Developing a Novel Glutamine Antagonist to Treat Pulmonary Fibrosis
Abstract
Background/Rationale: Approximately 250,000 Americans suffer from lung fibrosis with 100,000 new cases expected a year. Currently there are no pharmacologic therapies to cure, stop, or reverse the unremitting, fatal fibrosis of this devastating disease. It is expected that two-thirds of patients with the deadliest form of pulmonary fibrosis, idiopathic pulmonary fibrosis, will die within 3-5 years of diagnosis. A critical barrier to treating this disease is the lack of understanding of the pathways leading to fibrosis as well as those regulating the resolution of fibrosis. Pulmonary fibrosis is the common final end point for a diverse group of disorders such as occupational or environmental exposures, chronic hypersensitivity pneumonitis, idiopathic pulmonary fibrosis, silicosis, radiation pneumonitis, or collagen vascular diseases. Why some patients develop pulmonary fibrosis and others heal normally is unknown. In pulmonary fibrosis, it appears as if the normal wound healing mechanisms, necessary to heal, become dysregulated and continue to be activated laying down scar even though there is no obvious injury. Recently it has become clear that cells in the body can be controlled by manipulating the nutrients the cells use; this is called metabolic reprogramming of the cells. One of the critical regulators of a cell’s response is the amino acid glutamine. Due to their high metabolic needs, inflamed cells rely upon glutamine for activation, proliferation, and function. This proposal seeks to target this enhanced glutamine metabolism to treat pulmonary fibrosis. Indeed, preliminary data in animal models of pulmonary fibrosis demonstrate that inhibition of glutamine metabolism not only inhibits but may actually reverse in part the lung fibrosis. Established chronic lung fibrosis will be treated with a novel inhibitor X-083. This drug is a precursor of the drug DON, a drug that has long been used as an inhibitor of glutamine metabolism in the research setting. However, DON is toxic to the gut, which limits its use in humans. X-083 is a DON pro-drug that is preferentially activated by inflammatory cells and has similar efficacy as DON but is less toxic. Inhibiting glutamine metabolism with the DON prodrug X-083 represents a novel and potent treatment for pulmonary fibrosis by promoting the resolution of wound healing and potentially reversing lung fibrosis. Hypothesis: Inhibiting glutamine metabolism with the DON pro-drug X-083 is a novel and potent treatment for pulmonary fibrosis by inhibiting pro-fibrotic and promoting resolution pathways. Specific Aims: Aim 1: Define the ability of glutamine antagonism with X-083 to inhibit and reverse aberrant fibrotic responses in a chronic progressive pulmonary fibrosis. Aim 2: Perform metabolic flux analysis to define the precise metabolic pathways upregulated during chronic pulmonary fibrosis and then ultimately inhibited upon treatment with X-083. Short-Term and Long-Term Impact: The short-term impact of this proposal is to provide the preclinical rationale for the development of the glutamine inhibitor X-083 as a novel human treatment for pulmonary fibrosis. This will represent a completely new approach for this deadly disease for which the current treatments do not stop or reverse the fibrosis. It is envisioned that treatment with this oral agent would be able to start upon diagnosis of pulmonary fibrosis, regardless of stage, and not only prevent worsening of the disease but promote the resolution phase of wound healing and actually lead to reversal of the fibrosis. Long-term impact would be enormous if the drug is able to not only slow down but reverse pulmonary fibrosis, resulting in decreased mortality and morbidity for this devastating disease. This would be of impact not only to civilians with pulmonary fibrosis but also to military personnel, Veterans, and their beneficiaries. Relevance to Topic Area: This proposal specifically addresse
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010224
Entities
People
- Maureen Horton
Organizations
- Johns Hopkins University
- United States Army