Anticancer compounds for B cell cancer therapy targeting cellular stress response — ScienceDaily
Researchers at The Wistar Institute and collaborators from the University of Notre Dame are developing anticancer compounds targeting a pathway of the endoplasmic reticulum (ER) stress response implicated in the development of multiple myeloma (MM), chronic lymphocytic leukemia (CLL) and lymphoma. The study was published online today in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research.
The ER is an important organelle in our cells that oversees the quality control of protein folding under normal conditions and responds to the accumulation of misfolded proteins found under stressful conditions by activating specific mechanisms and signaling pathways such as the IRE-1/XBP-1 pathway that triggers a cascade of events that brings cells back to normal physiological conditions.
The laboratory of Chih-Chi Andrew Hu, Ph.D., professor in the Immunology, Microenvironment & Metastasis Program at Wistar, and collaborators show that targeting the ER stress signaling response is an effective strategy against various B cell cancers that rely upon ER stress signaling response to survive under stressful conditions.
The Wistar Institute and Notre Dame teams are working together to advance a new class of compounds to inhibit IRE-1 protein and block the function of the IRE-1/XBP-1 pathway, which promotes survival of malignant B cells such as MM and CLL cells. The IRE-1 inhibitors being developed by Hu and collaborators have shown promising activity in several preclinical cancer models, compared to other commercially available IRE-1 inhibitors having variable and inconsistent ability to selectively target ER stress signaling in vitro and in vivo.
“We carefully compared many published inhibitors of the IRE-1/XBP-1 pathway with our own inhibitors, showing that our compounds are the most reliable small molecule inhibitors for targeting this pathway in malignant B cells and that many of the other published inhibitors we tested have subpar activity or adverse off-target effects,”