Targeting Constitutive Heterochromatin for Lung Cancer Treatment
Abstract
Lung cancers are the leading cause of cancer-related deaths among both women and men, with 150,000 deaths expected in 2018. Despite recent treatment advances, including targeted- and immuno-therapies, the expected 5-year survival rate of a patient diagnosed with metastatic lung cancer is less than 5%. Therefore, novel treatment strategies are badly needed, especially those that target metastatic disease and therapy-resistant cancer stem cells (CSCs), which are central to disease recurrence. 0ur laboratory is interested in identifying and developing less toxic and more effective treatments for lung cancer. Our efforts have identified a novel dependency of lung cancer cells that involves their ability to duplicate their constitutive heterochromatin. Constitutive heterochromatin, which makes up about 7% of the human genome, is generally localized around the centromeres and telomeres of a cell and was traditionally viewed as “junk DNA.” However, recent studies have shown that these regions play important roles in chromosome organization and segregation, as well as silencing of repetitive DNA (i.e., ancient viral genes). Constitutive heterochromatin harbors a unique epigenetic profile of hypo-acetylated and histone H3 lysine 9 tri-methylation (H3K9me3) modified nucleosomes, which function to compact the chromatin and repress repetitive DNA transcription. We have discovered a novel dependency of NSCLC and SCLC cells that could lead to an entirely new way to effectively treat these diseases. We identified a protein called FBX044 that is essential for the duplication of constitutive heterochromatin in lung cancer cells. In the absence of FBX044, constitutive heterochromatin becomes transcriptionally activated, leading to extensive DNA breaks, growth arrest, and cell death. FBX044 inhibition also significantly reduced the CSC population of cancer cell lines. Remarkably, we generated FBX044 knockout mice and found they are normal, suggesting FBX044 is uniquely required for lung cancer cell growth and survival. The goals of this proposal are to perform preclinical studies to evaluate whether targeting FBX044 or the associated H3K9me3 enzyme, SUV39H1, is an effective therapeutic approach for the treatment for established lung cancers (Aim 1) and eradication of lung CSCs to prevent metastasis and disease recurrence (Aim 2). This work could lead to an entirely new therapeutic approach for lung cancer treatment that exploits the epigenetic regulation of constitutive heterochromatin formation. No current or past lung cancer clinical trial has evaluated a drug that targets constitutive heterochromatin formation as a therapeutic mechanism. Since this epigenetic pathway is uniquely required for lung cancer cell growth and survival, but not normal cells, inhibitors of this pathway are expected to exhibit significantly reduced side effects compared to currently used therapies. Thus, this research proposal addresses the Department of Defense Lung Cancer Research Program Area of Emphasis, “Identify innovative strategies for the prevention and treatment of lung cancer.” The impact of this research could be the development of FBX044/SUV39H1 inhibitors, which could be ready for clinical trial testing in a 3-5 year timeline. These novel drugs, which function through a unique therapeutic mechanism, would be expected to provide benefit for all NSCLC and SCLC patients, with the ultimate goal of significantly lowering the mortality of this deadly disease.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910619
Entities
People
- Charles Spruck
Organizations
- Sanford Burnham Prebys Medical Discovery Institute
- United States Army