Novel cancer treatment paradigm targeting hypoxia-induced factor in conjunction with current therapies to overcome resistance

Abstract

Chemotherapy, radiotherapy, targeted therapy, and immunotherapy are established cancer treatment modalities that are widely used due to their demonstrated efficacy against tumors and favorable safety profiles or tolerability. Nevertheless, treatment resistance continues to be one of the most pressing unsolved conundrums in cancer treatment. Hypoxia-inducible factors (HIFs) are a family of transcription factors that regulate cellular responses to hypoxia by activating genes involved in various adaptations, including erythropoiesis, glucose metabolism, angiogenesis, cell proliferation, and apoptosis. Despite this critical function, overexpression of HIFs has been observed in numerous cancers, leading to resistance to therapy and disease progression. In recent years, much effort has been poured into developing innovative cancer treatments that target the HIF pathway. Combining HIF inhibitors with current cancer therapies to increase anti-tumor activity and diminish treatment resistance is one strategy for combating therapeutic resistance. This review focuses on how HIF inhibitors could be applied in conjunction with current cancer treatments, including those now being evaluated in clinical trials, to usher in a new era of cancer therapy.

Spatial Transcriptomics in Breast Cancer Reveals Tumour Microenvironment-Driven Drug Responses and Clonal Therapeutic Heterogeneity

“…This lower sensitivity can be due to an enrichment in DNA repair functions, which may help cancer cells repair DNA damage efficiently, contributing to treatment resistance. Indeed, upregulation of DNA repair mechanisms and hypoxia have been linked to chemoresistance in breast cancer [71,72]. On the other hand, the tumour periphery was more enriched in an invasive phenotype, inflammation, ECM stiffness and epithelial to mesenchymal transition (EMT).…”

Illuminating new possibilities: Effects of copper oxide nanoparticles on gastrointestinal adenocarcinoma cells in hypoxic condition

“…Hypoxia is a prevalent characteristic of solid tumors that plays crucial roles in tumor progression by inducing metastasis, immunosuppression and therapy resistance [ 12 ]. Accordingly, targeting HIF-1α as the key mediator of hypoxia adaptation presents promising opportunities for the development of more effective anticancer treatments.…”

“…In well-oxygenated conditions, prolyl hydroxylation leads to von-Hippel-Lindau protein-dependent ubiquitination and rapid proteasomal degradation of HIF-1α. Hypoxia inhibits hydroxylation of HIF-1α, allowing its accumulation and translocation to the nucleus where it forms a heterodimer with HIF-1β and activates the transcription of several genes involved in angiogenesis, metastasis, immunosuppression, and the development of therapeutic resistance [ 12 , 13 ]. Hence, induction of HIF-1 in hypoxic condition makes it an attractive candidate for selective targeting of cancer cells, as normal cells are unlikely to be affected.…”

Therapeutic Targeting of Hypoxia-Inducible Factors in Cancer

“…These range from small molecules aimed at inhibiting HIF activity to gene therapies designed to modulate the expression of HIF-responsive genes. Furthermore, understanding the HIF pathway offers insights into the development of new diagnostic markers for early detection and prognosis of cancer [5].…”