Increased mTOR activation in idiopathic multicentric Castleman disease

Area of Science:

• Hematology
• Immunology
• Oncology

Background:

• Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder with limited treatment options for nonresponders to IL-6 inhibition.
• The underlying mechanisms and signaling pathways in iMCD remain poorly understood.
• Previous observations suggested mTOR pathway activation in a subset of iMCD patients.

Purpose of the Study:

• To investigate the role of mammalian target of rapamycin (mTOR) signaling in iMCD pathogenesis.
• To explore mTOR activation in tissue and serum proteomes of iMCD patients.
• To identify potential novel therapeutic targets for iMCD.

Main Methods:

• Immunohistochemistry (IHC) on lymph node biopsies from iMCD patients (N=26) and controls.
• Proteomic analysis of serum samples from iMCD patients (N=88) and controls (N=42).
• Functional studies on peripheral monocytes and T cells from iMCD patients in remission.

Main Results:

• Increased mTORC1 activation (pS6, p4EBP1, p70S6K) observed in iMCD lymph nodes compared to controls and other lymphoproliferative disorders.
• Serum proteomic data revealed significantly enriched mTORC1 signaling in iMCD patients.
• Elevated mTOR pathway activation found in monocytes and T cells of iMCD patients, further augmented by IL-6 stimulation.

Conclusions:

• mTOR pathway activation is a key feature in iMCD pathogenesis.
• mTOR signaling represents a promising novel therapeutic target for iMCD.
• Sirolimus, an mTOR inhibitor, is being investigated in a clinical trial for iMCD.