Researchers at Johns Hopkins University and the University of Maryland School of Pharmacy have developed a set of novel, first-in-class drugs that inhibit hypoxia-inducible factors 1 and 2, a pair of transcription factors considered to be "master regulators" of cancer progression. The study, to be published April 2 in the Journal of Experimental Medicine (JEM), shows that these drugs, when combined with immunotherapy, can completely eliminate breast, colorectal, melanoma, and prostate tumors in mice, suggesting that they could eventually be used to treat a broad range of cancers in humans.
Hypoxia-inducible factors 1 and 2 (HIF-1/2) are known as master regulators of cancer progression because they control the activity of hundreds of genes crucial for the survival, growth, and spread (metastasis) of cancer cells. Among other functions, HIF-1/2 promote the formation of new blood vessels to supply tumors with nutrients and enhance the ability of tumor cells to invade surrounding tissues. They also suppress the ability of immune cells to attack tumors, which limits the effectiveness of immunotherapies such as immune checkpoint inhibitors.
HIF-1/2 levels rise in response to low oxygen levels (hypoxia), a condition commonly found in the center of rapidly growing tumors. The presence of hypoxia, and elevated HIF-1/2 levels, is a key predictor of treatment failure and poor patient survival in a broad range of cancers. Belzutifan, a specific inhibitor of HIF-2, has been approved for therapeutic use in several cancers, including advanced renal cell carcinoma. But, since HIF-1 and HIF-2 have distinct roles in promoting cancer progression, drugs that target both transcription factors simultaneously could be more effective.
"Dual HIF-1/2 inhibition presents a promising therapeutic strategy, particularly for cancer types with a known propensity for intratumoral hypoxia and/or resistance to conventional therapy," says Gregg L. Semenza, co-senior author of the new JEM study and a professor at Johns Hopkins University School of Medicine.
Semenza and colleagues worked with Professor Alexander D. MacKerell's group in the Computer-Aided Drug Design Center at the University of Maryland School of Pharmacy to identify drug molecules capable of binding to both HIF-1 and HIF-2. SILCS, a computer-aided drug design technology, was used to predict small molecules that might bind based on the known crystal structure of HIF-2. "The SILCS approach enabled the selection of compounds with a high probability of binding to HIF-2, allowing experimental efforts to focus on testing hundreds, rather than millions, of chemical compounds, thereby accelerating the drug discovery process," MacKerell says.
Semenza's team, including first author Dr. Shaima Salman, tested these candidate molecules and identified several compounds that bound to both HIF-1 and HIF-2, triggering their degradation and preventing them from activating their target genes. "These compounds showed broad and potent HIF inhibitor activity in a variety of cancer cell lines," Salman says.
Individually, the drugs were able to inhibit the growth of breast, colorectal, head and neck, melanoma, and prostate tumors in mice, reducing tumor vascularization and limiting tumor invasiveness.
The drugs were even more effective in combination with the immune checkpoint inhibitors anti-CTLA-4 or anti-PD1. Combination therapy caused complete remission in over 50% of mice with either breast, colorectal, melanoma, or prostate tumors, many of which were resistant to treatment with immune checkpoint inhibitors alone. These animals remained tumor free, even when rechallenged with an injection of fresh tumor cells.
Semenza and colleagues found that dual HIF-1/2 inhibitors alter the type of immune cells found within tumors, decreasing immunosuppressive cell types while increasing the frequency of T cells and NK cells that are capable of killing tumor cells (especially when treated with immune checkpoint inhibitors).
"We saw an increased response to immune checkpoint inhibitors with HIF inhibitor treatment across a broad sampling of cancer types, suggesting that this combination will have widespread clinical utility," Semenza says. Adding to the drugs' therapeutic potential, the researchers note that their dual HIF-1/2 inhibitors can be administered orally and showed no safety concerns in mice, even when given for extended periods in amounts well above the effective dose.
Salman et al., 2026. J. Exp. Med. https://rupress.org/jem/article-lookup/doi/10.1084/jem.20251009?PR
