Abstract 182P
Background
Malignant pleural effusion (MPE) is a common complication of many tumor types, arising at the onset of terminal cancer with a median survival of 3-12 months. Herein, we have characterized and evaluated the activity of thiostrepton (TS) on malignant and immune cell types present in MPE from patients diagnosed with primary lung, breast, prostate, pancreatic and ovarian cancers. TS targets mitochondrial peroxiredoxin 3 (PRX3) and disrupts redox homeostasis preferentially in malignant tissues, presenting a promising therapeutic approach currently under investigation in the MITOPE clinical trial.
Methods
MPE was collected, with Institutional Review Board approval, from 11 patients at the University of Vermont Medical Center via thoracentesis. Cellular material from MPE was phenotyped by flow cytometry for identification of resident cell populations. The activity of TS to inhibit its primary molecular target, mitochondrial PRX3, was evaluated in cells derived from MPE. The amount of PRX3 inhibition and cell viability were quantified following treatment of MPE with increasing concentrations of TS.
Results
The cellular material from MPE was found to be primarily composed of CD45+/ CD56-/CD3+ T-cells (∼96%) expressing either CD4 (∼85%) or CD8 (∼12%) with a small subset (∼1%) of CD4/CD8 double positive cells. A small percentage (∼2%) of CD56+/CD3- natural killer (NK) cells and CD56-/CD3- (∼1%) B cells were also present in MPE. Both adherent (CD4-) and non-adherent (CD4+) cell populations were cultured in MPE fluid for 24 hours in the presence of 2.5 or 5 μM TS. Non-adherent (CD4+) and adherent (CD4-) cell populations were separated and PRX3 inhibition through covalent crosslinking by TS was evaluated by protein western blotting.
Conclusions
MPE cellular material from patients with malignancy is primarily composed of CD45+/CD3+ T cells. TS covalently adducted and inhibited mitochondrial PRX3 in adherent, malignant, (CD4-) and non-adherent, immune, (CD4+) cell populations in a dose dependent manner. These results indicate that TS retains anti-cancer activity in MPE fluid and targets cellular components of malignant and immune origin. This study for the first time demonstrates the ability of TS to inhibit PRX3 and induce cell death in patient derived MPE.
Legal entity responsible for the study
Dr. Brian Cunniff and RS Oncology.
Funding
RS Oncology.
Disclosure
B. Cunniff: Financial Interests, Personal, Invited Speaker: RS Oncology. G. Naumov: Financial Interests, Personal and Institutional, Sponsor/Funding: RS Oncology. All other authors have declared no conflicts of interest.