Metronomic Chemotherapy Offsets Hif Alpha Induction Upon Maximum-Tolerated Dose In Metastatic Cancers

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)-1 alpha and (HIF)-2 alpha (hereafter referred to as HIF alpha). 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 HIF alpha in models of advanced, metastatic colon and breast cancer. Our results revealed that LDM chemotherapy could offset paralog-specific, MTD-dependent HIF alpha induction in colon cancers disseminating to the liver and lungs, while limiting HIF alpha and hypoxia in breast cancer lung metastases. Moreover, we assessed the translational significance of HIF alpha 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 HIF alpha-targeting therapies. Altogether, these results suggest LDM chemotherapy as a potential maintenance strategy to stave off HIF alpha induction within the intra-metastatic tumor microenvironment.