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Mechanism of Kemeng Fang's Inhibition of Podocyte Apoptosis in Rats with Membranous Nephropathy through the PI3K/AKT Signaling Pathway
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Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6-blockade-refractory idiopathic multicentric

David C Fajgenbaum1, Ruth-Anne Langan1, Alberto Sada Japp2

  • 1Department of Medicine and.

The Journal of Clinical Investigation
|August 14, 2019
PubMed

Insights

Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic illness. Targeting the PI3K/Akt/mTOR pathway with sirolimus shows promise for patients refractory to IL-6 blockade, offering durable remissions.

Area of Science:

  • Hematology
  • Oncology
  • Immunology

Background:

  • Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder characterized by cytokine-induced lymphoproliferation and systemic inflammation.
  • Patients refractory to interleukin-6 (IL-6) blockade lack targeted therapies, necessitating the identification of novel therapeutic targets.
  • The thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) subtype of iMCD presents unique challenges.

Observation:

  • Analysis of IL-6 blockade-refractory iMCD-TAFRO patients revealed increased CD8+ T cell activation.
  • Elevated levels of VEGF-A and heightened activity within the PI3K/Akt/mTOR signaling pathway were observed.
  • Immunohistochemistry confirmed elevated mTOR signaling via phosphorylated S6 in iMCD lymph node tissues.

Findings:

  • Administration of the mTOR inhibitor, sirolimus, significantly reduced CD8+ T cell activation and decreased VEGF-A levels.
  • Sirolimus treatment resulted in durable clinical responses and ongoing remissions in all three treated iMCD-TAFRO patients.
  • The observed responses included remissions lasting 66, 19, and 19 months.

Implications:

  • This study identifies the PI3K/Akt/mTOR signaling pathway as the first pharmacologically targetable mechanism in IL-6 blockade-refractory iMCD.
  • Precision medicine targeting this pathway offers a new therapeutic strategy for iMCD patients with refractory disease.
  • Prospective clinical trials evaluating sirolimus for treatment-refractory iMCD are planned, including NCT03933904.
Abstract

Keywords:
CytokinesHematologyImmunologyLymphomas

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