Nature
Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Institut PLAsCAN, Centre de Recherche en Cancérologie de Lyon INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard, Lyon, France.
Published: August 2023
Netrin-1 is upregulated in cancers as a protumoural mechanism. Here we describe netrin-1 upregulation in a majority of human endometrial carcinomas (ECs) and demonstrate that netrin-1 blockade, using an anti-netrin-1 antibody (NP137), is effective in reduction of tumour progression in an EC mouse model. We next examined the efficacy of NP137, as a first-in-class single agent, in a Phase I trial comprising 14 patients with advanced EC. As best response we observed 8 stable disease (8 out of 14, 57.1%) and 1 objective response as RECIST v.1.1 (partial response, 1 out of 14 (7.1%), 51.16% reduction in target lesions at 6 weeks and up to 54.65% reduction during the following 6 months). To evaluate the NP137 mechanism of action, mouse tumour gene profiling was performed, and we observed, in addition to cell death induction, that NP137 inhibited epithelial-to-mesenchymal transition (EMT). By performing bulk RNA sequencing (RNA-seq), spatial transcriptomics and single-cell RNA-seq on paired pre- and on-treatment biopsies from patients with EC from the NP137 trial, we noted a net reduction in tumour EMT. This was associated with changes in immune infiltrate and increased interactions between cancer cells and the tumour microenvironment. Given the importance of EMT in resistance to current standards of care, we show in the EC mouse model that a combination of NP137 with carboplatin-paclitaxel outperformed carboplatin-paclitaxel alone. Our results identify netrin-1 blockade as a clinical strategy triggering both tumour debulking and EMT inhibition, thus potentially alleviating resistance to standard treatments.
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http://dx.doi.org/10.1038/s41586-023-06367-z | DOI Listing |
Cell Death Differ
October 2023
Apoptosis, Cancer and Development Laboratory- Equipe labellisée 'La Ligue', Labex DEVweCAN, Institut Convergence PLAsCAN, Centre de Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard, 69008, Lyon, France.
Drug resistance and cancer relapse represent significant therapeutic challenges after chemotherapy or immunotherapy, and a major limiting factor for long-term cancer survival. Netrin-1 was initially identified as a neuronal navigation cue but has more recently emerged as an interesting target for cancer therapy, which is currently clinically investigated. We show here that netrin-1 is an independent prognostic marker for clinical progression of breast and ovary cancers.
View Article and Find Full Text PDFNature
August 2023
Apoptosis, Cancer and Development Laboratory - Equipe labellisée 'La Ligue', LabEx DEVweCAN, Institut PLAsCAN, Centre de Recherche en Cancérologie de Lyon INSERM U1052-CNRS UMR5286, Université de Lyon, Université Claude Bernard Lyon1, Centre Léon Bérard, Lyon, France.
Netrin-1 is upregulated in cancers as a protumoural mechanism. Here we describe netrin-1 upregulation in a majority of human endometrial carcinomas (ECs) and demonstrate that netrin-1 blockade, using an anti-netrin-1 antibody (NP137), is effective in reduction of tumour progression in an EC mouse model. We next examined the efficacy of NP137, as a first-in-class single agent, in a Phase I trial comprising 14 patients with advanced EC.
View Article and Find Full Text PDFPurinergic Signal
September 2022
Department of Pharmacology, College of Medicine, Hallym University, Chuncheon, Gangwon-do, 24252, Republic of Korea.
Even though macrophages have the potential to harm tissues through excessive release of inflammatory mediators, they play protective roles to maintain tissue integrity. In this study, we hypothesized that lysophosphatidylcholine (LPC), via G2A and A receptors, puts brakes on macrophages by the induction of adenosine release which could contribute to termination of inflammation. Mechanistically, LPC-induced PGE production followed by the activation of cAMP/protein kinase A (PKA) pathway which results in the activation of LKB1/AMPK signaling pathway leading to increasing Mg influx concomitantly with an increase in mitochondrial membrane potential (MMP, Δψ) and ATP production.
View Article and Find Full Text PDFJ Mol Cell Cardiol
October 2021
Department of Cardiology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China. Electronic address:
Aims: Pathological cardiac hypertrophy induced by activation of the renin-angiotensin-aldosterone system (RAAS) is one of the leading causes of heart failure. However, in current clinical practice, the strategy for targeting the RAAS is not sufficient to reverse hypertrophy. Here, we investigated the effect of prostaglandin E1 (PGE1) on angiotensin II (AngII)-induced cardiac hypertrophy and potential molecular mechanisms underlying the effect.
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