Rationally designed drug combination screen with the drug repurposing candidate Auranofin using patientderived NSCLC and PDAC 3D organoids.

Non-small cell lung cancer (NSCLC) and pancreatic cancer (PDAC) are two of the most common and lethal malignancies worldwide. Survival outcomes for the majority of these patients remain very poor due to an advanced stage at diagnosis and their rapid progressive nature. The first-line treatment of advanced NSCLC in most patients still consists of conventional chemotherapy to achieve tumor response or stable disease. Current treatment options for PDAC are limited since only 10-20% of the patients is eligible for curative surgical resection. The remaining patient population is treated with gemcitabine/nab-paclitaxel or FOLFIRINOX which have only modest improvements in survival due to chemoresistance in most patients. Therefore, there is a high unmet need for novel and more effective treatment approaches for both cancer types. This dire need for new therapeutic options encouraged me to provide the fastest way towards clinical application. Therefore, we used the orally available, lipophilic, organogold compound Auranofin (AF), which is included in the list of the ReDo (Repurposing Drugs in Oncology) project established by the Belgian non-profit Anticancer fund. I was the first to show the therapeutic anticancer potential of AF in mutant p53 NSCLC and PDAC cancer cell lines in which it triggered distinct molecular cell death mechanisms (apoptosis, ferroptosis and immunogenic cell death) by inhibiting the thioredoxin and glutathione redox systems and inducing oxidative stress (Freire Boullosa et al., 2021). Furthermore, I showed the relevance of targeting thioredoxin reductase in NSCLC patients, since it is overexpressed in NSCLC cells compared to the surrounding tissue. Despite these promising results as a single agent, I am convinced that the true power of AF lies within rationally designed drug combination strategies. This is supported by my recent work on the highly synergistic combination of AF and the PARP-1 inhibitor Olaparib which is effective in in vitro and in vivo NSCLC and PDAC models (ongoing). In addition, an increasing number of publications highlights the potential of AF in combination with chemotherapeutic agents, mTOR inhibitors, ROS inducers, etc. which resulted in several Phase I and II clinical trials. Therefore, the goal of this study is to perform a high-throughput drug combination screening with AF and a literature-based / clinically available drug panel based on standard of care regimens and inhibitors of KRAS effector pathways, in a set of patient-derived NSCLC and PDAC 3D organoids using our in-house developed drug screening platform Orbits. This allows us to study for the first time which AF drug combination strategies are the most promising and which baseline patient characteristics are related to therapy response using the most clinically relevant in vitro model available to date based on the genomic and transcriptomic characterization of these organoid lines. Overall, drug repurposing of the off-patent drug AF will contribute to a positive impact on patient outcome and quality of life, to a faster clinical implementation and to a lower healthcare cost.

Keywords:COMBINATION THERAPY, ORGANOID, ONCOLOGY

Disciplines:Cancer therapy