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Case Study

Identification of Therapeutic Target for a Rare Disease Lymphangioleiomyomatosis (LAM)

The Metabolon Global Discovery Panel identified an increase in prostaglandins in TSC2-deficient cells after estradiol treatment, pointing to COX-2 as a therapeutic target for lymphangioleiomyomatosis.

Metabolomics identifies potential therapeutic targets in rare diseases that might otherwise go undetected.

Metabolomics identifies potential therapeutic targets in rare diseases that might otherwise go undetected.

The Challenge: New Therapeutic Strategies are Needed for Lymphangioleiomyomatosis

LAM is a progressive pulmonary disease that affects women almost exclusively. The pathology of LAM is characterized by widespread proliferation of abnormal smooth muscle cells, typically including a tuberous sclerosis complex 2 (TSC2) mutation that leads to mTORC1 activation. Though treatment with the mTOR inhibitor, sirolimus (rapamycin), showed clinical benefit in LAM patients, it was discontinued due to side effects. Therefore, new therapeutic strategies are needed for LAM. The marked female predominance of LAM strongly suggests that estradiol contributes to disease pathogenesis. However, the metabolic impact of estradiol on TSC2 deficiency is unclear.1

Metabolon Insight: Metabolomics Identifies New Target for Lymphangioleiomyomatosis

To examine the possible effects of estradiol on metabolic pathways, the researchers used TSC2-deficient ELT3 cells derived from rat uteri, a common model for LAM research.

A metabolomic screen was performed using the Metabolon Global Discovery Panel after treating cells with estradiol in culture. Results from the panel revealed significant increases in COX-2 and prostaglandins including PGE2, PGD2, and 6-keto-PGF1α in estradiol-treated cells along with altered MAPK pathway in both in vitro and in vivo models.1 Considering prostaglandin levels could serve as biomarkers of COX-2 expression, as COX-2 converts arachidonic acids to prostaglandins, it follows that COX-2 could be a viable therapeutic target in LAM.

Researchers also established through preclinical studies in an ELT3 xenograft tumor model that TSC2 mutation associated with LAM development can lead to mTOR activation and thereby mediate COX-2 expression and prostaglandin production. COX-2 levels were found to be significantly higher in the lungs of LAM tumor xenograft models and were specifically increased in pulmonary LAM nodules. Furthermore, analysis of clinical samples revealed that mean serum prostaglandin levels (PGE2 and 6-keto-PGF1α) of LAM patients were higher than that of healthy women.

Considering known withdrawal effects from rapamycin treatment, inhibition of COX-2 with aspirin may also have therapeutic benefit in LAM and TSC-related diseases. Aspirin reduced COX-2 levels without impacting MAPK expression and reduced tumor size in ELT3 xenograft tumors when administered for 3 weeks. PGE2 levels were also significantly reduced in response to aspirin in a TSC2 deficient cell model. Therefore, aspirin and/or other COX-1/COX-2 inhibitors may have significant benefit in slowing LAM progression.

The Solution: Metabolon Identified Molecular Signatures of Pathogenesis in Lymphangioleiomyomatosis

The Global Discovery Panel identified that estradiol enhanced the expression of COX-2 and induced the production of PGE2 in TSC2-deficient cells in vitro and in vivo models, while COX-2 inhibition led to reduced tumor volume in vivo. These results revealed a new biomarker of pathogenesis and identified COX-2 as a potential therapeutic target for LAM.

The Outcome: New Therapeutic Strategies for Lymphangioleiomyomatosis

Insights gained from the Global Discovery Panel identified COX-2 and COX-dependent inflammatory mediators as useful biomarkers, predictive of prognosis and treatment outcome in LAM patients. This research led to a pilot clinical trial investigating COX-2 inhibition in LAM and TSC (COLA).


1. Li C, Lee P-S, Sun Y, et al. Estradiol and mTORC2 cooperate to enhance prostaglandin biosynthesis and tumorigenesis in TSC2-deficient LAM cells. Journal of Experimental Medicine. 2014;211(1):15-28.

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