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Alterations in Polyamine Metabolism in Patients With Lymphangioleiomyomatosis and Tuberous Sclerosis Complex
Yan Tang1, Souheil El-Chemaly1, Angelo Taveira-Dasilva2
1Pulmonary and Critical Care Medicine Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA.
Background:
Lymphangioleiomyomatosis (LAM), a destructive lung disease that affects primarily women, is caused by loss-of-function mutations in TSC1 or TSC2, leading to hyperactivation of mechanistic/mammalian target of rapamycin complex 1 (mTORC1). Rapamycin (sirolimus) treatment suppresses mTORC1 but also induces autophagy, which promotes the survival of TSC2-deficient cells. Based on the hypothesis that simultaneous inhibition of mTORC1 and autophagy would limit the availability of critical nutrients and inhibit LAM cells, we conducted a phase 1 clinical trial of sirolimus and hydroxychloroquine for LAM. Here, we report the analyses of plasma metabolomic profiles from the clinical trial.
Methods:
We analyzed the plasma metabolome in samples obtained before, during, and after 6 months of treatment with sirolimus and hydroxychloroquine, using univariate statistical models and machine learning approaches. Metabolites and metabolic pathways were validated in TSC2-deficient cells derived from patients with LAM. Single-cell RNA-Seq was employed to assess metabolic enzymes in an early-passage culture from an LAM lung.
Results:
Metabolomic profiling revealed changes in polyamine metabolism during treatment, with 5'-methylthioadenosine and arginine among the most highly upregulated metabolites. Similar findings were observed in TSC2-deficient cells derived from patients with LAM. Single-cell transcriptomic profiling of primary LAM cultured cells revealed that mTORC1 inhibition upregulated key enzymes in the polyamine metabolism pathway, including adenosylmethionine decarboxylase 1.
Conclusions:
Our data demonstrate that polyamine metabolic pathways are targeted by the combination of rapamycin and hydroxychloroquine, leading to upregulation of 5'-methylthioadenosine and arginine in the plasma of patients with LAM and in TSC2-deficient cells derived from a patient with LAM upon treatment with this drug combination.
Trial Registry:
ClinicalTrials.gov; No.: NCT01687179; URL: www.clinicaltrials.gov. Partners Human Research Committee, protocol No. 2012P000669.
Insights
This study shows that combining sirolimus and hydroxychloroquine for lymphangioleiomyomatosis (LAM) upregulates polyamine metabolism, specifically 5'-methylthioadenosine and arginine, in patients and LAM cells.
Area of Science:
- Biochemistry
- Oncology
- Pulmonology
Background:
- Lymphangioleiomyomatosis (LAM) is a lung disease caused by TSC1/TSC2 mutations, leading to mTORC1 hyperactivation.
- Rapamycin (sirolimus) inhibits mTORC1 but induces autophagy, promoting LAM cell survival.
- A combination therapy of sirolimus and hydroxychloroquine was hypothesized to inhibit LAM cells by targeting both mTORC1 and autophagy.
Purpose of the Study:
- To analyze plasma metabolomic profiles from a phase 1 clinical trial of sirolimus and hydroxychloroquine for LAM.
- To investigate the metabolic changes associated with this combination therapy in LAM patients and TSC2-deficient cells.
Main Methods:
- Plasma samples from a 6-month clinical trial were analyzed using univariate statistics and machine learning.
- Metabolites and pathways were validated in TSC2-deficient LAM cells.
- Single-cell RNA-Seq assessed metabolic enzymes in cultured LAM cells.
Main Results:
- Treatment led to significant changes in polyamine metabolism, with 5 -methylthioadenosine and arginine being highly upregulated.
- These findings were consistent in both patient plasma and TSC2-deficient LAM cells.
- mTORC1 inhibition upregulated key polyamine metabolism enzymes, including adenosylmethionine decarboxylase 1.
Conclusions:
- The combination of rapamycin and hydroxychloroquine targets polyamine metabolic pathways in LAM.
- This dual inhibition leads to the upregulation of 5 -methylthioadenosine and arginine.
- The study provides insights into the metabolic effects of combination therapy for LAM.
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