Metronomic chemotherapy offsets HIFα induction upon maximum‐tolerated dose in metastatic cancers

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Title: Metronomic chemotherapy offsets HIFα induction upon maximum‐tolerated dose in metastatic cancers
Authors: Schito, LuanaRey, SergioXu, Pinget al.
Permanent link: http://hdl.handle.net/10197/12323
Date: 7-Sep-2020
Online since: 2021-07-12T15:31:37Z
Abstract: Conventional maximum‐tolerated dose (MTD) chemotherapy relies on periodic, massive cancer cell ablation events followed by treatment‐free intermissions, stereotypically resulting in resistance, relapse, and mortality. Furthermore, MTD chemotherapy can promote metastatic dissemination via activation of a transcriptional program dependent on hypoxia‐inducible factor (HIF)‐1α and (HIF)‐2α (hereafter referred to as HIFα). Instead, frequent low‐dose metronomic (LDM) chemotherapy displays less adverse effects while preserving significant pre‐clinical anticancer activity. Consequently, we hereby compared the effect of MTD or LDM chemotherapy upon HIFα in models of advanced, metastatic colon and breast cancer. Our results revealed that LDM chemotherapy could offset paralog‐specific, MTD‐dependent HIFα induction in colon cancers disseminating to the liver and lungs, while limiting HIFα and hypoxia in breast cancer lung metastases. Moreover, we assessed the translational significance of HIFα activity in colorectal and breast TCGA/microarray data, by developing two compact, 11‐gene transcriptomic signatures allowing the stratification/identification of patients likely to benefit from LDM and/or HIFα‐targeting therapies. Altogether, these results suggest LDM chemotherapy as a potential maintenance strategy to stave off HIFα induction within the intra‐metastatic tumor microenvironment.
Funding Details: University College Dublin
Funding Details: Canadian Institutes of Health Research (CIHR
Canadian Breast Cancer Foundation
Type of material: Journal Article
Publisher: EMBO Press
Journal: EMBO Molecular Medicine
Volume: 12
Issue: 9
Copyright (published version): 2020 the Authors
Keywords: Breast cancerColon cancerHIF-1HypoxiaLow-dose metronomic
DOI: 10.15252/emmm.201911416
Language: en
Status of Item: Peer reviewed
ISSN: 1757-4676
This item is made available under a Creative Commons License: https://creativecommons.org/licenses/by/3.0/ie/
Appears in Collections:Conway Institute Research Collection
Medicine Research Collection

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