BACKGROUND: Pancreatic cancer is one of the most lethal cancers in Australia, with a five-year survival rate of 12%. Patients are often diagnosed with advanced stage disease and have limited treatment options, highlighting the need for the identification of new therapies. We established a patient-derived organoid (PDO) biobank from pancreatic ductal adenocarcinoma (PDAC) patients. PDO’s represent a novel tool for pre-clinical screening of an individual patient response to chemotherapy and/or targeted therapies, with the major advantage being that PDOs closely resemble the primary tissue from which they are derived and match the patient response to chemotherapy with potential for truly personalised treatment selection.
METHODS: Biospecimens used in this research were collected by the Victorian Cancer Biobank, Victoria, Australia with appropriate ethics approval. The Victorian Cancer Biobank is supported by the Victorian Government. PDAC PDO’s generated underwent whole genome and transcriptome sequencing. Of these, 12 PDOs underwent a drug screen with 68 targeted compounds selected based on potentially actionable mutations. Current standard-of-care chemotherapies were also included in the drug screen to benchmark treatment benefit. Treatment success was based on quantification of cell viability and cell death, as well as image-based readouts. Compounds were identified that had either a cytotoxic effect, inducing both significant changes in cell viability and cell death, or cytostatic if only inducing changes in cell viability.
RESULTS: The PDO biobank captures a diverse spectrum of PDAC patients, with PDO chemotherapy responses consistent with those of the patient. The drug screen revealed that while a number of targeted therapies failed across multiple PDOs, some, including WEE1 and HSP90 inhibitors, showed efficacy across all PDO’s. A differential response was observed for CDK4/6 inhibitors, that was consistent with the expected response based on the patient genetic profile. Intriguingly, alteration of cell-death pathways was revealed as a promising therapeutic opportunity.
SIGNIFICANCE: We have identified several promising targeted compounds that may have therapeutic potential in PDAC. Patient-derived xenografts have been established for all PDOs to validate these findings in the presence of a complex stromal network and provide the pre-clinical rationale for the initiation of a future clinical trial for PDAC patients.