Novel Dual HIF-1/2 Inhibitors Achieve Complete Tumor Remission in Combination with Immunotherapy
核心洞察
Researchers at Johns Hopkins University (搜索) and University of Maryland developed first-in-class dual HIF-1/2 inhibitors (搜索) that target master regulators of cancer progression.
The novel compounds achieved complete remission in over 50% of mice with breast, colorectal, melanoma (搜索), or prostate tumors when combined with immune checkpoint inhibitors.
The drugs alter tumor immune microenvironments by decreasing immunosuppressive cells while increasing tumor-killing T cells and NK cells.
Researchers at Johns Hopkins University (搜索) and the University of Maryland School of Pharmacy (搜索) have developed a breakthrough class of dual inhibitors targeting hypoxia-inducible factors 1 and 2 (HIF-1 (搜索)/2), transcription factors that serve as "master regulators" of cancer progression. The study, published April 2 in the Journal of Experimental Medicine, demonstrates that these first-in-class compounds can completely eliminate multiple tumor types in mice when combined with immunotherapy.
Targeting Cancer's Master Regulators
HIF-1 (搜索)/2 control the activity of hundreds of genes crucial for cancer cell survival, growth, and metastasis. These transcription factors promote new blood vessel formation to supply tumors with nutrients, enhance tumor cell invasiveness, and suppress immune cell function, thereby limiting the effectiveness of immunotherapies such as immune checkpoint inhibitors.
HIF-1 (搜索)/2 levels rise in response to hypoxia, a low-oxygen condition commonly found in rapidly growing tumor centers. The presence of hypoxia and elevated HIF-1/2 levels serves as a key predictor of treatment failure and poor patient survival across a broad range of cancers. While belzutifan, a specific HIF-2 (搜索) inhibitor, has gained approval for several cancers including advanced renal cell carcinoma (搜索), the distinct roles of HIF-1 and HIF-2 in cancer progression suggest that dual targeting could prove more effective.
"Dual HIF-1 (搜索)/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 study and professor at Johns Hopkins University (搜索) School of Medicine.
Computer-Aided Drug Discovery Accelerates Development
The research team collaborated with Professor Alexander D. MacKerell's group at the Computer-Aided Drug Design Center at the University of Maryland School of Pharmacy (搜索) to identify compounds capable of binding both HIF-1 (搜索) and HIF-2 (搜索). Using SILCS, a computer-aided drug design technology, researchers predicted 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 (搜索), allowing experimental efforts to focus on testing hundreds, rather than millions, of chemical compounds, thereby accelerating the drug discovery process," MacKerell explains.
First author Dr. Shaima Salman and Semenza's team tested these candidate molecules and identified several compounds that bound to both HIF-1 (搜索) and HIF-2 (搜索), triggering their degradation and preventing activation of target genes. "These compounds showed broad and potent HIF inhibitor activity in a variety of cancer cell lines," Salman notes.
Remarkable Efficacy Across Multiple Cancer Types
When tested individually, the dual HIF-1/2 inhibitors (搜索) demonstrated significant antitumor activity against breast, colorectal, head and neck, melanoma (搜索), and prostate tumors in mice. The compounds reduced tumor vascularization and limited tumor invasiveness across these diverse cancer types.
The therapeutic potential expanded dramatically when the HIF inhibitors were combined with immune checkpoint inhibitors anti-CTLA-4 or anti-PD1 (搜索). This combination therapy achieved complete remission in over 50% of mice bearing breast, colorectal, melanoma (搜索), or prostate tumors, including many that were resistant to immune checkpoint inhibitor monotherapy. Remarkably, these animals remained tumor-free even when rechallenged with fresh tumor cell injections.
Reshaping the Tumor Immune Microenvironment
The researchers discovered that dual HIF-1/2 inhibitors (搜索) fundamentally alter the composition of immune cells within tumors. The treatment decreased immunosuppressive cell populations while increasing the frequency of tumor-killing T cells and NK cells, particularly when combined 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 states.
Clinical Translation Potential
The dual HIF-1/2 inhibitors (搜索) demonstrate several characteristics favorable for clinical development. The compounds can be administered orally and showed no safety concerns in mice, even when given for extended periods at doses well above the effective therapeutic level. This safety profile, combined with the broad efficacy across multiple cancer types, positions these compounds as promising candidates for human clinical trials.
The research represents a significant advance in cancer therapeutics, offering a novel approach to overcome immunotherapy resistance while targeting fundamental mechanisms of cancer progression across diverse tumor types.