Role of Subtype-Specific Essential Factor Networks in Small Cell Lung Cancer
Abstract
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 131,880 deaths in 2021. More importantly, there is a higher prevalence of lung cancer risk for military Service Members and Veterans versus civilians. Higher exposures to smoking and other environmental factors (carcinogens, hazardous chemicals, toxic materials, etc.) can contribute significantly to developing lung cancer during and after a military service obligation. 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. Consequently, the emotional burdens of disclosing a poor prognosis can negatively impact both members of the military service and their families as they face challenges in battling a disease with limited treatment options. To overcome this barrier, discoveries in classifying small-cell lung cancer into molecular subtypes, based on the high expression of specific genes driving this cancer, can serve as a molecular fingerprint to develop more precise, target-based therapeutics. 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 based on the degree of molecular subtypes present. In recent decades, small-cell lung cancer has been classified into four molecular subtypes based on their distinctive gene expression patterns. Our previous research focused on identifying a factor known as the BAP1/ASXL3/BRD4 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 the A-subtype of small-cell lung cancer. Now, we are working towards expanding this methodology to discover another target for a different molecular subtype of small-cell lung cancer, known as POU2F3-subtype (or P-subtype). In this case, we found a promising target, known as C11orf53, which is an essential, highly expressed factor that may serve as a potent therapeutic target for patients expressing the P-subtype of small-cell lung cancer. One of the main challenges in treating small-cell lung cancer comes from the complex nature of tumors mixed with different molecular subtypes. By conducting biochemical and genetic studies, we can further identify contributing factors to each subtype, investigate the mechanistic role they play in cancer development, and create a synergistic combination of fast-acting drug therapeutics that can specifically target this mechanism by changing gene expression to reduce tumor growth. We hope our research contributions will help advance small-cell lung cancer treatment by discovering new biomarkers for specific molecular subtypes and categorizing treatment plans for patients based on their tumor gene expression profiles in the coming years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310360
Entities
People
- Lu Wang
Organizations
- Northwestern University
- United States Army