Pharmacological Activation of PP2A as a Novel Treatment Approach for Pulmonary Fibrosis

  • Ohlmeyer, Michael (PI)

Project Details

Description

The proposed research addresses the Pulmonary Fibrosis Topic Area of the Fiscal Year 2019 Peer Reviewed Medical Research Program. Pulmonary fibrosis is characterized by scarring of the lung; in some instances this occurs as a consequence of an underlying disease such as asthma or COPD (chronic obstructive pulmonary disease). Fibrosis of the lung may also develop in response to a number of environmental factors associated with military service including chemical, metal, blast dust, smoke, or burn pit exposure. There is a very serious condition, Idiopathic Pulmonary Fibrosis (IPF), where the underlying cause of fibrosis is unknown (hence idiopathic), and there is progressive and irreversible scaring of the lung. There is a strong correlation of incidence of IPF with age; hence, the military population most affected are Veterans and older Americans generally. The clinical prognosis with IPF is dismal, with a median survival of only 2-3 years, and the condition is prevalent with approximately 40,000 deaths per year in the US. Existing drugs only slow disease progression in mild or moderate disease and new treatments are urgently needed. IPF and pulmonary fibrosis more generally is caused by overactive or inappropriately activated cells in the lung called fibroblasts. Fibroblasts secrete collagen, the protein that, in large part, forms the matrix of scar tissue. In IPF, and pulmonary fibrosis, fibroblasts over-secrete collagen and the fibroblasts hyper-proliferate, leading to replacement of normal, functional lung tissue, with scar tissue that does allow oxygen from air to reach the circulation. Protein phosphatase 2A (PP2A) is an enzyme whose activity generally restrains the growth and proliferation of cells, including cancer cells, and PP2A is often regarded as a tumor suppressor. Low or diminished PP2A activity is characteristic of many cancers and leukemias and increasing, or activating, PP2A activity has been suggested as a way of treating cancer. Prototype drug molecules that activate PP2A have been shown to suppress the growth of cancer cells in the test tube and in mouse models of cancer. Crucially for this research project, PP2A activity has also been shown to be diminished in fibroblasts from IPF patients versus normal lungs. Therefore, the research proposes to test PP2A activators in cellular and animal models of IPF and show that they will restrain the growth and proliferation of IPF fibroblasts. We will also test if the PP2A activators will act on cell signaling pathways to suppress the over-secretion of collagen. The proposed research will focus on a particular class of PP2A activator molecule where there are multiple reports of anti-cancer effects in mouse models. We will use a published compound in cellular models of pulmonary fibrosis and in parallel synthesize new, improved compounds that will have a better chance of showing enhanced therapeutic effects in animal models of pulmonary fibrosis. Positive outcome of the proposed research would show that a new therapeutic approach, PP2A activation, was a useful way to treat pulmonary fibrosis, and publication would be of great interest to the research community in the pharmaceutical industry and academia. Also, the new compounds proposed for synthesis may themselves be suitable for clinical development or serve as leads for development of new pulmonary fibrosis drugs.

StatusFinished
Effective start/end date1/07/201/07/20

Funding

  • U.S. Army: $199,586.00

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