BU researchers identify potential colorectal cancer inhibitor

(Boston)—In the U.S., colorectal cancer (CRC) is the second and third most common cause of cancer death in men and women, respectively. While there have been significant advances in the early diagnostic techniques and targeted therapies, mortality and morbidity related to CRC remains high.

The critical role of Wnt/β-catenin (a signaling pathway that regulates key cellular functions) in CRC tumorigenesis makes it an attractive therapeutic target. β-catenin is the prime target as it contributes to several aspects of CRC including tumor initiation and to progression, metastasis and cancer stem cells and influences therapeutic response. Despite concerted attempts, Wnt pathway inhibitors, especially those targeting β-catenin’s activity in the nucleus, have not meaningfully progressed beyond the preclinical stage.

Now researchers at Boston University School of Medicine (BUSM) have developed a promising anti-cancer compound, Factor Quinolinone Inhibitors (FQIs) that specifically impede LSF (a protein involved in many biological processes) DNA-binding, partner protein-binding and transactivation activities. “Given the critical role of Wnt signaling in CRC tumorigenesis, we set out to examine the effect of FQIs on CRC tumor growth and found we could successfully establish the significant results of LSF inhibition in the suppressed tumor growth,” explains corresponding author Vipul Chitalia, MD, PhD, associate professor of medicine at BUSM.

The researchers used several sets of experiments to evaluate the effect of LSF inhibition with FQI-compound in both experimental models and cell culture experiments. The goal was to reduce the activity of the Wnt signaling pathway in the models and assess its effect on tumors. The results showed that experimental models who received FQI treatment experienced significantly reduced tumor growth.

According to the researchers, this illustrates how specifically targeting the pathology of cancer at transcriptional levels profoundly influences successful treatment outcomes. “Such interplay of cancer pathology needs to be better defined to understand the drivers of heightened risk of tumor growth in CRC patients,” says first author Saran Lotfollahzadeh, MD, Post-doctoral research fellow in BUSM’s renal and vascular section. 

These finding appear online in the American Journal of Pathology.

Funding for this study was provided by NIH R01HL132325, R21 DK119740 and American Heart Association CAT-HD Center grant # 857078 (VCC and SL); by an Ignition Award from the Office of Technology at Boston University (SES, VCC, UH) and Shepherd Therapeutics for support.

Note to editors:  SES and UH are co-founders of Lamerigen, Inc. SES, EAY and UH received financial support from Shepherd Therapeutics.