Discipline: Biological Sciences
Subcategory: Cancer Research
Session: 3
Room: Exhibit Hall A
Merilyn Palmer - Winthrop University
Co-Author(s): Melissa Fath-University of Iowa, Iowa City, IA; John Henrich-University of Iowa, Iowa City, IA; Dijie Liu-Univeristy of Iowa, Iowa City, IA; Sue O?Dorisio-University of Iowa, Iowa City, IA; Doug Spitz-University of Iowa, Iowa City, IA
Small Cell Lung Cancer (SCLC) is the most aggressive form of lung cancer and is currently incurable. Although SCLC may initially respond to chemotherapy and radiotherapy, resistance to both therapies result in metastases, progression, and ultimately death. There is thus a critical need for a new therapeutic strategy for treating SCLC. Preliminary data demonstrates that many grade III lung NEC tumors highly express G protein coupled receptor, CXCR4, which can be targeted for both diagnosis and therapy. Peptide receptor radiotherapy targeting CXCR4 with beta particle emission 177Lu-pentixather(177Lu) damages metabolic structures such as mitochondria and genes necessary for the assembly and function of mitochondria, leading to increased generation of reactive oxygen species and formation of hydroperoxides in cancer cells that already exist in a state of increased metabolic oxidative stress, relative to normal cells. The purpose of my study was to examine combinations of agents that increase oxidative stress in SCLC. Thioredoxin is a cofactor that donates reducing equivalents using an intermolecular cysteine thiol-disulfide exchange reaction resulting in detoxification of hydroperoxides. Auranofin (Au) is an excellent inhibitor of mitochondrial thioredoxin reductase (TR) that is FDA approved as an anti-rheumatic drug. Combining Au with GPX4 inhibitors and gamma radiation could target cell membrane lipid peroxidation in SCLC cells leading to cell death. We hypothesize that inhibition of TR using pharmacologically relevant Au, will enhance clonogenic cell death in combination, respectively, with GPX4 inhibitors, ionizing radiation, and 177Lu via metabolic oxidative stress. SCLC DMS53 and DMS273 were treated with 0.5 ?M & 1 ?M Au in combination with GPX4 inhibitors ML210 and ML162 for 24h then clonogenic assay was performed. SCLC DMS53 and DMS273 were treated with 1.5 ?M of Au for 2h then irradiated with gamma radiation emitted by cesium-137 decay for 2 and 4gy then clonogenic assay was performed. SCLC DMS53 and DMS273 were treated with 1?M Au and/or 177Lu at 1?Ci and 10?Ci then collected for clonogenic assay. After identifying that 177Lu + Au worked well, we evaluated the toxicity in mice models. H292 NSCLC (control) and DMS273 SCLC were grown in mice. Mice were treated combination of 177Lu at varying dosages and/or 2mg/kg Au 1h before and daily for 3 total days. 21 days after radionuclide injection, mice were sacrificed, organs were harvested and plasma was tested for BUN and AST to test for kidney and liver damage. WBC and RBS were measured to test for bone marrow suppression. The results displayed combination of Au w/ GPX4 inhibitors and irradiation enhanced clonogenic cell death in SCLC. Au in combination with 177Lu showed no significant effects on the kidney and liver and did not increase myelosuppression. Mice treated with Lu-Pentixather had a decrease in WBC and RBC however adding Au did not exacerbate the toxicity. Future direction is to conduct a biodistribution trial with dose escalation using 177Lu on SCLC patients.
Funder Acknowledgement(s): Continuing Umbrella of Research Experiences; National Cancer Institute of the National Institutes of Health; Carver College of Medicine Office of Cultural Affairs & Diversity Initiatives; National Cancer Institute R01 182804; Neuroendocrine Spore Developmental grant P50 CA174521
Faculty Advisor: Melissa Fath, PhD, Melissa-fath@uiowa.edu
Role: I played a role in conducting clonogenic assay with DMS53 and DMS273 small cell lung cancer cells. I treated both DMS53 and DMS273 with Auranofin then irradiated them with gamma radiation emitted by cesium137 decay at 2 and 4gy. I then evaluated the cell killing after being treated with GPX4 inhibitors and irradiation. I also harvested the organs of mice sacrificed after being treated with Auranofin and Lu-Pentixather.