Increased mTOR activation in idiopathic multicentric Castleman disease

Abstract

Idiopathic multicentric Castleman disease (iMCD) is a rare and poorly understood hematologic disorder characterized by lymphadenopathy, systemic inflammation, cytopenias, and life-threatening multiorgan dysfunction. Interleukin-6 (IL-6) inhibition effectively treats approximately one-third of patients. Limited options exist for nonresponders, because the etiology, dysregulated cell types, and signaling pathways are unknown. We previously reported 3 anti-IL-6 nonresponders with increased mTOR activation who responded to mTOR inhibition with sirolimus. We investigated mTOR signaling in tissue and serum proteomes from iMCD patients and controls. mTOR activation was increased in the interfollicular space of iMCD lymph nodes (N = 26) compared with control lymph nodes by immunohistochemistry (IHC) for pS6, p4EBP1, and p70S6K, known effectors and readouts of mTORC1 activation. IHC for pS6 also revealed increased mTOR activation in iMCD compared with Hodgkin lymphoma, systemic lupus erythematosus, and reactive lymph nodes, suggesting that the mTOR activation in iMCD is not just a product of lymphoproliferation/inflammatory lymphadenopathy. Further, the degree of mTOR activation in iMCD was comparable to autoimmune lymphoproliferative syndrome, a disease driven by mTOR hyperactivation that responds to sirolimus treatment. Gene set enrichment analysis of serum proteomic data from iMCD patients (n = 88) and controls (n = 42) showed significantly enriched mTORC1 signaling. Finally, functional studies revealed increased baseline mTOR pathway activation in peripheral monocytes and T cells from iMCD remission samples compared with healthy controls. IL-6 stimulation augmented mTOR activation in iMCD patients, which was abrogated with JAK1/2 inhibition. These findings support mTOR activation as a novel therapeutic target for iMCD, which is being investigated through a trial of sirolimus (NCT03933904).

The Role of mTOR Inhibitors in Hematologic Disease: From Bench to Bedside

“…Recently, IL-6 stimulation augmented mTOR activation in idiopathic multicentric Castleman disease (iMCD) patients was reported, furthermore, the degree of mTOR activation in iMCD was comparable to ALPS. This finding supports inhibition of mTOR activation as a novel therapeutic target for iMCD, and is currently under investigation in a clinical study (NCT03933904) ( 126 ).…”

Cytokine Storm

“…Patients with idiopathic multicentric Castleman’s disease who have progressive organ dysfunction and who do not have a response to anti–interleukin-6 therapy are often treated with combination cytotoxic chemotherapy to nonspecifically eliminate hyperinflammatory cells. 81 Other elevated serum cytokines and cellular signaling pathways that could be considered for therapeutic targeting include CXCL13, CXCL10 (interferon-inducible protein 10 [IP-10]), VEGF-A, 82 type I interferon, 83 mTOR complex 1 (mTORC1), 84 and JAK-STAT3. These findings have led to treatment with the mTORC1 inhibitor sirolimus in patients with idiopathic multicentric Castleman’s disease who do not have a response to anti–interleukin-6 therapy.…”

ACCELERATE: A Patient-Powered Natural History Study Design Enabling Clinical and Therapeutic Discoveries in a Rare Disorder

“…Furthermore, data extracted into ACCELERATE have served as critical correlative data for translational research performed on biospecimens around the world; patient data and tissue biospecimens collected from ACCELERATE have been used in published and ongoing translational and clinical studies that have led to treatment guidelines, critical biological insights, and the discovery of therapeutic targets ( Figure 6 ). 14 , 15 , 16 , 17 , 18 , 19 Overall, ACCELERATE patient data and tissue samples have enabled translational research studies that shed light on iMCD pathogenesis and will serve as an engine for future discovery.…”

“…In the past 3 years, data and tissue samples collected for ACCELERATE have been used in 5 published studies that have identified key cell types, signaling pathways, chemokines, therapeutic targets, and optimal treatment approaches. 14 , 15 , 16 , 17 , 19 The ACCELERATE model may also be helpful for other rare disease research studies.…”