AT
Classification of breast cancer (BC) is dependent on location and invasiveness, which aids treatment choice for clinicians [1]. Categories include ductal, lobular and connective tissue; some BC cells overexpress certain receptors such as estrogen and progesterone, which aids doctors design more targeted and personalised therapy [1]. Existing treatments for BC include surgery, chemotherapy, hormone therapy, radiotherapy and cancer drugs. Since the 1950s, the U.S. Food and Drug Administration has approved a vast number of drugs for BC treatment, with methotrexate sodium being among the first in 1953 [1]. Understandably, as decades have passed, developments in anti-cancer drug research have evolved greatly and scientists routinely assess the tumour microenvironment for hallmarks to develop treatment. One example of the tumour hallmarks is hypoxia, which occurs when there are deficient oxygen levels in tissues. There are an abundant number of compounds that are effective in hypoxic conditions and used in anti-cancer treatments – for example, Evofosfamide.
Evofosfamide is a hypoxia-activated prodrug that has anti-cancer potential; in the presence of cellular oxidoreductases in hypoxia, it releases bromosio-phosphoramide mustard, which acts as an alkylating genotoxin and causes DNA damage and subsequent cell death [2]. The prodrug has shown success in Phase I/II trials and previous studies have investigated its use as a monotherapy as well as in conjunction with other anti-cancer agents such as cisplatin [2]. Reduced levels of the enzyme cyclic GMP-AMP synthase (cGAS) in hypoxia results in low activation of the stimulator of interferon genes (STING). Activaton of cGAS-STING leads to type I interferon signalling and there is a suggestion that compounds that cause DNA damage under hypoxia could contribute to the cGAS-STING pathway and initiate type I interferon action [2]. This would promote natural killer cells and their anti-tumour activity, thereby increasing success of BC treatment [2]. As Evofosfamide shows activity in hypoxia, this prodrug has potential as a promoter of the cGAS-STING pathway.
Das et al. investigated the effect of Evofosfamide on BC cell lines and hypothesised that this prodrug would contribute to the cGAS-STING pathway by promoting type I interferon signalling cascades. They treated BC cell lines MCF-7, MDA-MB-231 and the natural killer cell line NK-92 with 50mM Evofosfamide and incubated them in normoxic conditions (5% CO2) and in a Whitley H35 Hypoxystation at 37oC with an atmosphere of 95% N2, 5% CO2, and 1% O2. In hypoxic conditions, the prodrug improved cell death in MCF-7 and MDA-MB-23, as well as increasing levels of reactive oxygen species, fragmenting DNA, activating caspase 3/7 and cleavage of poly (ADP-ribose) polymerase proteins. They also found that under hypoxic conditions there was a downregulation of the cGAS-STING pathway in both BC cell lines, but when treated with Evofosfamide, this downregulation was counteracted and type I interferon signalling genes were restored. Therefore, this compound shows potential as a BC drug, but progression to Phase III studies is imperative to ensure safety and monitor symptom development [2].
Advances in BC treatment are fundamental to reducing fatalities, so investigations into the mechanisms behind the success of anti-cancer drugs, such as Evofosfamide, is imperative. It is hoped that progression through Phase III trials will be more common for more drugs, and therefore approved for use in cancer treatment.
Written by DWS Microbiologist, Kirsty McTear
References
- Mohini Chaurasia, Singh R, Sur S, Flora SJS. A review of FDA approved drugs and their formulations for the treatment of breast cancer. Frontiers in Pharmacology. 2023 Jul 28;14.
- Das S, Venkatesh GH, Moustafa Elsayed WS, Khouzam RA, Mahmood AS, Nawafleh HH, et al. Evofosfamide Enhances Sensitivity of Breast Cancer Cells to Apoptosis and Natural-Killer-Cell-Mediated Cytotoxicity Under Hypoxic Conditions. Cancers. 2025 Jun 14;17.
English