المؤلفون: Zhang, Lindy, Lemberg, Kathryn M, Calizo, Ana, Varadhan, Ravi, Siegel, Alan H, Meyer, Christian F, Blakeley, Jaishri O, Pratilas, Christine A

المصدر: Neuro-Oncology Advances ; volume 5, issue 1 ; ISSN 2632-2498

مصطلحات موضوعية: Surgery, Oncology, Neurology (clinical)

الوصف: Background Malignant peripheral nerve sheath tumors (MPNST) are aggressive soft tissue sarcomas originating from cellular components within the nerve sheath. The incidence of MPNST is highest in people with neurofibromatosis type 1 (NF1), and MPNST is the leading cause of death for these individuals. Complete surgical resection is the only curative therapeutic option, but is often unfeasible due to tumor location, size, or presence of metastases. Evidence-based choices of chemotherapy for recurrent/refractory MPNST remain elusive. To address this gap, we conducted a retrospective analysis of our institutional experience in treating patients with relapsed MPNST in order to describe patient outcomes related to salvage regimens. Methods We conducted a retrospective electronic health record analysis of patients with MPNST who were treated at Johns Hopkins Hospital from January 2010 to June 2021. We calculated time to progression (TTP) based on salvage chemotherapy regimens. Results Sixty-five patients were included in the analysis. Upfront therapy included single or combined modalities of surgery, chemotherapy, or radiotherapy. Forty-eight patients received at least 1 line of chemotherapy, which included 23 different regimens (excluding active clinical studies). Most patients (n = 42, 87.5%) received a combination of doxorubicin, ifosfamide, or etoposide as first-line chemotherapy. Salvage chemotherapy regimens and their TTP varied greatly, with irinotecan/temozolomide-based regimens having the longest average TTP (255.5 days, among 4 patients). Conclusions Patients with advanced or metastatic MPNST often succumb to their disease despite multiple lines of therapy. These data may be used as comparative information in decision-making for future patients and clinical trials.

الإتاحة: https://doi.org/10.1093/noajnl/vdad156Test
https://academic.oup.com/noa/article-pdf/5/1/vdad156/54715972/vdad156.pdfTest

المؤلفون: Lemberg, Kathryn M., Koontz, Danielle W., Young, David J., DiDomizio, P. Galen, King, Anne, Chen, Allen R., Gamper, Christopher J., Colantuoni, Elizabeth, Milstone, Aaron M., Cooper, Stacy L.

المصدر: Pediatric Quality & Safety ; volume 7, issue 2, page e545 ; ISSN 2472-0054

الوصف: Introduction: Meaningful engagement in quality improvement (QI) projects by trainees is often challenging. A fellow-led QI project aimed to improve adherence to a blood culture clinical decision algorithm and reduce unnecessary cultures in pediatric oncology inpatients. Methods: We visualized preintervention rates of blood cultures drawn on pediatric oncology inpatients using a control chart. Following the introduction of the algorithm to our division, an Ishikawa fishbone diagram of cause-and-effect identified two areas for improvement: prescriber education on the algorithm and targeted feedback on its use. We developed two interventions to support algorithm awareness and use: (1) bundled educational interventions and (2) targeted chart review and feedback. Fellows reviewed >750 blood culture episodes and adjudicated each as “adherent” or “nonadherent” to the algorithm. In addition, fellows provided direct feedback to prescribers regarding nonadherent episodes and discussed strategies for algorithm adherence. Results: Blood culture rates in preintervention, intervention, and follow-up periods were 33.35, 25.24, and 22.67 cultures/100 patient-days, respectively. The proportion of nonadherent culture episodes decreased from 47.14% to 11.11%. The use of the algorithm did not prolong the time to cultures drawn on patients with new fever. Seventy-five percent of fellows provided feedback to inpatient teams on algorithm use. Following this project, trainees reported feeling more qualified to apply QI principles to patient care. Conclusions: Implementation of a clinical decision algorithm reduced the rate of cultures drawn on pediatric oncology inpatients. Fellow-led education of the care team decreased the proportion of nonadherent culture episodes and provided active engagement in QI.

الإتاحة: https://doi.org/10.1097/pq9.0000000000000545Test

المؤلفون: Zou, Ying S., Morsberger, Laura, Hardy, Melanie, Ghabrial, Jen, Stinnett, Victoria, Murry, Jaclyn B., Long, Patty, Kim, Andrew, Pratilas, Christine A., Llosa, Nicolas J., Ladle, Brian H., Lemberg, Kathryn M., Levin, Adam S., Morris, Carol D., Haley, Lisa, Gocke, Christopher D., Gross, John M.

المصدر: Genes; Jun2023, Vol. 14 Issue 6, p1139, 15p

مصطلحات موضوعية: GENE fusion, EWING'S sarcoma, CHROMOSOME analysis, CHROMOSOME abnormalities, GENE rearrangement, CHROMOSOMAL translocation

مستخلص: Ewing sarcomas (ES) are rare small round cell sarcomas often affecting children and characterized by gene fusions involving one member of the FET family of genes (usually EWSR1) and a member of the ETS family of transcription factors (usually FLI1 or ERG). The detection of EWSR1 rearrangements has important diagnostic value. Here, we conducted a retrospective review of 218 consecutive pediatric ES at diagnosis and found eight patients having data from chromosome analysis, FISH/microarray, and gene-fusion assay. Three of these eight ES had novel complex/cryptic EWSR1 rearrangements/fusions by chromosome analysis. One case had a t(9;11;22)(q22;q24;q12) three-way translocation involving EWSR1::FLI1 fusion and 1q jumping translocation. Two cases had cryptic EWSR1 rearrangements/fusions, including one case with a cryptic t(4;11;22)(q35;q24;q12) three-way translocation involving EWSR1::FLI1 fusion, and the other had a cryptic EWSR1::ERG rearrangement/fusion on an abnormal chromosome 22. All patients in this study had various aneuploidies with a gain of chromosome 8 (75%), the most common, followed by a gain of chromosomes 20 (50%) and 4 (37.5%), respectively. Recognition of complex and/or cryptic EWSR1 gene rearrangements/fusions and other chromosome abnormalities (such as jumping translocation and aneuploidies) using a combination of various genetic methods is important for accurate diagnosis, prognosis, and treatment outcomes of pediatric ES. [ABSTRACT FROM AUTHOR]

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المؤلفون: Rais, Rana, Lemberg, Kathryn M., Tenora, Lukáš, Arwood, Matthew L., Pal, Arindom, Alt, Jesse, Wu, Ying, Lam, Jenny, Aguilar, Joanna Marie H., Zhao, Liang, Peters, Diane E., Tallon, Carolyn, Pandey, Rajeev, Thomas, Ajit G., Dash, Ranjeet P., Seiwert, Tanguy, Majer, Pavel, Leone, Robert D., Powell, Jonathan D., Slusher, Barbara S.

المصدر: Science Advances ; volume 8, issue 46 ; ISSN 2375-2548

الوصف: 6-Diazo-5-oxo- l -norleucine (DON) is a glutamine antagonist that suppresses cancer cell metabolism but concurrently enhances the metabolic fitness of tumor CD8 + T cells. DON showed promising efficacy in clinical trials; however, its development was halted by dose-limiting gastrointestinal (GI) toxicities. Given its clinical potential, we designed DON peptide prodrugs and found DRP-104 [isopropyl( S )-2-(( S )-2-acetamido-3-(1 H -indol-3-yl)-propanamido)-6-diazo-5-oxo-hexanoate] that was preferentially bioactivated to DON in tumor while bioinactivated to an inert metabolite in GI tissues. In drug distribution studies, DRP-104 delivered a prodigious 11-fold greater exposure of DON to tumor versus GI tissues. DRP-104 affected multiple metabolic pathways in tumor, including decreased glutamine flux into the TCA cycle. In efficacy studies, both DRP-104 and DON caused complete tumor regression; however, DRP-104 had a markedly improved tolerability profile. DRP-104’s effect was CD8 + T cell dependent and resulted in robust immunologic memory. DRP-104 represents a first-in-class prodrug with differential metabolism in target versus toxicity tissue. DRP-104 is now in clinical trials under the FDA Fast Track designation.

الإتاحة: https://doi.org/10.1126/sciadv.abq5925Test

المؤلفون: Lemberg, Kathryn M., Gori, Sadakatali S., Tsukamoto, Takashi, Rais, Rana, Slusher, Barbara S.

المصدر: The Journal of Clinical Investigation

مصطلحات موضوعية: Drug Delivery Systems, Neoplasms, Review Series, Tumor Microenvironment, Animals, Humans, Antineoplastic Agents, General Medicine

الوصف: Metabolic inhibitors have been used in oncology for decades, dating back to antimetabolites developed in the 1940s. In the past 25 years, there has been increased recognition of metabolic derangements in tumor cells leading to a resurgence of interest in targeting metabolism. More recently there has been recognition that drugs targeting tumor metabolism also affect the often acidic, hypoxic, immunosuppressive tumor microenvironment (TME) and non-tumor cell populations within it, including immune cells. Here we review small-molecule metabolic inhibitors currently in clinical development for oncology applications. For each agent, we evaluate the preclinical studies demonstrating antitumor and TME effects and review ongoing clinical trials. The goal of this Review is to provide an overview of the landscape of metabolic inhibitors in clinical development for oncology.

الوصول الحر: https://explore.openaire.eu/search/publication?articleId=doi_dedup___::2fb267534863cbd115bb41ee478188a6Test
https://doi.org/10.1172/jci148550Test

المؤلفون: Alt, Jesse, Gori, Sadakatali S., Lemberg, Kathryn M., Pal, Arindom, Veeravalli, Vijayabhaskar, Wu, Ying, Aguilar, Joanna M.H., Dash, Ranjeet P., Tenora, Lukáš, Majer, Pavel, Sun, Qi, Slusher, Barbara S., Rais, Rana

المساهمون: Institute of Organic Chemistry and Biochemistry of the Academy of Sciences of the Czech Republic-CureSearch Young Investigator Award, Bloomberg Kimmel Institute for Cancer Immunotherapy-Ministry of Education, Youth and Sports of the Czech Republic, National Institutes of Health, NIH

المصدر: Current Drug Metabolism ; volume 22, issue 9, page 735-745 ; ISSN 1389-2002

مصطلحات موضوعية: Clinical Biochemistry, Pharmacology

الوصف: Background: Metabolomic analyses from our group and others have shown that tumors treated with glutamine antagonists (GA) exhibit robust accumulation of formylglycinamide ribonucleotide (FGAR), an intermediate in the de novo purine synthesis pathway. The increase in FGAR is attributed to the inhibition of the enzyme FGAR amidotransferase (FGAR-AT) that catalyzes the ATP-dependent amidation of FGAR to formylglycinamidine ribonucleotide (FGAM). While perturbation of this pathway resulting from GA therapy has long been recognized, no study has reported systematic quantitation and analyses of FGAR in plasma and tumors. Objective: Herein, we aimed to evaluate the efficacy of our recently discovered tumor-targeted GA prodrug, GA-607 (isopropyl 2-(6-acetamido-2-(adamantane-1-carboxamido)hexanamido)-6-diazo-5-oxohexanoate), and demonstrate its target engagement by quantification of FGAR in plasma and tumors. Methods: Efficacy and pharmacokinetics of GA-607 were evaluated in a murine EL4 lymphoma model followed by global tumor metabolomic analysis. Liquid chromatography-mass spectrometry (LC-MS) based methods employing the ion-pair chromatography approach were developed and utilized for quantitative FGAR analyses in plasma and tumors. Results: GA-607 showed preferential tumor distribution and robust single-agent efficacy in a murine EL4 lymphoma model. While several metabolic pathways were perturbed by GA-607 treatment, FGAR showed the highest increase qualitatively. Using our newly developed sensitive and selective LC-MS method, we showed a robust >80- and >10- fold increase in tumor and plasma FGAR levels, respectively, with GA-607 treatment. Conclusion: These studies describe the importance of FGAR quantification following GA therapy in cancer and underscore its importance as a valuable pharmacodynamic marker in the preclinical and clinical development of GA therapies.

الإتاحة: https://doi.org/10.2174/1389200222666210831125041Test
https://eurekaselect.com/article/download/195977Test
https://www.eurekaselect.com/195977/articleTest

المؤلفون: Dixon, Scott J., Lemberg, Kathryn M., Lamprecht, Michael R., Skouta, Rachid, Zaitsev, Eleina M., Gleason, Caroline E., Patel, Darpan N., Bauer, Andras J., Cantley, Alexandra M., Yang, Wan Seok, Morrison, Barclay, Stockwell, Brent R.

المساهمون: National Institutes of Health, Arnold and Mabel Beckman Foundation, Columbia University, Empire State Development's Division of Science, Technology and Innovation, Canadian Institutes of Health Research, National Science Foundation

المصدر: Cell ; volume 149, issue 5, page 1060-1072 ; ISSN 0092-8674

الإتاحة: https://doi.org/10.1016/j.cell.2012.03.042Test
https://api.elsevier.com/content/article/PII:S009286741200520X?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S009286741200520X?httpAccept=text/plainTest

المؤلفون: Bauer, Andras J., Gieschler, Simone, Lemberg, Kathryn M., McDermott, Ann E., Stockwell, Brent R.

المساهمون: Arnold and Mabel Beckman Foundation, Howard Hughes Medical Institute, National Institutes of Health

المصدر: Biochemistry ; volume 50, issue 17, page 3408-3410 ; ISSN 0006-2960 1520-4995

مصطلحات موضوعية: Biochemistry

الإتاحة: https://doi.org/10.1021/bi2003247Test

المؤلفون: Tenora, Lukáš, Alt, Jesse, Dash, Ranjeet P., Gadiano, Alexandra J., Novotná, Kateřina, Veeravalli, Vijayabhaskar, Lam, Jenny, Kirkpatrick, Quinn R., Lemberg, Kathryn M., Majer, Pavel, Rais, Rana, Slusher, Barbara S.

المساهمون: Ministerstvo ?kolstv?, Ml?de?e a Telov?chovy, National Cancer Institute, National Institute of Neurological Disorders and Stroke, Bloomberg~Kimmel Institute for Cancer Immunotherapy, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic

المصدر: Journal of Medicinal Chemistry ; volume 62, issue 7, page 3524-3538 ; ISSN 0022-2623 1520-4804

الإتاحة: https://doi.org/10.1021/acs.jmedchem.8b02009Test

المؤلفون: Lemberg, Kathryn M., Schweidenback, Caterina T.H., Baker, Tania A.

المصدر: Journal of Molecular Biology ; volume 374, issue 5, page 1158-1171 ; ISSN 0022-2836

مصطلحات موضوعية: Molecular Biology, Structural Biology

الإتاحة: https://doi.org/10.1016/j.jmb.2007.09.079Test
https://api.elsevier.com/content/article/PII:S0022283607012910?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S0022283607012910?httpAccept=text/plainTest