel alkaloids with anticancer activity have been found in China, and some of them are promising for developing as anticancer agents. Objective: This review aims to provide a comprehensive overview of the information about alkaloid anticancer agents disclosed in Chinese patents, and discusses their potential to be developed as anticancer drugs used clinically. Methods: Anticancer alkaloids disclosed in Chinese patents in recent 5 years were presented according to their mode of actions. Their study results published on PubMed, and SciDirect databases were presented. Results: More than one hundred anticancer alkaloids were disclosed in Chinese patents and their mode of action referred to arresting cell cycle, inhibiting protein kinases, affecting DNA synthesis and p53 expression, etc. Conclusion: Many newly found alkaloids displayed potent anticancer activity both in vitro and in vivo, and some of the anticancer alkaloids acted as protein kinase inhibitors or CDK inhibitors possess the potential for developing as novel anticancer agents.

ATP Non-Competitive Ser/Thr Kinase Inhibitors as Potential Anticancer Agents

2009 ◽  
Vol 9 (7) ◽  
pp. 778-786 ◽  
Author(s):  
Giorgio Cozza ◽  
Andrea Bortolato ◽  
Ernesto Menta ◽  
Ennio Cavalletti ◽  
Silvano Spinelli ◽  
...  
Keyword(s):  
Anticancer Agents ◽  
Kinase Inhibitors

scholarly journals Thrombotic microangiopathy in dasatinib-treated patients with chronic myeloid leukemia

2019 ◽  
Vol 4 (1-2) ◽  
pp. 41-45 ◽  
Author(s):  
Takeo Koshida ◽  
Sylvia Wu ◽  
Hitoshi Suzuki ◽  
Rimda Wanchoo ◽  
Vanesa Bijol ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Tyrosine Kinase Inhibitors ◽  
Thrombotic Microangiopathy ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kidney Biopsy ◽  
Kinase Inhibitor ◽  
Target Effect

Dasatinib is the second-generation tyrosine kinase inhibitor used in the treatment of chronic myeloid leukemia. Proteinuria has been reported with this agent. We describe two kidney biopsy–proven cases of dasatinib-induced thrombotic microangiopathy that responded to stoppage of dasatinib and using an alternate tyrosine kinase inhibitor. Certain specific tyrosine kinase inhibitors lead to endothelial injury and renal-limited thrombotic microangiopathy. Hematologists and nephrologists need to be familiar with this off-target effect of dasatinib.

scholarly journals Regulation of Rho GTPases by RhoGDIs in Human Cancers

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1037 ◽  
Author(s):  
Cho ◽  
Kim ◽  
Baek ◽  
Kim ◽  
Lee
Keyword(s):  
Cell Migration ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Rho Gtpases ◽  
Rho Gtpase ◽  
Regulatory Mechanisms ◽  
Malignant Phenotype ◽  
Cellular Processes ◽  
Human Cancers

Rho GDP dissociation inhibitors (RhoGDIs) play important roles in various cellular processes, including cell migration, adhesion, and proliferation, by regulating the functions of the Rho GTPase family. Dissociation of Rho GTPases from RhoGDIs is necessary for their spatiotemporal activation and is dynamically regulated by several mechanisms, such as phosphorylation, sumoylation, and protein interaction. The expression of RhoGDIs has changed in many human cancers and become associated with the malignant phenotype, including migration, invasion, metastasis, and resistance to anticancer agents. Here, we review how RhoGDIs control the function of Rho GTPases by regulating their spatiotemporal activity and describe the regulatory mechanisms of the dissociation of Rho GTPases from RhoGDIs. We also discuss the role of RhoGDIs in cancer progression and their potential uses for therapeutic intervention.

scholarly journals Novel Benzenesulfonate Scaffolds with a High Anticancer Activity and G2/M Cell Cycle Arrest

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1790
Author(s):  
Katarzyna Malarz ◽  
Jacek Mularski ◽  
Michał Kuczak ◽  
Anna Mrozek-Wilczkiewicz ◽  
Robert Musiol
Keyword(s):  
Cell Cycle ◽  
Anticancer Activity ◽  
Cell Cycle Arrest ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
P53 Protein ◽  
Structural Similarity ◽  
M Cell ◽  
Cycle Arrest ◽  
Small Series

Sulfonates, unlike their derivatives, sulphonamides, have rarely been investigated for their anticancer activity. Unlike the well-known sulphonamides, esters are mainly used as convenient intermediates in a synthesis. Here, we present the first in-depth investigation of quinazoline sulfonates. A small series of derivatives were synthesized and tested for their anticancer activity. Based on their structural similarity, these compounds resemble tyrosine kinase inhibitors and the p53 reactivator CP-31398. Their biological activity profile, however, was more related to sulphonamides because there was a strong cell cycle arrest in the G2/M phase. Further investigation revealed a multitargeted mechanism of the action that corresponded to the p53 protein status in the cell. Although the compounds expressed a high submicromolar activity against leukemia and colon cancers, pancreatic cancer and glioblastoma were also susceptible. Apoptosis and autophagy were confirmed as the cell death modes that corresponded with the inhibition of metabolic activity and the activation of the p53-dependent and p53-independent pathways. Namely, there was a strong activation of the p62 protein and GADD44. Other proteins such as cdc2 were also expressed at a higher level. Moreover, the classical caspase-dependent pathway in leukemia was observed at a lower concentration, which again confirmed a multitargeted mechanism. It can therefore be concluded that the sulfonates of quinazolines can be regarded as promising scaffolds for developing anticancer agents.

scholarly journals “It’s not lupus”. A placental site trophoblastic tumor presenting as a lupus-like paraneoplastic syndrome. A grand round case

Lupus ◽  
2021 ◽  
pp. 096120332098176
Author(s):  
Sarah J van der Lely ◽  
Jeffrey Boorsma ◽  
Marc Hilhorst ◽  
Jesper Kers ◽  
Joris Roelofs ◽  
...  
Keyword(s):  
Nephrotic Syndrome ◽  
Lupus Erythematosus ◽  
Kidney Biopsy ◽  
Gestational Trophoblastic Disease ◽  
Grand Round ◽  
Placental Site Trophoblastic Tumor ◽  
Trophoblastic Tumor ◽  
Anchoring Bias ◽  
Placental Site ◽  
History Of

Introduction: Placental site trophoblastic tumor (PSTT) is a rare subtype of gestational trophoblastic disease. Association of PSTT and nephrotic syndrome is exceedingly rare and has been described in 8 cases thus far. In all cases hysterectomy was performed within months after onset of symptoms, leading to immediate remission of nephrotic syndrome, except for one patient who died of complications of PSTT. Case: We describe the history of a woman in which PSTT was discovered years after onset of nephrotic syndrome. Kidney biopsy revealed lupus-like mesangiocapillary nephritis and over time the patient developed additional symptoms mimicking systemic lupus erythematosus (SLE). Discussion: We provide an overview of the literature on this clinical entity and elaborate on its pathophysiology. In addition, we reflect on the phenomenon of anchoring bias, that led physicians to assume the patient had SLE without questioning this diagnosis in the light of the unexplained finding of increased tumor markers.

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