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A First-in-Class Pan-Lysyl Oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer

ABSTRACT: A First-in-Class Pan-Lysyl Oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer

PROVIDER: PRJNA775961 | ENA |

REPOSITORIES: ENA

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A First-in-Class Pan-Lysyl Oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer

Project description:The lysyl oxidase family represents a promising target in stromal targeting of solid tumours due to the importance of this family in cross-linking and stabilising fibrillar collagens, and its known role in tumour desmoplasia. Using small-molecule drug design approaches, we generated and validated PXS-5505, a first-in-class, highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumour desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumour perfusion, and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, whilst also demonstrating anti-fibrotic effects in human PDX models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of the first pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma.

2023-05-18 | GSE186748 | GEO

A first-in-class pan-lysyl oxidase inhibitor impairs stromal remodeling and enhances gemcitabine response and survival in pancreatic cancer.

Project description:The lysyl oxidase family represents a promising target in stromal targeting of solid tumors due to the importance of this family in crosslinking and stabilizing fibrillar collagens and its known role in tumor desmoplasia. Using small-molecule drug-design approaches, we generated and validated PXS-5505, a first-in-class highly selective and potent pan-lysyl oxidase inhibitor. We demonstrate in vitro and in vivo that pan-lysyl oxidase inhibition decreases chemotherapy-induced pancreatic tumor desmoplasia and stiffness, reduces cancer cell invasion and metastasis, improves tumor perfusion and enhances the efficacy of chemotherapy in the autochthonous genetically engineered KPC model, while also demonstrating antifibrotic effects in human patient-derived xenograft models of pancreatic cancer. PXS-5505 is orally bioavailable, safe and effective at inhibiting lysyl oxidase activity in tissues. Our findings present the rationale for progression of a pan-lysyl oxidase inhibitor aimed at eliciting a reduction in stromal matrix to potentiate chemotherapy in pancreatic ductal adenocarcinoma.

| S-EPMC10518255 | biostudies-literature

Transcriptome analysis of Y79 retinoblastoma cells upon Lysyl oxidase propeptide (LOX-PP) overexpression

Project description:Lysyl oxidase (LOX) is an copper dependent amine oxidase enzyme involved in cross linking of collagens and elastins. Lysyl oxidase propeptide (LOX-PP) is 18 kDa region cleaved during maturation of LOX and its anti-tumorigenic role were studied in various cancers. The effect of LOX-PP overexpression in retinoblastoma cancer cells (Y79) using transient transfection of LOX-PP gene accessed for global gene deregulations. The analysis resulted in RB cancer cell death through deregulation of retinoblastoma in cancer, cell cycle, apoptosis, focal adhesion-PI3K-AKT signaling and DNA repair mechanism pathway. Further validations were done using RT-PCR and western blot analysis. Our results provide evidence that inducing apoptosis through AKT-NFκB signaling.

2019-09-01 | GSE119413 | GEO

Lysyl oxidase-like 2 (LOXL2) a new regulator of cell polarity required for metastatic dissemination of basal-like breast carcinomas

Project description:Basal-like breast carcinoma is characterized by the expression of basal/myoepithelial markers, undifferentiated phenotype, highly aggressive behaviour and a frequent triple negative status (ESR-, PR-, Her2neu-). We have previously shown that epithelial-mesenchymal transition (EMT) occurs in basal-like breast tumours and identified Lysyl- Oxidase-Like 2 (LOXL2) as an EMT player and a poor prognosis marker in squamous cell carcinomas. We now show that LOXL2 mRNA is overexpressed in basal-like human breast carcinomas. Identification of new molecular markers in basal breast carcinomas 58 (IDC) infiltrative breast ductal carcinoma samples (Grade 3)

2011-10-20 | E-GEOD-29581 | biostudies-arrayexpress

Lysyl oxidase-like 2 (LOXL2) a new regulator of cell polarity required for metastatic dissemination of basal-like breast carcinomas

2011-10-21 | GSE29581 | GEO

GATA3 Reprograms Basal Breast Cancer Cells towards a Luminal Subtype and Inhibits Metastases through Suppression of Lysyl Oxidase

Project description:The transcription factor GATA3 is essential for luminal cell differentiation during mammary gland development and critical for formation of the luminal subtypes of breast cancer. Ectopic expression of GATA3 promoted global alterations of the transcriptome of basal triple-negative breast cancer cells resulting in molecular and cellular changes associated with a more differentiated, luminal tumor subtype and a concomitant reduction in primary tumor growth, lung metastasis, and macrophage recruitment at the metastatic site. Importantly, we demonstrate that the inhibition of metastases by GATA3 results from the suppression of lysyl oxidase (LOX) expression, a metastasis promoting matrix protein that affects cell proliferation, cross-linking of extracellular collagen types, and establishment of the metastatic niche. There are 2 samples sent in triplicates.

2011-08-31 | E-GEOD-24249 | biostudies-arrayexpress

Transcriptome analysis of Y79 retinoblastoma cells upon Lysyl oxidase propeptide (LOX-PP) overexpression

Project description:Transcriptome analysis of Y79 retinoblastoma cells upon Lysyl oxidase propeptide (LOX-PP) overexpression

| PRJNA489199 | ENA

GATA3 Reprograms Basal Breast Cancer Cells towards a Luminal Subtype and Inhibits Metastases through Suppression of Lysyl Oxidase

2011-09-01 | GSE24249 | GEO

Neutrophils expressing lysyl oxidase-like 4 protein are present in colorectal cancer liver metastases resistant to anti-angiogenic therapy

Project description:Colorectal cancer liver metastases (CRCLM) that present with a replacement histopathological growth pattern (HGP) are resistant to neoadjuvant anti-angiogenic therapy. Surrogate biomarkers are not available to preoperatively identifypatients with these tumors. Here we identify differentially expressed genes between CRCLM with a replacement HGP and those with a desmoplastic HGP using RNA sequencing.We demonstrate that LOXL4 is transcriptionally upregulated in replacement HGP CRCLM compared with desmoplastic HGP CRCLM and the adjacent normal liver. Interestingly, lysyl oxidase-like 4 (LOXL4) protein was expressed by neutrophils present in the tumor microenvironment in replacement HGP CRCLM. We further demonstrate that LOXL4 expression is higher in circulating neutrophils of cancer patients compared with healthy control patients and its expression can be induced by stimulation with lipopolysaccharide and TNF-alpha. Our study is the first to show the expression of LOXL4 in neutrophils and reveals the potential for LOXL4-expressing neutrophils to support the replacement HGP phenotype and to serve as a surrogate biomarker for this subtype of CRCLM.

2020-05-27 | GSE151165 | GEO

Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of Lysyl Oxidase

Project description:Arterial stiffness and cardiac dysfunction in Hutchinson-Gilford Progeria Syndrome corrected by inhibition of Lysyl Oxidase

| PRJNA694470 | ENA