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

EMBO Molecular Medicine
Luana SchitoRobert S Kerbel

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 ...Continue Reading

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Citations

Jun 3, 2021·Cancers·Marina Elena CazzanigaMaria Grazia Cerrito
Nov 2, 2021·Frontiers in Cell and Developmental Biology·Haoran XiaJianye Wang

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Datasets Mentioned

BETA
GSE28722
GSE2034
GSE3494

Methods Mentioned

BETA
RNAseq

Clinical Trials Mentioned

NCT00442637

Software Mentioned

R
METABRIC
ImageJ

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