Due to a lack of actionable treatment methods, triple-negative breast cancer (TNBC) has a poor clinical prognosis. TNBCs account for 15% of new breast cancer diagnoses and lack the expression of molecular components such as ER-, PR, or HER2. With these receptors’ expression missing, cancer medicines aimed at them will be ineffective in malignant triple-negative cells.
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Breast Cancer
The primary treatment option for the majority of TNBC individuals is chemotherapy. TNBCs, as a subtype of breast cancer, are aggressive malignancies with the highest mortality rate of any breast cancer subtype. In 2018, metastatic TNBC was responsible for 150,000 fatalities worldwide.
As a result, an effective therapy option for TNBC will be novel in cancer management. While there are treatments for people with ER-positive breast cancer, patients with triple-negative breast cancer (TNBC), which lacks ER, PR, and HER2 receptors, have few therapy options. TNBC is prevalent in women under age 40 and has a worse prognosis than other types of breast cancer. The study conducted in isolated research cells, such as human cancer tissue, and human tumors produced in mice, was described in a report published online in the journal Nature Cancer.
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Compound ERX-41 provides new approaches for therapy in hard-to-treat cancers
Scientists in this study isolated and named a new compound, ERX-41. This substance binds to a biological protein, lysosomal acid lipase A (LIPA). LIPA is present in the endoplasmic reticulum, an organelle in the cell responsible for processing and folding proteins. Cancers develop quickly when a tumor cell manufactures more proteins, putting stress on the endoplasmic reticulum. LIPA is seen more in malignant than normal cells. Following LIPA binding, ERX-41 prevents the processing of proteins in the cell’s endoplasmic reticulum, causing the cell to bloat and eventually die.
Triple-negative breast cancer is harder to manage. It is aggressive and resists therapy. The discovery of ERX-41 provides a new method for better management of TNBCs. ERX-41 testing in mice with malignant tumors similar to humans showed tumor reduction.
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In the research, scientists discovered that ERX-41 works against certain malignancies with high endoplasmic reticulum stress, such as difficult-to-treat pancreatic cancers, ovarian tumors, and glioblastoma, an aggressive and deadly primary brain tumor. Following ERX-41 treatment, histologic examination of various body organs revealed no significant alterations in their gross histology. The number of plasma and antibody-secreting cells, as well as immunoglobulin expression, was unaffected.
The researchers show that ERX-41 activity is dependent on its endoplasmic reticulum location. ERX-41 is, however, independent of LIPA lipase action. LIPA binding to ERX-41 reduces the expression of several endoplasmic reticulum-resident proteins involved in protein folding. This specific susceptibility has a broad therapy window and no consequences in non-malignant breast epithelial cells or animals.
Clinical significance
The clinical implications suggest a targeted therapy for cell tumors, such as breast, brain, pancreatic, and ovarian malignancies, in which tiny, orally accessible compounds that target LIPA impede protein, generate endoplasmic reticulum stress, and cause tumor cell death. ERX-41 reportedly killed malignant cells in human tissue with cancerous tumors removed.
Conclusion
Scientists have shown a novel therapy drug (ERX-41) with a distinct molecular target and mechanism of action (disruption of protein folding and activation of endoplasmic reticulum stress) that may be useful in treating patients with numerous tumors such as TNBC. The implications of this remain to be seen.
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References
Liu, X., Viswanadhapalli, S., Kumar, S. et al. Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress. Nat Cancer 3, 866–884 (2022). https://doi.org/10.1038/s43018-022-00389-8
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