LOXL2 Inhibitors and Breast Cancer Progression

Ferreira, Sandra; Saraiva, Nuno; Rijo, Patrícia; Fernandes, Ana Sofia

doi:10.3390/antiox10020312

Cited by 72 publications

(59 citation statements)

References 80 publications

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“…Similarly, other studies have shown that MMP9 and CTSS inhibitors effectively inhibit tumor growth as well [ 47 ]. Additionally, PAT-1251 (newly designated GB2064), which targets LOXL2, has been used in phase 1 clinical trials for the treatment of lung disease as well as metastatic breast cancer [ 48 , 49 ]. Studies have also shown that SPP1 is an important target of BET inhibitors, which can effectively inhibit the growth of melanoma cells [ 19 ].…”

Section: Discussionmentioning

confidence: 99%

The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis

Mason

Chava

Reddi

et al. 2021

Cancers

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Melanoma accounts for the majority of all skin cancer-related deaths and only 1/3rd of melanoma patients with distal metastasis survive beyond five years. However, current therapies including BRAF/MEK targeted therapies or immunotherapies only benefit a subset of melanoma patients due to the emergence of intrinsic or extrinsic resistance mechanisms. Effective treatment of melanoma will thus require new and more effective therapeutic agents. Towards the goal of identifying new therapeutic agents, we conducted an unbiased, druggable epigenetic drug screen using a library of 32 epigenetic inhibitors obtained from the Structural Genome Consortium that targets proteins encoding for epigenetic regulators. This chemical genetic screening identified TP-472, which targets bromodomain-7/9, as the strongest inhibitor of melanoma growth in both short- and long-term survival assays and in mouse models of melanoma tumor growth. Mechanistically, using a transcriptome-wide mRNA sequencing profile we identified TP-472 treatment downregulates genes encoding various extracellular matrix (ECM) proteins, including integrins, collagens, and fibronectins. Reactome-based functional pathway analyses revealed that many of the ECM proteins are involved in extracellular matrix interactions required for cancer cell growth and proliferation. TP-472 treatment also upregulated several pro-apoptotic genes that can inhibit melanoma growth. Collectively, our results identify BRD7/9 inhibitor TP-472 as a potentially useful therapeutic agent for melanoma therapy.

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Section: Discussionmentioning

confidence: 99%

The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis

Mason

Chava

Reddi

et al. 2021

Cancers

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“…Lysyl oxidase like-2 (LOXL2) [98], an ECM remodeling enzyme that is upregulated in desmoplastic tumors and helps in maintaining the protumorigenic stroma [99], has also been evaluated as a therapeutic target in PDAC. Inhibition of LOXL2, using the humanized monoclonal antibody Simtuzumab, showed promising results in preclinical models of breast cancer [100], which, combined with the fact that PDAC undergoes extensive desmoplasia, formed the basis of a phase II clinical trial of the combination of Simtuzumab and gemcitabine for metastatic PDAC patients. However, the combination did not provide any survival benefit [101,102].…”

Section: Cafs As Therapeutic Targetsmentioning

confidence: 99%

Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma: An Update on Heterogeneity and Therapeutic Targeting

Vaish

Jain

Are

et al. 2021

IJMS

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Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related morbidity and mortality in the western world, with limited therapeutic strategies and dismal long-term survival. Cancer-associated fibroblasts (CAFs) are key components of the pancreatic tumor microenvironment, maintaining the extracellular matrix, while also being involved in intricate crosstalk with cancer cells and infiltrating immunocytes. Therefore, they are potential targets for developing therapeutic strategies against PDAC. However, recent studies have demonstrated significant heterogeneity in CAFs with respect to their origins, spatial distribution, and functional phenotypes within the PDAC tumor microenvironment. Therefore, it is imperative to understand and delineate this heterogeneity prior to targeting CAFs for PDAC therapy.

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“…High levels of LOXL2 in cancers are associated with increased metastatic potential possibly due to their effect on tumor cell invasion and migration [61]. In breast cancer, increased LOXL2 expression by the tumor stroma is associated with poor prognosis [34]. Most published studies have focused on the canonical enzymatic function of LOXL2 in regulating collagen crosslinking and fibril formation, supporting tumorigenesis [23].…”

Section: Discussionmentioning

confidence: 99%

A pan-cancer analysis of matrisome proteins reveals CTHRC1and LOXL2 as major ECM regulators across cancers

Harikrishnan

Prabhu

Balasubramanian

2021

Preprint

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The extracellular matrix as part of the tumor microenvironment can regulate cancer cell growth and progression. Using TCGA data from 30 cancer types, the top 5% of matrisome genes with amplifications or deletions that affect survival in cancers were identified. Eight of these genes show altered expression in ~50% or more cancers affecting survival in ~20% or more. Among them SNED1 is the most downregulated and CTHRC1 and LOXL2 most upregulated. Differential gene expression analysis of SNED-1 did not identify any genes it regulates across cancers, while CTHRC1 and LOXL2 affected 19 and 5 genes respectively in 3 or more cancers. STRING analysis of these genes classified them as extracellular, involved prominently in ECM organization. Their correlation and co-occurrence in context of their effect on survival and staging of the disease identified MMP13, POSTN and SFRP4 along with COL11A1, COL10A1, COL1A1, ADAMTS12 and PPAPDC1A as possible interactors of CTHRC1 and LOXL2 in cancers. These are implicated in collagen organization, making it vital to matrisome regulation of cancers. Clinical Proteomic Tumor Analysis Consortium data confirms the changes in expression of these genes along with CTHRC1 and LOXL2 in breast and lung cancer, further supporting their implication as vital pan-cancer matrisome mediators.

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LOXL2 Inhibitors and Breast Cancer Progression

Cited by 72 publications

References 80 publications

The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis

The BRD9/7 Inhibitor TP-472 Blocks Melanoma Tumor Growth by Suppressing ECM-Mediated Oncogenic Signaling and Inducing Apoptosis

Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma: An Update on Heterogeneity and Therapeutic Targeting

A pan-cancer analysis of matrisome proteins reveals CTHRC1and LOXL2 as major ECM regulators across cancers

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