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Effect of ADI-PEG 20 treatment on murine liver chromatin landscape at single cell resolution.

ABSTRACT: Effect of ADI-PEG 20 treatment on murine liver chromatin landscape at single cell resolution.

PROVIDER: PRJNA791376 | ENA |

REPOSITORIES: ENA

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Effect of ADI-PEG 20 treatment on murine liver chromatin landscape at single cell resolution.

Project description:We demonstrate the effects of 4-week ADI-PEG 20 on murine liver chromatin accessibility by single-cell ATAC-sequencing

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Ph 1-2 Study ADI-PEG 20 Plus FOLFOX in Subjects With Advanced GI Malignancies Focusing on Hepatocellular Carcinoma

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Phase 1b study of pegylated arginine deiminase (ADI-PEG 20) plus Pembrolizumab in advanced solid cancers.

Project description:BackgroundPegylated arginine deiminase (ADI-PEG 20) is a metabolism-based strategy that depletes arginine, resulting in tumoral stress and cytotoxicity. Preclinically, ADI-PEG 20 modulates T-cell activity and enhances the therapeutic efficacy of programmed death-1 (PD-1) inhibition.MethodsA phase 1b study, including a dose-escalation cohort and an expansion cohort, was undertaken to explore the effects of ADI-PEG 20 in combination with pembrolizumab, an anti-PD-1 antibody, for safety, pharmacodynamics, and response. CD3 levels and programmed death-ligand 1 (PD-L1) expression were assessed in paired biopsies collected prior to and after ADI-PEG 20 treatment but before pembrolizumab.ResultsTwenty-five patients, nine in the dose-escalation cohort and sixteen in the expansion cohort, were recruited. Treatment was feasible with adverse events consistent with those known for each agent, except for Grade 3/4 neutropenia which was higher than expected, occurring in 10/25 (40%) patients. Mean arginine levels were suppressed for 1-3 weeks, but increased gradually. CD3+ T cells increased in 10/12 (83.3%) subjects following ADI-PEG 20 treatment, including in three partial responders (p = .02). PD-L1 expression was low and increased in 3/10 (30%) of subjects. Partial responses occurred in 6/25 (24%) heavily pretreated patients, in both argininosuccinate synthetase 1 proficient and deficient subjects.ConclusionsThe immunometabolic combination was safe with the caveat that the incidence of neutropenia might be increased compared with either agent alone. ADI-PEG 20 treatment increased T cell infiltration in the low PD-L1 tumor microenvironment. The recommended phase 2 doses are 36 mg/m2 weekly for ADI-PEG 20 and 200 mg every 3 weeks for pembrolizumab.

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Phase 1 trial of ADI-PEG 20 and liposomal doxorubicin in patients with metastatic solid tumors.

Project description:BackgroundArginine depletion interferes with pyrimidine metabolism and DNA damage repair pathways. Preclinical data demonstrated that depletion of arginine by PEGylated arginine deiminase (ADI-PEG 20) enhanced liposomal doxorubicin (PLD) cytotoxicity in cancer cells with argininosuccinate synthase 1 (ASS1) deficiency. The objective of this study was to assess safety and tolerability of ADI-PEG 20 and PLD in patients with metastatic solid tumors.MethodsPatients with advanced ASS1-deficient solid tumors were enrolled in this phase 1 trial of ADI-PEG 20 and PLD following a 3 + 3 design. Eligible patients were given intravenous PLD biweekly and intramuscular (IM) ADI-PEG 20 weekly. Toxicity and efficacy were evaluated according to the Common Terminology Criteria for Adverse Events (version 4.0) and Response Evaluation Criteria in Solid Tumors (version 1.1), respectively.ResultsOf 15 enrolled patients, 9 had metastatic HER2-negative breast carcinoma. We observed no dose-limiting toxicities or treatment-related deaths. One patient safely received 880 mg/m2 PLD in this study and 240 mg/m2 doxorubicin previously. Treatment led to stable disease in 9 patients and was associated with a median progression-free survival time of 3.95 months in 15 patients. Throughout the duration of treatment, decreased arginine and increased citrulline levels in peripheral blood remained significant in a majority of patients. We detected no induction of anti-ADI-PEG 20 antibodies by week 8 in one third of patients.ConclusionConcurrent IM injection of ADI-PEG 20 at 36 mg/m2 weekly and intravenous infusion of PLD at 20 mg/m2 biweekly had an acceptable safety profile in patients with advanced ASS1-deficient solid tumors. Further evaluation of this combination is under discussion.

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Transcriptome analysis of Arabidopsis thaliana shoots and roots, exposed to PEG-induced osmotic shock, PEG+Histidine, PEG+SHAM [20190613_174740_sham_cont]

Project description:In order to better understand the context of root water stress and its relationship to other stresses, I undertook an evaluation of osmotic water stress by transcriptome analyses. Whole transcriptome MARSeq (Diego Adhemar Jaitin, 2017) analysis can enable us to study the changes in gene expression (changes in transcript prevalence) in depth under different treatments. It is a cost effective method to develop transcriptional activity. It uses relatively small amounts of RNA and reads sequences from the 3’-polyA containing end. This method can reveal underlying trends that can help us understand the less obvious processes happening in our system. To carry this out I processed whole transcriptome data separately from WT seedling roots exposure to PEG, and from roots under 30% PEG + 5mM HIS, 30% PEG + 1mM SHAM for 0, 1, 2, 3 h.

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Transcriptome analysis of Arabidopsis thaliana shoots and roots, exposed to PEG-induced osmotic shock, PEG+Histidine, PEG+SHAM [20190311_172119_Peg_SHAMf1_res]

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