Assessing the Preclinical Efficacy of Combined Ferroptotic Agent and Secretory TRAIL-Armed NK Cells for Pseudomyxoma Peritonei
Abstract
Rationale: Pseudomyxoma peritonei (PMP) is a rare malignancy that is reported in one to two per 1,000,000 people annually. We have evaluated and treated over 600 PMP patients since 2001 and perform over 40 cytoreductive procedures a year. Therefore, we are uniquely positioned to successfully develop a novel strategy to treat PMP. PMP usually originates from goblet cells in the appendix and spreads to the lining of the peritoneal cavity. PMP responds poorly to systemic chemotherapy and frequently recurs despite aggressive, morbid locoregional surgical therapy. Although encouraging treatment results have been reported with the combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), PMP recurrence is common. Thus, we need to develop a second-line therapy to improve the efficacy of CRS followed by HIPEC. Since several studies have revealed that the cytokine TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) induces apoptosis in a wide variety of tumor cells but does not cause toxicity to most normal cells, we attempted to develop a TRAIL-based therapy. However, studies on the pharmacokinetics of TRAIL reveal that intravenous bolus-injected TRAIL protein is rapidly eliminated from serum (elimination half-life: 23-31 min). Thus, researchers have spent several years developing a secretory TRAIL-armed natural killer (NK) cell-based therapy to overcome this obstacle. Researchers previously reported that secretory TRAIL-armed NK cells are able to accumulate selectively at tumor sites and exert tumoricidal effects through TRAIL release. Moreover, considering recent studies, a combined treatment of TRAIL and ferroptotic agent synergistically induces cytotoxicity and effectively enhances tumoricidal efficacy against subcutaneous xenografts. Ferroptosis is a unique, iron-dependent form of regulated cell death. Iron-dependent accumulation of lipid peroxidation and reactive oxygen species and depletion of plasma membrane polyunsaturated fatty acids results in a well-known lethal event. Interestingly, researchers observed a synergistic interaction between ferroptotic agent and the apoptotic agent TRAIL through the endoplasmic reticulum (ER) stress response. These studies suggest that the crosstalk between the ER stress sensor-associated signaling pathway and the mitochondrial signaling pathway orchestrates synergistic cytotoxicity during the combined treatment with ferroptotic agent and TRAIL. Objectives: We hypothesize that a combinatorial treatment of secretory TRAIL-armed NK cells and the FDA- approved ferroptotic agent artesunate (ART) can be used for second-line therapy by controlling residual microscopic disease of PMP after CRS and HIPEC. To test this hypothesis, we propose the following specific aims: Aim 1: Assess the genetic signatures of tumor tissues from PMP patients, establish three-dimensional ex vivo tumoroid cultures of PMP, and examine the crosstalk between the ART-associated ER stress response pathway and the TRAIL-associated mitochondrial pathway in the synergistic induction of apoptosis during TA treatment (secretory TRAIL-armed NK cells + ART) in tumoroid cultures. Aim 2: Establish a humanized patient-derived xenograft (PDX) mouse model and assess the preclinical efficacy of the TA treatment in PDX tumors. Methods: After we obtain tumor tissues and blood from PMP patients, we will identify transcriptional signatures of TRAIL receptor genes from the tumor tissues and isolate NK cells from the blood. We will generate secretory TRAIL-armed NK cells and expand them. Next, we will establish three-dimensional ex vivo PMP tumoroid cultures with TRAIL receptor-positive tissues and assess the biological effect of the TA treatment on tumoroids using viability assay and biochemical assay. We will perform combination index analysis to assess the synergistic interactions. We will also employ biochemical and molecular techniques to investigate the mechanism of synerg
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211095
Entities
People
- Yong Lee
Organizations
- Cedars-Sinai Medical Center
- United States Army