Decreasing Lung Tumor Progression Through Transcriptional Reprogramming of Tumor-Associated Endothelial Cells
Abstract
Compared to other organs, lung has a robust blood capillary network, providing unique microenvironment for highly metastatic lung cancers and frequent metastases from other cancers. Lung endothelial cells form tumor vessels that are essential to provide tumor cells with nutrients and oxygen to support tumor growth and metastases. Existing treatments to inhibit growth of tumor-associated vessels (anti-angiogenic treatments) have not significantly improved cancer patients’ survival; there is a critical need for new approaches. There is a general agreement that tumor blood vessels are abnormal, the endothelial layer is disorganized and leaky, making it easier for tumor cells to enter the blood circulation and to invade secondary organs during tumor metastasis. Also, the tumor vessels have decreased perfusion, preventing efficient delivery of anti- cancer drugs. Normalization of tumor vessel will prevent vessel leakiness and improve delivery of anti- cancer drugs. Presence of tumor cells in the lung induces the changes in the normal lung endothelial cells (EC) and they become tumor-associated endothelial cells (TEC). The key regulators that control EC-to-TEC transition are poorly understood. Based on genome-wide comparison of EC and TEC expression profiles from human lung adenocarcinomas (LUAD) we have identified the FoxF1 gene as a critical regulator of EC-to-TEC transition. FOXF1 protein is present in normal EC but is rapidly decreased in TEC of mouse and human LUAD. Low FoxF1 predicts poor survival in LUAD patients. Our preliminary data using mouse lung cancer models show that increasing FoxF1 levels in endothelial cells inhibits lung cancer progression and metastases. Our proposed studies will validate FOXF1 as a therapeutic target and yield important insights into the mechanisms of FoxF1-regulated lung tumorigenesis. Moreover, these studies will expand our understanding on the contribution of lung endothelial cells to tumor progression in non-small cell lung cancers and directly lead to the development of new clinical strategies to inhibit tumor progression and metastases in human lung cancers. We also propose studies to test the efficacy of nanoparticle FoxF1 delivery in mouse models of lung cancer. We will determine whether FoxF1 gene therapy will be an efficient therapeutic approach to inhibit lung adenocarcinoma progression and metastasis. This proposal addresses following Areas of Emphasis: (1) Identify innovative strategies for the treatment of lung cancer and (2) Identify innovative strategies for the prevention of the recurrence of or metastasis from lung cancer. The nanoparticle polymers used in this application are non-toxic and some of them (PEI, PEG) are currently used in phase 2 clinical trials in patients with advanced ovarian cancers. The minicircle vector is designed for gene therapy and can be used in humans. It consists of human DNA sequence but lacks bacterial and viral sequences as required by FDA guidelines. If our preclinical studies are successful, they can directly lead to clinical trials in patients with advanced lung adenocarcinomas within 3-5 years. Results from the proposed studies will benefit patients with non-small cell lung cancers including lung adenocarcinomas with K-Ras mutations. NSCLC with K-ras mutations are among the most aggressive and treatment-resistant lung tumors. Since military personnel and Veterans have twice the incidence of lung cancer and have poorer outcomes compared to the general population, the new treatment targets and therapeutics approaches proposed to be tested in this application may ultimately benefit and lead to the improved outcomes for military patients with lung cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310660
Entities
People
- Tatiana Kalin
Organizations
- United States Army
- University of Arizona