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Publication Record


An autoimmune-based, paraneoplastic neurologic syndrome following checkpoint inhibition and concurrent radiotherapy for merkel cell carcinoma: case report.
Sherry AD, Bezzerides M, Khattab MH, Luo G, Ancell KK, Kirschner AN
(2020) Strahlenther Onkol 196: 664-670
MeSH Terms: Aged, Antibodies, Monoclonal, Humanized, Antineoplastic Agents, Immunological, Antineoplastic Combined Chemotherapy Protocols, Autoimmune Diseases of the Nervous System, Axilla, Carboplatin, Carcinoma, Merkel Cell, Combined Modality Therapy, Deglutition Disorders, Etoposide, Fatal Outcome, Fingers, Hallucinations, Humans, Lymphatic Metastasis, Male, Neuralgia, Palliative Care, Paraneoplastic Syndromes, Nervous System, Parenteral Nutrition, Total, Pneumonia, Aspiration, Positron Emission Tomography Computed Tomography, Radioimmunotherapy, Radiotherapy, High-Energy, Radiotherapy, Intensity-Modulated, Skin Neoplasms
Show Abstract · Added March 3, 2020
PURPOSE - Merkel cell carcinoma is highly sensitive to both radiation and immunotherapy. Moreover, concurrent radioimmunotherapy may capitalize on anti-tumor immune activity and improve Merkel cell treatment response, although an enhanced immune system may cross-react with native tissues and lead to significant sequelae.
METHODS - Here we present a case study of a patient with metastatic Merkel cell carcinoma treated with radiotherapy concurrent with pembrolizumab.
RESULTS - After radioimmunotherapy, the patient developed sensory neuropathy, visual hallucinations, and mixed motor neuron findings. Neurologic dysfunction progressed to profound gastrointestinal dysmotility necessitating parenteral nutrition and intubation with eventual expiration.
CONCLUSION - This case represents a unique autoimmune paraneoplastic neurologic syndrome, likely specific to neuroendocrine tumors and motivated by concurrent radioimmunotherapy. Recognition of the potential role of radioimmunotherapy may provide an advantage in anticipating these severe sequelae.
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27 MeSH Terms
Cleavage of arrestin-3 by caspases attenuates cell death by precluding arrestin-dependent JNK activation.
Kook S, Vishnivetskiy SA, Gurevich VV, Gurevich EV
(2019) Cell Signal 54: 161-169
MeSH Terms: Animals, Apoptosis, Arrestins, COS Cells, Caspases, Chlorocebus aethiops, Etoposide, MAP Kinase Kinase 4, MAP Kinase Kinase Kinase 5
Show Abstract · Added March 18, 2020
The two non-visual subtypes, arrestin-2 and arrestin-3, are ubiquitously expressed and bind hundreds of G protein-coupled receptors. In addition, these arrestins also interact with dozens of non-receptor signaling proteins, including c-Src, ERK and JNK, that regulate cell death and survival. Arrestin-3 facilitates the activation of JNK family kinases, which are important players in the regulation of apoptosis. Here we show that arrestin-3 is specifically cleaved at Asp366, Asp405 and Asp406 by caspases during the apoptotic cell death. This results in the generation of one main cleavage product, arrestin-3-(1-366). The formation of this fragment occurs in a dose-dependent manner with the increase of fraction of apoptotic cells upon etoposide treatment. In contrast to a caspase-resistant mutant (D366/405/406E) the arrestin-3-(1-366) fragment reduces the apoptosis of etoposide-treated cells. We found that caspase cleavage did not affect the binding of the arrestin-3 to JNK3, but prevented facilitation of its activation, in contrast to the caspase-resistant mutant, which facilitated JNK activation similar to WT arrestin-3, likely due to decreased binding of the upstream kinases ASK1 and MKK4/7. The data suggest that caspase-generated arrestin-3-(1-366) prevents the signaling in the ASK1-MKK4/7-JNK1/2/3 cascade and protects cells, thereby suppressing apoptosis.
Copyright © 2018 Elsevier Inc. All rights reserved.
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9 MeSH Terms
Etoposide and cisplatin versus paclitaxel and carboplatin with concurrent thoracic radiotherapy in unresectable stage III non-small cell lung cancer: a multicenter randomized phase III trial.
Liang J, Bi N, Wu S, Chen M, Lv C, Zhao L, Shi A, Jiang W, Xu Y, Zhou Z, Wang W, Chen D, Hui Z, Lv J, Zhang H, Feng Q, Xiao Z, Wang X, Liu L, Zhang T, Du L, Chen W, Shyr Y, Yin W, Li J, He J, Wang L
(2017) Ann Oncol 28: 777-783
MeSH Terms: Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Carboplatin, Carcinoma, Non-Small-Cell Lung, Chemoradiotherapy, Cisplatin, Etoposide, Female, Humans, Kaplan-Meier Estimate, Lung Neoplasms, Male, Middle Aged, Neoplasm Staging, Paclitaxel, Proportional Hazards Models
Show Abstract · Added April 18, 2017
Background - The optimal chemotherapy regimen administered currently with radiation in patients with stage III non-small cell lung cancer (NSCLC) remains unclear. A multicenter phase III trial was conducted to compare the efficacy of concurrent thoracic radiation therapy with either etoposide/cisplatin (EP) or carboplatin/paclitaxel (PC) in patients with stage III NSCLC.
Patients and methods - Patients were randomly received 60-66 Gy of thoracic radiation therapy concurrent with either etoposide 50 mg/m2 on days 1-5 and cisplatin 50 mg/m2 on days 1 and 8 every 4 weeks for two cycles (EP arm), or paclitaxel 45 mg/m2 and carboplatin (AUC 2) on day 1 weekly (PC arm). The primary end point was overall survival (OS). The study was designed with 80% power to detect a 17% superiority in 3-year OS with a type I error rate of 0.05.
Results - A total of 200 patients were randomized and 191 patients were treated (95 in the EP arm and 96 in the PC arm). With a median follow-up time of 73 months, the 3-year OS was significantly higher in the EP arm than that of the PC arm. The estimated difference was 15.0% (95% CI 2.0%-28.0%) and P value of 0.024. Median survival times were 23.3 months in the EP arm and 20.7 months in the PC arm (log-rank test P = 0.095, HR 0.76, 95%CI 0.55-1.05). The incidence of Grade ≥2 radiation pneumonitis was higher in the PC arm (33.3% versus 18.9%, P = 0.036), while the incidence of Grade ≥3 esophagitis was higher in the EP arm (20.0% versus 6.3%, P = 0.009).
Conclusion - EP might be superior to weekly PC in terms of OS in the setting of concurrent chemoradiation for unresectable stage III NSCLC.
Trial registration ID - NCT01494558.
© The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
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17 MeSH Terms
Pharmacologically Increasing Mdm2 Inhibits DNA Repair and Cooperates with Genotoxic Agents to Kill p53-Inactivated Ovarian Cancer Cells.
Carrillo AM, Hicks M, Khabele D, Eischen CM
(2015) Mol Cancer Res 13: 1197-205
MeSH Terms: Animals, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Cell Line, Tumor, Cell Proliferation, Cisplatin, Comet Assay, DNA Breaks, Double-Stranded, DNA Damage, DNA Repair, Etoposide, Female, Fibroblasts, HEK293 Cells, Humans, Imidazoles, Mice, Mice, Transgenic, Mutagens, Ovarian Neoplasms, Piperazines, Proto-Oncogene Proteins c-mdm2, Tumor Suppressor Protein p53
Show Abstract · Added February 22, 2016
UNLABELLED - The Mdm2 oncogene is a negative regulator of the p53 tumor suppressor and recently identified inhibitor of DNA break repair. Nutlin-3 is a small-molecule inhibitor of Mdm2-p53 interaction that can induce apoptosis in cancer cells through activation of p53. Although this is a promising therapy for those cancers with wild-type p53, half of all human cancers have inactivated p53. Here, we reveal that a previously unappreciated effect of Nutlin is inhibition of DNA break repair, stemming from its ability to increase Mdm2 protein levels. The Nutlin-induced increase in Mdm2 inhibited DNA double-strand break repair and prolonged DNA damage response signaling independent of p53. Mechanistically, this effect of Nutlin required Mdm2 and acted through Nbs1 of the Mre11-Rad50-Nbs1 DNA repair complex. In ovarian cancer cells, where >90% have inactivated p53, Nutlin combined with the genotoxic agents, cisplatin or etoposide, had a cooperative lethal effect resulting in increased DNA damage and apoptosis. Therefore, these data demonstrate an unexpected consequence of pharmacologically increasing Mdm2 levels that when used in combination with genotoxic agents induces synthetic lethality in ovarian cancer cells, and likely other malignant cell types, that have inactivated p53.
IMPLICATIONS - Data reveal a therapeutically beneficial effect of pharmacologically increasing Mdm2 levels combined with chemotherapeutic agents for malignancies that have lost functional p53.
©2015 American Association for Cancer Research.
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23 MeSH Terms
Caspase-cleaved arrestin-2 and BID cooperatively facilitate cytochrome C release and cell death.
Kook S, Zhan X, Cleghorn WM, Benovic JL, Gurevich VV, Gurevich EV
(2014) Cell Death Differ 21: 172-84
MeSH Terms: Animals, Apoptosis, Arrestins, BH3 Interacting Domain Death Agonist Protein, Caspase 3, Caspases, Cell Line, Cytochromes c, Etoposide, Mice, Mitochondria, Protein Binding, Protein Isoforms, Recombinant Proteins, Tumor Necrosis Factor-alpha
Show Abstract · Added February 12, 2015
Apoptosis is programmed cell death triggered by activation of death receptors or cellular stress. Activation of caspases is the hallmark of apoptosis. Arrestins are best known for their role in homologous desensitization of G protein-coupled receptors (GPCRs). Arrestins quench G protein activation by binding to activated phosphorylated GPCRs. Recently, arrestins have been shown to regulate multiple signalling pathways in G protein-independent manner via scaffolding signalling proteins. Here we demonstrate that arrestin-2 isoform is cleaved by caspases during apoptosis induced via death receptor activation or by DNA damage at evolutionarily conserved sites in the C-terminus. Caspase-generated arrestin-2-(1-380) fragment translocates to mitochondria increasing cytochrome C release, which is the key checkpoint in cell death. Cells lacking arrestin-2 are significantly more resistant to apoptosis. The expression of wild-type arrestin-2 or its cleavage product arrestin-2-(1-380), but not of its caspase-resistant mutant, restores cell sensitivity to apoptotic stimuli. Arrestin-2-(1-380) action depends on tBID: at physiological concentrations, arrestin-2-(1-380) directly binds tBID and doubles tBID-induced cytochrome C release from isolated mitochondria. Arrestin-2-(1-380) does not facilitate apoptosis in BID knockout cells, whereas its ability to increase caspase-3 activity and facilitate cytochrome C release is rescued when BID expression is restored. Thus, arrestin-2-(1-380) cooperates with another product of caspase activity, tBID, and their concerted action significantly contributes to cell death.
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15 MeSH Terms
Etoposide catechol is an oxidizable topoisomerase II poison.
Jacob DA, Gibson EG, Mercer SL, Deweese JE
(2013) Chem Res Toxicol 26: 1156-8
MeSH Terms: Catechols, Cytochrome P-450 CYP3A, DNA, DNA Breaks, Double-Stranded, DNA Topoisomerases, Type II, Etoposide, Humans, Oxidation-Reduction
Show Abstract · Added January 4, 2016
Topoisomerase II regulates DNA topology by generating transient double-stranded breaks. The anticancer drug etoposide targets topoisomerase II and is associated with the formation of secondary leukemias in patients. The quinone and catechol metabolites of etoposide may contribute to strand breaks that trigger leukemic translocations. To further analyze the characteristics of etoposide metabolites, we extend our previous analysis of etoposide quinone to the catechol. We demonstrate that the catechol is ∼2-3-fold more potent than etoposide and under oxidative reaction conditions induces high levels of double-stranded DNA cleavage. These results support a role for etoposide catechol in contributing to therapy-induced DNA damage.
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8 MeSH Terms
Thr 163 phosphorylation causes Mcl-1 stabilization when degradation is independent of the adjacent GSK3-targeted phosphodegron, promoting drug resistance in cancer.
Nifoussi SK, Vrana JA, Domina AM, De Biasio A, Gui J, Gregory MA, Hann SR, Craig RW
(2012) PLoS One 7: e47060
MeSH Terms: Animals, Antineoplastic Agents, Apoptosis, Blotting, Western, CHO Cells, Cell Line, Tumor, Cisplatin, Cricetinae, Cytarabine, Drug Resistance, Neoplasm, Etoposide, Flow Cytometry, Glycogen Synthase Kinase 3, Humans, Myeloid Cell Leukemia Sequence 1 Protein, Phosphorylation, Protein Stability, Proto-Oncogene Proteins c-bcl-2, Threonine, Vinblastine
Show Abstract · Added March 20, 2014
The antiapoptotic Bcl-2 family member Mcl-1 is a PEST protein (containing sequences enriched in proline, glutamic acid, serine, and threonine) and is subject to rapid degradation via multiple pathways. Impaired degradation leading to the maintenance of Mcl-1 expression is an important determinant of drug resistance in cancer. Phosphorylation at Thr 163 in the PEST region, stimulated by 12-O-tetradecanoylphorbol acetic acid (TPA)-induced activation of extracellular signal-regulated kinase (ERK), is associated with Mcl-1 stabilization in BL41-3 Burkitt lymphoma cells. This contrasts with the observation that Thr 163 phosphorylation in normal fibroblasts primes glycogen synthase kinase (GSK3)-induced phosphorylation at Ser 159, producing a phosphodegron that targets Mcl-1 for degradation. In the present follow-up studies in BL41-3 cells, Mcl-1 degradation was found to be independent of the GSK3-mediated pathway, providing a parallel to emerging findings showing that Mcl-1 degradation through this pathway is lost in many different types of cancer. Findings in Mcl-1-transfected CHO cells corroborated those in BL41-3 cells in that the GSK3-targeted phosphodegron did not play a major role in Mcl-1 degradation, and a phosphomimetic T163E mutation resulted in marked Mcl-1 stabilization. TPA-treated BL41-3 cells, in addition to exhibiting Thr 163 phosphorylation and Mcl-1 stabilization, exhibited an ∼10-fold increase in resistance to multiple chemotherapeutic agents, including Ara-C, etoposide, vinblastine, or cisplatin. In these cancer cells in which Mcl-1 degradation is not dependent on the GSK3/phosphodegron-targeted pathway, ERK activation and Thr 163 phosphorylation are associated with pronounced Mcl-1 stabilization and drug resistance - effects that can be suppressed by inhibition of ERK activation.
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20 MeSH Terms
Phosphorylation of Rad9 at serine 328 by cyclin A-Cdk2 triggers apoptosis via interfering Bcl-xL.
Zhan Z, He K, Zhu D, Jiang D, Huang YH, Li Y, Sun C, Jin YH
(2012) PLoS One 7: e44923
MeSH Terms: Active Transport, Cell Nucleus, Apoptosis, Biocatalysis, Cell Cycle Proteins, Cell Nucleus, Cyclin A, Cyclin-Dependent Kinase 2, Etoposide, HeLa Cells, Humans, Mitochondria, Phosphorylation, RNA Interference, Serine, Signal Transduction, Topoisomerase II Inhibitors, Up-Regulation, bcl-X Protein
Show Abstract · Added July 28, 2015
Cyclin A-Cdk2, a cell cycle regulated Ser/Thr kinase, plays important roles in a variety of apoptoticprocesses. However, the mechanism of cyclin A-Cdk2 regulated apoptosis remains unclear. Here, we demonstrated that Rad9, a member of the BH3-only subfamily of Bcl-2 proteins, could be phosphorylated by cyclin A-Cdk2 in vitro and in vivo. Cyclin A-Cdk2 catalyzed the phosphorylation of Rad9 at serine 328 in HeLa cells during apoptosis induced by etoposide, an inhibitor of topoisomeraseII. The phosphorylation of Rad9 resulted in its translocation from the nucleus to the mitochondria and its interaction with Bcl-xL. The forced activation of cyclin A-Cdk2 in these cells by the overexpression of cyclin A,triggered Rad9 phosphorylation at serine 328 and thereby promoted the interaction of Rad9 with Bcl-xL and the subsequent initiation of the apoptotic program. The pro-apoptotic effects regulated by the cyclin A-Cdk2 complex were significantly lower in cells transfected with Rad9S328A, an expression vector that encodes a Rad9 mutant that is resistant to cyclin A-Cdk2 phosphorylation. These findings suggest that cyclin A-Cdk2 regulates apoptosis through a mechanism that involves Rad9phosphorylation.
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18 MeSH Terms
Neuroendocrine carcinoma in an adolescent with hypercortisolemia.
Fagan EL, Slone JS, Shoemaker AH, Black J, Berlin J, E Engel M
(2012) J Pediatr Hematol Oncol 34: e117-9
MeSH Terms: Adolescent, Adrenalectomy, Adrenocortical Hyperfunction, Antineoplastic Combined Chemotherapy Protocols, Carboplatin, Carcinoma, Neuroendocrine, Combined Modality Therapy, Etoposide, Humans, Male, Neoadjuvant Therapy, Tomography, X-Ray Computed
Show Abstract · Added May 2, 2013
We present a 16-year-old boy with weakness, hypercortisolemia, and markedly elevated adrenocorticotropic hormone. Computed tomographic imaging revealed hepatic lesions and a calcified pancreatic mass. Biopsy of the hepatic lesions revealed moderately differentiated neuroendocrine carcinoma. The primary tumor could not be determined. The patient received neoadjuvant chemotherapy with carboplatin and etoposide followed by therapeutic bilateral adrenalectomy and tumor debulking. Despite significant clinical improvement, restaging revealed progressive hepatic disease. The patient died 9 months after diagnosis. Autopsy revealed disseminated neuroendocrine carcinoma. The rarity of this tumor compels a cooperative investigational model involving pediatric and adult oncologists.
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12 MeSH Terms
Copy number polymorphisms and anticancer pharmacogenomics.
Gamazon ER, Huang RS, Dolan ME, Cox NJ
(2011) Genome Biol 12: R46
MeSH Terms: Antineoplastic Agents, Biomarkers, Pharmacological, Carboplatin, Cell Line, Tumor, Cisplatin, Daunorubicin, Etoposide, Gene Dosage, Gene Expression, Genetic Predisposition to Disease, Genetic Variation, Genome, Human, Genome-Wide Association Study, Humans, Inhibitory Concentration 50, Neoplasms, Oligonucleotide Array Sequence Analysis, Pharmacogenetics, Phenotype, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Topoisomerase II Inhibitors
Show Abstract · Added February 22, 2016
BACKGROUND - Recent studies have investigated the contribution of copy number variants (CNVs) to disease susceptibility in a multitude of complex disorders, including systemic lupus erythematosus, Crohn's disease, and various neurodevelopmental disorders. Relatively few CNV studies, however, have been conducted on pharmacologic phenotypes even though these structural variants are likely to play an important role. We developed a genome-wide method to identify CNVs that contribute to heterogeneity in drug response, focusing on drugs that are widely used in anticancer treatment regimens.
RESULTS - We conducted a comprehensive genome-wide study of CNVs from population-scale array-based and sequencing-based surveys by analyzing their effect on cellular sensitivity to platinating agents and topoisomerase II inhibitors. We identified extensive CNV regions associated with cellular sensitivity to functionally diverse chemotherapeutics, supporting the hypothesis that variation in copy number contributes to variation in drug response. Interestingly, although single nucleotide polymorphisms (SNPs) tag some of the CNVs associated with drug sensitivity, several of the most significant CNV-drug associations are independent of SNPs; consequently, they represent genetic variations that have not been previously interrogated by SNP studies of pharmacologic phenotypes.
CONCLUSIONS - Our findings demonstrate that pharmacogenomic studies may greatly benefit from the study of CNVs as expression quantitative trait loci, thus contributing broadly to our understanding of the complex traits genetics of CNVs. We also extend our PACdb resource, a database that makes available to the scientific community relationships between genetic variation, gene expression, and sensitivity to various drugs in cell-based models.
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22 MeSH Terms