Abstract C57: Organoid profiling identifies common responders to chemotherapy in pancreatic cancer

Abstract

Pancreatic cancer is the most lethal common solid malignancy. Systemic therapies are often ineffective and predictive biomarkers to guide treatment are urgently needed. We generated a pancreatic cancer patient-derived organoid (PDO) library that recapitulates the mutational spectrum and transcriptional subtypes of primary pancreatic cancer. New driver oncogenes were nominated and transcriptomic analyses revealed unique clusters. PDOs exhibited heterogeneous responses to standard-of-care chemotherapeutics and investigational agents. In a case study manner, we find that PDO therapeutic profiles paralleled patient outcomes and that PDOs enable longitudinal assessment of chemosensitivity and evaluation of synchronous metastases. We derived organoid-based gene expression signatures of chemosensitivity that predicted improved responses for many patients to chemotherapy in both the adjuvant and advanced disease settings. Finally, we nominated alternative treatment strategies for chemorefractory PDOs using targeted agent therapeutic profiling. We propose that combined molecular and therapeutic profiling of PDOs may predict clinical response and enable prospective therapeutic selection. Citation Format: Herve Tiriac, Pascal Belleau, Dannielle Engle, Dennis Plenker, Astrid Deschenes, Tim Somerville, Fieke Froeling, Richard Moffitt, Jennifer Knox, Alexander Krasnitz, Steven Gallinger, David Tuveson. Organoid profiling identifies common responders to chemotherapy in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr C57.

Patient-Derived Cancer Organoids as Predictors of Treatment Response

“…An organoid-derived pharmaco-transcriptomic signature was developed to predict drug sensitivity to gemcitabine monotherapy but it did not predict response in patients receiving a combination treatment with other chemotherapeutics (33). Similar correlation between clinical response and gemcitabine sensitivity in pancreatic cancer organoids were found by others as well (37).…”

“…Pancreatic cancer organoid cultures derived from multiple different metastatic sites from the same patient showed a differential sensitivity towards 5-FU, but not towards the other chemotherapeutics tested. This suggests the existence of cancer subclones that differ between metastatic sites which are maintained in their respective cancer organoids (33).…”

“…The opportunity to derive cancer organoids form different tumor sites provides the opportunity to select treatment options to which all distinct tumor locations share sensitivity. Multiple studies have successfully used this approach and showed differential as well as similar treatment responses for several anti-cancer agents between organoids derived from multiple tumor sites (33,34,51,52). In clinical practice, taking multiple biopsies from one tumor or taking biopsies from multiple metastases might however not always be feasible which could potentially limit this application into the clinic.…”

Metabolic Heterogeneity in Patient Tumor-Derived Organoids by Primary Site and Drug Treatment

“…Tumor organoids have emerged as an appealing method to tailor anti-cancer treatments by performing high-throughput drug screening directly on a patient's tumor cells (1)(2)(3). In vitro organoids, fully encapsulated in a basement membrane matrix, recapitulate the genetic and histopathological characteristics of the original tumor, along with its complex 3-dimensional organization (4)(5)(6)(7)(8)(9). Organoid cultures also preserve interactions between tumor cells, immune cells (10), and fibroblasts (11), which can influence tumor drug response and are potential drug targets (12,13).…”

Elucidation of tumor-stromal heterogeneity and the ligand-receptor interactome by single cell transcriptomics in real-world pancreatic cancer biopsies

“…Therefore, efforts at expanding precision medicine approaches in PDAC beyond DNA alterations have led to patient-derived organoids (PDOs) being used for prospective therapeutic prediction. While initial reports primarily utilized surgical resection samples for establishing PDOs, more recently, the feasibility of using limited biopsy material has also been confirmed, garnering the possibility of incorporating PDOs into precision medicine trials in patients with advanced PDAC (7,8). Nonetheless, although…”