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Orthotopic Implantation and Peripheral Immune Cell Monitoring in the II-45 Syngeneic Rat Mesothelioma Model
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Endoplasmic Reticulum Stress Signaling as a Therapeutic Target in Malignant Pleural Mesothelioma

Duo Xu1,2, Haitang Yang3, Zhang Yang4

  • 1Department of General Thoracic Surgery, Department for BioMedical Research (DBMR), Inselspital, Bern University Hospital, University of Bern, 3008 Bern, Switzerland. duo.xu@dbmr.unibe.ch.

Cancers
|October 11, 2019
PubMed

Insights

Malignant pleural mesothelioma (MPM) cells exhibit deregulated endoplasmic reticulum (ER) stress and unfolded protein response (UPR). The agent HA15 targets this vulnerability, showing promise for treating MPM, even in chemotherapy-resistant cases.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Malignant pleural mesothelioma (MPM) is an aggressive cancer with poor prognosis and limited therapeutic strategies.
  • Current treatments for MPM lack targeted therapies, necessitating novel approaches.
  • Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) signaling are implicated in cancer development and progression.

Purpose of the Study:

  • To investigate the role of ER stress and UPR signaling in MPM.
  • To evaluate the therapeutic potential of targeting the ER stress/UPR axis in MPM.
  • To assess the efficacy and safety of HA15, a novel ER stress-inducing agent, in MPM models.

Main Methods:

  • Integrated molecular characterization of MPM patient tumors from The Cancer Genome Atlas (TCGA) dataset.
  • Pharmacological treatment of MPM cells and patient-derived xenograft (PDX) mouse models with HA15.
  • Assessment of cell viability, apoptosis, and autophagy induction.
  • Comparative analysis of HA15 efficacy and toxicity against standard chemotherapy.

Main Results:

  • MPM tumors show characteristic deregulation of ER stress and UPR signaling.
  • HA15 selectively suppresses MPM cell viability, including chemotherapy-refractory cells.
  • HA15 enhances ER stress, induces pro-apoptotic UPR and autophagy, leading to cell death in MPM.
  • HA15 demonstrates anti-tumor efficacy in MPM PDX models with acceptable toxicity.

Conclusions:

  • ER stress/UPR signaling pathways represent a therapeutic vulnerability in MPM.
  • HA15 is a promising therapeutic agent for MPM, effective in both treatment-naïve and resistant settings.
  • Targeting ER stress offers a novel strategy for improving outcomes in malignant pleural mesothelioma.
Keywords:
HA15autophagyendoplasmic reticulum (ER) stressmalignant pleural mesothelioma (MPM)unfolded protein response (UPR)

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