OHSU Researchers Develop Novel Cancer Drug SU212 Targeting Triple-Negative Breast Cancer
核心洞察
Oregon Health & Science University researchers have developed SU212, an experimental drug that suppresses tumor growth and metastasis in triple-negative breast cancer (搜索) through a novel mechanism targeting the ENO1 (搜索) enzyme.
The molecule operates through non-orthosteric inhibition, inducing degradation of enolase 1 (搜索) rather than simply blocking it, disrupting cancer cells' metabolic advantage in humanized mouse models.
SU212 shows potential for treating other cancers with ENO1 (搜索) dysregulation including gliomas, pancreatic cancer (搜索), and thyroid carcinoma (搜索), with particular promise for patients with concurrent metabolic diseases like diabetes (搜索).
Oregon Health & Science University researchers have developed a promising experimental cancer drug called SU212 that demonstrates significant efficacy against triple-negative breast cancer (搜索), one of the most aggressive and treatment-resistant forms of breast cancer. The findings, published in Cell Reports Medicine, show the molecule successfully suppressed tumor growth and metastasis in humanized mouse models by targeting a critical metabolic enzyme.
Novel Mechanism Targets Cancer Metabolism
SU212 operates through a unique non-orthosteric inhibition mechanism, binding to enolase 1 (搜索) (ENO1 (搜索)), an enzyme that regulates glucose levels inside human cells and is overexpressed in cancer cells. Unlike traditional inhibitors that simply block enzyme activity, SU212 induces the enzyme to degrade, ultimately disrupting the metabolic advantage that cancer cells rely on for rapid proliferation.
"It's an important step forward to treat triple-negative breast cancer (搜索)," said senior author Sanjay V. Malhotra, Ph.D., co-director of the Center for Experimental Therapeutics in the OHSU Knight Cancer Institute. "Triple-negative breast cancer is an aggressive form of cancer and there are no effective drugs available right now."
ENO1 (搜索) plays a fundamental role in glycolysis, the metabolic pathway by which glucose is converted into energy. Cancer cells notoriously upregulate this process to fuel their rapid growth, and ENO1 overexpression in cancerous tissues amplifies this metabolic flux, contributing to tumor survival and aggressiveness.
Addressing Critical Unmet Medical Need
Triple-negative breast cancer (搜索) accounts for as many as 15% of all breast cancers and presents a formidable challenge due to its lack of hormone receptors and HER2 expression, effectively eliminating many targeted therapy options available for other breast cancer subtypes. This aggressive malignancy disproportionately affects younger women and is associated with poor prognosis, high rates of recurrence, and widespread metastasis.
The research team employed humanized mouse models, which are engineered to carry human immune cells, thus more accurately replicating the complex interactions between tumor cells and the immune system found in patients. This advanced modeling approach enhances the translational relevance of SU212's efficacy, providing a more precise prediction of its therapeutic potential in humans.
Broader Therapeutic Applications
Beyond triple-negative breast cancer (搜索), SU212 shows promise for treating other malignancies characterized by ENO1 (搜索) dysregulation. Malhotra expects the molecule could be useful in treating gliomas, pancreatic cancer (搜索), and thyroid carcinoma (搜索).
"A drug that targets enolase 1 (搜索) could help improve the treatment of these cancers too," he said.
Of particular significance is the molecule's potential dual relevance in cancer and metabolic diseases. Since ENO1 (搜索) is intrinsically linked to glucose metabolism, SU212 might offer distinct advantages for patients battling concurrent metabolic disorders such as diabetes (搜索). Malhotra noted that the effect of SU212 may be especially important in treating cancer patients who also have metabolic diseases like diabetes, a chronic condition causing high levels of blood-sugar to build up in the blood.
Path to Clinical Translation
The next critical step involves advancing SU212 toward clinical trials for human patients, a process that requires substantial investment of resources to garner Food and Drug Administration approval and initiate clinical trials. This transition demands rigorous toxicological profiling, formulation optimization, and substantial investment to navigate regulatory pathways.
Malhotra's research journey spans from the National Cancer Institute in Bethesda, Maryland, where the molecule was initially developed, through Stanford University, and now to OHSU, where he arrived in 2020. As co-director of OHSU's Center for Experimental Therapeutics, Malhotra and colleagues focus on moving discoveries from the lab as quickly as possible to patients in OHSU's hospital and clinics.
"There is definitely great science going on here, and we want to translate that science for the benefit of people," he said.
The research has received robust funding support from prominent institutions including the National Cancer Institute, the National Institute on Aging, the National Heart, Lung, and Blood Institute, alongside the Department of Defense and OHSU's own Biomedical Innovation Program, underscoring the high relevance and interdisciplinary nature of the project.