COLA: A Pilot Clinical Trial of COX-2 Inhibition in LAM and TSC
Abstract
Lymphangioleiomyomatosis or LAM is a lung disease that affects primarily women. In this disease, cysts (or holes) develop in the lungs and make breathing difficult. LAM can occur alone or as part of the genetic disease tuberous sclerosis complex (TSC), in which there are often many other medical problems, including seizures and tumors in other organs. LAM occurring both with and without TSC is due to mutations in the TSC2 gene, which results in increased activity of mTORC1 in the LAM cells, that makes the cells have uncontrolled growth. Sirolimus (rapamycin) blocks mTORC1 and has some benefit for the treatment of LAM, but does not seem to eliminate the LAM cells. In addition, breathing gets worse in LAM patients when sirolimus is stopped. Recently we have discovered that another protein is turned on in LAM cells, called COX-2. Activation of this protein also appears to contribute to LAM cell growth, based on studies in cell lines and mouse models of LAM. Importantly, there is a common class of medications that block COX-2, including aspirin and ibuprofen (Motrin, Advil). In addition, there are some specific COX-2 inhibitors, including celecoxib, that have fewer side effects than aspirin and ibuprofen. Based on these findings, we propose a clinical study to examine the safety and preliminary assessment of benefit of treating LAM patients with celecoxib at doses used for arthritis treatment. In addition to assessing the tolerance of LAM patients to this medication, we will examine the effects on lung function, exercise capacity, kidney tumor size, and quality of life. We will also measure VEGFD levels and develop a test for mutations in TSC2 in circulating LAM cells in the blood, by using next-generation sequencing, and track changes in LAM cell burden over time. In summary, this study aims to establish the safety of treatment with celecoxib in patients with LAM and TSC to assess potential benefit in a preliminary manner and to develop a test for LAM cells in the blood. If the pilot clinical trial is successful, the next step will be to do a randomized clinical trial comparing celecoxib with no treatment in mild to moderate LAM. The test for circulating LAM cells might be useful in many situations for the care of LAM patients, including diagnosis, following disease burden, and response to treatment. Those studies would occur after this trial is complete and the LAM biomarker is developed.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510511
Entities
People
- David J Kwiatkowski
Organizations
- United States Army