HIF-Prolyl Hydroxylase Domain Proteins (PHDs) in Cancer—Potential Targets for Anti-Tumor Therapy?

Abstract

Solid tumors are typically associated with unbridled proliferation of malignant cells, accompanied by an immature and dysfunctional tumor-associated vascular network. Consequent impairment in transport of nutrients and oxygen eventually leads to a hypoxic environment wherein cells must adapt to survive and overcome these stresses. Hypoxia inducible factors (HIFs) are central transcription factors in the hypoxia response and drive the expression of a vast number of survival genes in cancer cells and in cells in the tumor microenvironment. HIFs are tightly controlled by a class of oxygen sensors, the HIF-prolyl hydroxylase domain proteins (PHDs), which hydroxylate HIFs, thereby marking them for proteasomal degradation. Remarkable and intense research during the past decade has revealed that, contrary to expectations, PHDs are often overexpressed in many tumor types, and that inhibition of PHDs can lead to decreased tumor growth, impaired metastasis, and diminished tumor-associated immune-tolerance. Therefore, PHDs represent an attractive therapeutic target in cancer research. Multiple PHD inhibitors have been developed that were either recently accepted in China as erythropoiesis stimulating agents (ESA) or are currently in phase III trials. We review here the function of HIFs and PHDs in cancer and related therapeutic opportunities.

Hypoxia Pathway Proteins and Their Impact on the Blood Vasculature

“…Conversely, a majority of tumor types overexpress PHDs, making these oxygen sensors attractive therapeutic targets. For a more elaborated overview on the potential impact of PHD inhibitors for the treatment of cancer we refer to a recent review from our research group [173].…”

Vascularized Tumor Spheroid-on-a-Chip Model Verifies Synergistic Vasoprotective and Chemotherapeutic Effects

“…Recently, several vessel-normalizing compounds have been proposed, showing remarkable results, for example, chloroquine, Ang2-binding and Tie2-activating antibody (ABTAA), HS-173, or a glycolytic activator PFKFB3 blocker, all of which are expected to advance into clinical trials. Prolyl hydroxylases (PHD) inhibitors are also seen as great candidates for tumor blood vessel normalization. ,, We chose to evaluate DMOG as numerous positive outcomes were reported both in vitro and in rat models, − but they have not been validated in a human model.…”

“…Prolyl hydroxylases (PHD) inhibitors are also seen as great candidates for tumor blood vessel normalization. 7,9,19 We chose to evaluate DMOG as numerous positive outcomes were reported both in vitro and in rat models, 8−19 but they have not been validated in a human model. Several drug screening tools have emerged to evaluate chemotherapy drug efficacy, including organoids, 42−45 tumor spheroids, 46 patient derived xenografts, 45,47−49 or artificial intelligence-based approaches.…”

“…Hypoxia-inducible factors (HIFs) are transcription factors that control the cellular responses to hypoxia and are regulated by the prolyl hydroxylase domain protein (PHD). Consequently, PHD inhibition can stabilize HIFs, which in turn can reverse some of the cellular adaptations to hypoxia, improving blood flow and oxygenation . Dimethylallyl glycine (DMOG) is a PHD inhibitor demonstrated to possess osteogenic and angiogenic properties and has been most commonly studied in vitro , or loaded in bioscaffolds for bone regeneration. − Recently, blood vessel normalization via administration of DMOG has been demonstrated to sensitize tumor tissues to the anticancer drug cisplatin by increasing perfusion, oxygen, and drug distribution .…”

Self-Sustained Regulation or Self-Perpetuating Dysregulation: ROS-dependent HIF-YAP-Notch Signaling as a Double-Edged Sword on Stem Cell Physiology and Tumorigenesis

“…In fact, not only HIF but also PHDs are dysregulated in tumors. PHDs are often overexpressed in tumors by contradicting the expectations, and inhibition of PHDs can impair tumor growth, metastasis, and immune tolerance ( Gaete et al, 2021 ). Thus, HIFs and PHDs have been proposed as therapeutic targets against cancer.…”