Targeted Cell-Based Therapies for Metastatic Lung Tumors
Abstract
Lung cancer is the second leading cause of cancer death in men and women. Owing to occupational exposure to Agent Orange, asbestos, diesel exhaust, etc., combined with an increased prevalence of tobacco exposure in active duty military personnel and Veterans, the risk of non-small cell lung cancer (NSCLC) is higher by 50% in these populations compared to civilians. NSCLC remains undiagnosed until advanced stages in over 65% of the cases, enhancing the rate of metastatic lesions in distant organs. About 25-30% of NSCLC patients develop tumors in the brain that are referred to as metastatic brain tumors. The life expectancy for these patients is poor, with a median survival of only 3.4 months. These metastatic tumors in the brain are often presented with neurological symptoms and are diagnosed by MRI or PET brain scans. Most patients have multiple deposits of tumors at the time of diagnosis and, owing to the complexity of the brain, surgery becomes an inadequate therapeutic option. Numerous parallel therapeutic approaches, such as stereotactic radiosurgery (SRS), whole brain radiotherapy, and chemotherapy, have been tested with no promising evidence of improvement of the patient’s quality of life or the overall survival. Most of previously published studies utilize either subcutaneous or intracranial injection of metastatic tumor cells directly into the brain parenchyma to develop animal models of metastasis. However, these animal models do not mimic the actual clinical settings of lung to brain metastasis. To mimic a majority of the steps of metastatic colonization and blood vessel interactions, we have successfully created an in vivo imageable mouse model of NSCLC brain metastasis by intracarotid injection of malignant patient-derived brain-seeking NSCLC cells. This new mouse model provides a unique and valuable platform to test novel therapeutic approaches for lung to brain metastasis. Previous scientific studies have described the role a specific receptor (a molecular structure surface of a cell that binds with substances to produce an effect), EGFR (epidermal growth factor receptor), which primarily controls the growth of the cancer cells to play a vital role in the NSCLC to form secondary tumor lesions in the brain. Recent studies have shown that EGFR mutation status is associated with the expression of death receptor (DR)5 and play a role in the occurrence and development of NSCLC. In this regard, our preliminary data indicate that NSCLC cells express high levels of EGFR, DR4, and DR5 in vitro and in vivo in metastatic NSCLC. Therefore, simultaneous targeting of EGFR and DR4/5 in NSCLC offers a viable strategy to target lung to brain metastatic NSCLC. We have engineered a bimodal protein, ENb-TRAIL, consisting of cDNA fusions encoding EGFR-targeted ENb and a potent cytotoxic variant of tumor necrosis factor apoptosis-inducing ligand (TRAIL) and shown that it induces caspase-mediated apoptosis in a broad spectrum of tumors. The long-term goal of this proposal is to test the therapeutic efficacy of systemically delivered neural stem cells (NSC) targeting EGFR and DR4/5 in mouse models of lung to brain metastasis. Specifically, we will evaluate the response of NSCLC to stem cell-released ENb-TRAIL and assess the fate and efficacy of intracarotid artery (ICA)-delivered therapeutic stem cells in mouse models of lung to brain metastasis. We will also introduce the suicide gene, HSV-TK, into therapeutic NSC that will allow eliminate NSC to heighten their safety for clinical applications. In the next 3-5 years, we envision a therapeutic modality in which, at the time of metastatic lung tumor detection in the brain, NSC created from patients’ own cells will be engineered to express ENb-TRAIL and be injected via ICA into patients to target the metastatic lung tumor deposits in the brain. Given that a majority of patients with metastatic lung tumors in the brain do not undergo surgery and numerous systemic
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910506
Entities
People
- Khalid Shah
Organizations
- Brigham and Women's Hospital
- United States Army