Katherine Borden’s team seeks to shed light on how cells become cancerous. It particularly focuses on the disconnect between the transcriptome and the proteome. Her team focuses on dysregulated RNA processing as a major driver of this connect and explores its impacts in cancer. Further, her team, strives to leverage novel findings in RNA biochemistry in the clinic.
Katherine Borden’s team has discovered that much of this disconnect occurs at the RNA processing level, and that cellular proteins dysregulating the process can support the transformation to cancer. Indeed, changes in RNA processing can literally change the surface of the cell, imbuing it with the capacity to crawl, traverse membrane barriers and even produce extracellular vesicles that may also play roles in metastases.
Her laboratory combines cell biology, RNA biology and structural biology to provide fundamental insights into RNA processing and its dysregulation in cancer. Katherine Borden’s team uses eIF4E as a model protein for its studies. eIF4E is dysregulated in many cancer types including breast, prostate and leukemia.
Her lab focuses on RNA biology and the role that it plays in the evolution of cancers has led to several ground-breaking discoveries. The research work carried out in the lab has resulted in three pan-Canadian trials targeting eIF4E, and thus RNA biology. These trials were the first to demonstrate that eIF4E was a bona fide therapeutic target in humans.
Further, this work inspired clinical trials targeting eIF4E in solid tumors including prostate and oral cancers. At the molecular level, her studies were the first to demonstrate that RNA trafficking could underpin malignancy. Her studies continue to reveal new facets of RNA metabolism and to dissect the molecular basis for these activities. Her team actively explores both the relevance of RNA processing to control the protein output in the cell and the impacts of dysregulated RNA metabolism in supporting oncogenic phenotypes including driving physical changes to the cell.
The laboratory’s research work also led to the discovery of novel drug resistance mechanisms that can be targeted in cancer patients. These new resistance mechanisms were identified in the clinical trials carried out targeting eIF4E with ribavirin. Her team has made it possible to identify new means to restore drug sensitivity that are currently being tested in the clinical trials in AML patients.
Katherine Borden’s laboratory found that in patients and in the lab, cancer cells develop the ability to add a sugar called glucuronic acid onto drugs to deactivate them. Glucuronidation has been known since the 1950’s to deactivate drugs, but it was not considered inducible in cancer cells. Therefore, her lab identified how cancer cells induce glucuronidation to evade the effects of chemotherapies. This led to the discovery of small compounds (known as fragments) that can be used to selectively inhibit some glucuronidation enzymes over others, providing hope for one day reversing the trend.