2025 LCRF Leading Edge Research Grant Program
Lu Wang, PhD
Northwestern University Feinberg School of Medicine
Research Project:
Therapeutic targeting of ASXL3 protein stability in small cell lung cancer
*This project was awarded the Joan H. Schiller, MD Award for Scientific Merit, acknowledging the investigator whose proposal was selected for outstanding overall merit by the Foundation’s Scientific Advisory Board.
Summary:
The fight to eradicate the deaths of those suffering from lung cancer is still an ongoing battle. Lung cancer remains the leading cause of cancer mortality in the United States, with approximately 124,730 deaths in 2025. Despite improved screenings and medical advances in lung cancer treatment, lung cancer is still mainly diagnosed at later stages when the tumor has spread to other parts of the body, leading to difficulties in finding an effective treatment option at this point. This dilemma is especially the case for small-cell lung cancer, an aggressive form of lung cancer diagnosed at late stages for 70% of cases. Our ultimate goal is to implement the need for a more personalized approach to small-cell lung cancer clinical treatment by targeting mechanisms that contribute to tumor growth.
Our previous research focused on identifying a factor known as the BAP1/ASXL3 complex, which regulates one of the most predominant molecular subtypes of small-cell lung cancer (known as ASCL1-subtype or A-subtype) by controlling its gene expression patterns. As a result, we screened and optimized small-molecule drugs that could target this complex by inhibiting its function and promoting its breakdown through degradation. Using this approach, we saw a significant reduction in tumor progression in cells and animal studies targeting small-cell lung cancer.
In our current studies, we further discovered a new factor named MBD6, which is able to stabilize the oncogenic BAP1/ASXL3 complex by directly binding to a specific domain within the ASXL3 protein. Therefore, our hypothesis is to design a small molecule inhibitor to disrupt the interaction between MBD6 and ASXL3, in order to degrade the BAP1/ASXL3 protein in SCLC cells and reduce the tumor growth in both cell-based assays and animal models. We hope our research contributions will help advance small-cell lung cancer treatment by discovering new biomarkers and new treatment plans for patients in the coming years.