HIF inhibitors for ischemic retinopathies and cancers: options beyond anti-VEGF therapies

Abstract

Aberrant activation of the hypoxia inducible factor (HIF) pathway causing overexpression of angiogenic genes, like vascular endothelial growth factor (VEGF), is one of the underlying causes of ocular neovascularization (NV) and metastatic cancer. Consistently, along with surgical interventions, a number of anti-VEGF agents have been approved by FDA for the treatment of ocular neovascular diseases. These anti-VEGF agents, like ranibizumab/lucentis, have revolutionized the treatment in the past decade. However, substantial vision improvement is observed only in a subset of age-related macular degeneration patients receiving ranibizumab. Further, all current therapies are associated with limitations and side effects. For example, surgeries cause tissue destruction and inflammation while anti-VEGF therapies are expensive, require repeated administration, and offer temporary relief from vascular leakage. These factors impose significant cost and treatment burdens to both the patient and society. With an aging population in most western countries with a continually increasing number of patients on lifelong treatment for these retinal diseases, the focus of ocular drug development for neovascular diseases will be to improve efficacy while reducing treatment costs. Blocking the HIF pathway, a major regulator of ocular NV and cancer, offers an appealing therapeutic strategy. Therefore, this review summarizes HIF inhibitors that have been recently evaluated for the treatment of different cancers and ischemic retinopathies.

Tumor angiogenesis revisited: Regulators and clinical implications

“…These agents are classified based on their ability to inhibit a particular step in the HIF pathway, such as HIF protein expression and stability, HIF dimerization, binding of HIF to target DNA sequences. Many of these small molecules have been evaluated as cancer therapeutics . Chetomin disrupts the HIF‐1α/p300 complex and shows antitumor activity in multiple myeloma patient‐derived cell lines .…”

“…Many of these small molecules have been evaluated as cancer therapeutics. 411 Chetomin disrupts the HIF-1 /p300 complex and shows antitumor activity in multiple myeloma patient-derived cell lines. 412 EZN-2968, an antagonist of HIF-1 mRNA impairs the growth of prostate cancer cells.…”

Effect of acadesine on breast cancer cells under hypoxia

“…Один из механизмов такой сенситизации -блокирование акадезином HIF-1α-зависимых молекулярных каскадов. С учетом значи-тельной роли HIF-1α в усилении экспрессии VEGF-A соответственно, в развитии и поддержании сети вну-триопухолевых сосудистых капилляров [32] высокую эффективность может показать комбинация антиан-гиогенной терапии и акадезина. …”

Anti-angiogenic Therapy for Retinal Disease

“…Future anti-angiogenic approaches may include therapies upstream of the angiogenic secreted factors [e.g., HIF-1 (Subhani et al 2016)] or novel angiogenic secreted molecules [e.g., angiopoietin-like 4, or ANGPTL4 (Xin et al . 2013; Sodhi et al .…”