Abstract
Inhibition of mTOR is the standard of care for lymphangioleiomyomatosis (LAM). However, this therapy has variable tolerability and some patients show progressive decline of lung function despite treatment. LAM diagnosis and monitoring can also be challenging due to the heterogeneity of symptoms and insufficiency of non‐invasive tests. Here, we propose monoamine‐derived biomarkers that provide preclinical evidence for novel therapeutic approaches. The major histamine‐derived metabolite methylimidazoleacetic acid (MIAA) is relatively more abundant in LAM plasma, and MIAA values are independent of VEGF‐D. Higher levels of histamine are associated with poorer lung function and greater disease burden. Molecular and cellular analyses, and metabolic profiling confirmed active histamine signaling and metabolism. LAM tumorigenesis is reduced using approved drugs targeting monoamine oxidases A/B (clorgyline and rasagiline) or histamine H1 receptor (loratadine), and loratadine synergizes with rapamycin. Depletion of Maoa or Hrh1 expression, and administration of an L‐histidine analog, or a low L‐histidine diet, also reduce LAM tumorigenesis. These findings extend our knowledge of LAM biology and suggest possible ways of improving disease management.
Highlights
Lymphangioleiomyomatosis (LAM) is a rare low-grade neoplasm that affects almost exclusively women and is characterized by cystic lung destruction, which can lead to fatal respiratory failure in severe cases (Johnson et al, 2010; McCormack et al, 2016)
The therapies are centered on targeting histamine metabolism and signaling and have been assessed using an immunocompetent LAM cell model employing complementary strategies: approved drugs, gene expression depletion (Maoa and Hrh1), metabolite analog (a-methyl-DL-histidine), and a specific diet
methylimidazoleacetic acid (MIAA), the major product of histamine metabolism, can be combined with vascular endothelial growth factor D (VEGF-D) to reinforce a differential diagnosis, and measuring histamine levels can complement the estimates of disease burden and pulmonary function
Summary
Lymphangioleiomyomatosis (LAM) is a rare low-grade neoplasm that affects almost exclusively women and is characterized by cystic lung destruction, which can lead to fatal respiratory failure in severe cases (Johnson et al, 2010; McCormack et al, 2016). Most LAM cases are sporadic and somatic inactivation of TSC2 in an unknown cell type(s) is expected to be the central genetic alteration necessary for disease development (Carsillo et al, 2000). Germline or somatic mutations in TSC1/TSC2 cause abnormal activation of the mechanistic target of rapamycin (mTOR) (Goncharova et al, 2002; Saxton & Sabatini, 2017), and this is the basis of the standard of care use of mTOR allosteric inhibitors for LAM (McCormack et al, 2011). Through its central role in metabolism, mTOR activity is abnormally enhanced in many cancer types, and generally linked to stem cell-like features, which are present in LAM cells (Krymskaya, 2008; Ruiz de Garibay et al, 2015; Julian et al, 2017; Pacheco-Rodrıguez et al, 2019)
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