Current standard-of-care for patients with pancreatic ductal adenocarcinoma (PDAC) focusses on chemotherapeutic regimens and pancreatic cancer surgery. However, limited treatment options, late diagnosis in advanced tumor stages and the aggressive behavior of PDAC contribute to the high mortality of the disease. Consequently, there is an urgent need of precision medicine for pancreatic cancer patients. All over the world, numerous initiatives started in recent years to translate novel scientific discoveries into prospective clinical trials. One major approach pursues the stratification of PDAC patients according the tumor transcriptome to predict treatment response. Other strategies concentrate on genomic alterations and the identification of individualized targeted therapies. Further experimental studies are ongoing to detect novel biomarkers for cancer diagnosis, subtyping, treatment response prediction or clinical outcome. However, the challenge remains to transfer the knowledge into clinical practice. In this review, we summarize current literature and knowledge and highlight novel concepts of basic and clinical research uncovering suitable biomarkers and targeted therapies. Thus, we provide an overview of preclinical and clinical efforts of precision medicine in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Developing biomarkers for early detection and chemotherapeutic response prediction is crucial to improve the dismal prognosis of PDAC patients. However, molecular cancer signatures based on transcriptome analysis do not reflect intratumoral heterogeneity. To explore a more accurate stratification of PDAC phenotypes in an easily accessible matrix, plasma metabolome analysis using MxP^® Global Profiling and MxP^® Lipidomics was performed in 361 PDAC patients. We identified three metabolic PDAC subtypes associated with distinct complex lipid patterns. Subtype 1 was associated with reduced ceramide levels and a strong enrichment of triacylglycerols. Subtype 2 demonstrated increased abundance of ceramides, sphingomyelin and other complex sphingolipids, whereas subtype 3 showed decreased levels of sphingolipid metabolites in plasma. Pathway enrichment analysis revealed that sphingolipid-related pathways differ most among subtypes. Weighted correlation network analysis (WGCNA) implied PDAC subtypes differed in their metabolic programs. Interestingly, a reduced expression among related pathway genes in tumor tissue was associated with the lowest survival rate. However, our metabolic PDAC subtypes did not show any correlation to the described molecular PDAC subtypes. Our findings pave the way for further studies investigating sphingolipids metabolisms in PDAC.

Chemotherapy, the standard treatment for pancreatic ductal adenocarcinoma (PDAC), has only a modest effect on the outcome of patients with late-stage disease. Investigations of the genetic features of PDAC have demonstrated a frequent occurrence of mutations in genes involved in homologous recombination (HR), especially in the breast cancer susceptibility gene 2 (BRCA2). Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, is approved as a maintenance treatment for patients with advanced PDAC with germline BRCA1/2 mutations following a platinum-containing first-line regimen. Limitations to the use of PARP inhibitors are represented by the relatively small proportion of patients with mutations in BRCA1/2 genes and the modest capability of these substances of inducing objective response. We have previously shown that pancreatic cancer with BRCA2 mutations exhibits a remarkably enhanced sensitivity towards tumor-necrosis-factor-related apoptosis-inducing ligand (TRAIL) receptor-stimulating agents. We thus aimed to investigate the effect of combined treatment with PARP inhibitors and TRAIL receptor-stimulating agents in pancreatic cancer and its dependency on the BRCA2 gene status. The respective effects of TRAIL-targeting agents and the PARP inhibitor olaparib or of their combination were assessed in pancreatic cancer cell lines and patient-derived organoids. In addition, BRCA2-knockout and -complementation models were investigated. The effects of these agents on apoptosis, DNA damage, cell cycle, and receptor surface expression were assessed by immunofluorescence, Western blot, and flow cytometry. PARP inhibition and TRAIL synergized to cause cell death in pancreatic cancer cell lines and PDAC organoids. This effect proved independent of BRCA2 gene status in three independent models. Olaparib and TRAIL in combination caused a detectable increase in DNA damage and a concentration-dependent cell cycle arrest in the G2/M and S cell cycle phases. Olaparib also significantly increased the proportion of membrane-bound death receptor 5. Our results provide a preclinical rationale for the combination of PARP inhibitors and TRAIL receptor agonists for the treatment of pancreatic cancer and suggest that the use of PARP inhibitors could be extended to patients without BRCA2 mutations if used in combination with TRAIL agonists.

Was ist neu?: Epidemiologie In Deutschland werden im Jahr 2018 schätzungsweise 19 000 Menschen an einem Pankreaskarzinom erkranken. Die 5-Jahres-Überlebensrate (5-JÜR) aller Pankreaskarzinompatienten liegt mit rund 6 % sehr niedrig und die potenziell kurative Operation ist nur bei 15 – 20 % der Erkrankten möglich. Durch häufigeren Einsatz und Kombination systemischer Chemotherapeutika konnte in den letzten Jahren eine verbesserte Lebenserwartung erreicht werden. Resektables Stadium Nach vollständiger operativer Resektion eines Pankreaskarzinoms trägt eine adjuvante Chemotherapie zur Verlängerung des Gesamtüberlebens bei. Mittel der Wahl sind Gemcitabin oder 5-Fluorouracil (5-FU) und Folinsäure (FS). Kürzlich konnte für die Kombination aus Gemcitabin und Capecitabin (Gem-Cap) eine signifikante Verlängerung des Gesamtüberlebens im Vergleich zur Gemcitabin-Monotherapie gezeigt werden. Für den Einsatz einer adjuvanten Radiochemotherapie gibt es derzeit keine Empfehlung. Borderline-resektables Stadium Eine neoadjuvante Therapie hat bei Pankreaskarzinomen außerhalb klinischer Studien keinen Stellenwert. Eine Ausnahme stellen borderline-resektable Pankreaskarzinome dar. Fortgeschrittenes Stadium (M1) Patienten mit fortgeschrittenem oder metastasiertem Pankreaskarzinom profitieren von einer Chemotherapie. Für Patienten mit gutem ECOG-Status konnte kürzlich in 2 Phase-III-Studien eine signifikante Lebenszeitverlängerung durch die Kombination aus Gemcitabin plus nab-Paclitaxel (Gem-Nab) sowie durch das Kombinationsschema aus Folinsäure, 5-FU, Irinotecan und Oxaliplatin (FOLFIRINOX) gezeigt werden. In der Zweitlinie steht nanoliposomales Irinotecan oder Oxaliplatin kombiniert mit 5FU/FS (OFF) zur Verfügung. Personalisierte Therapien Die molekulare Charakterisierung des Pankreaskarzinoms hat Fortschritte gemacht und bietet schon heute Ansätze zur personalisierten Medizin. Bei gutem ECOG-Status sollte vor Zweitlinientherapie eine MSI-H/dMMR-Analyse erfolgen, um den möglichen Einsatz einer Checkpoint-Inhibitor-Therapie zu evaluieren. Bei BRCA-Mutationen kann die Gabe von PARP-Inhibitoren vielversprechend sein.

Background: As key constituents of cellular sphingolipid pools, sphingomyelin (SM) and ceramide (CER) are central to the regulation of cancer cell death and survival. The metabolic flux between these two lipids is a vital component of the cellular stress response, yet the underlying regulatory mechanisms in cancer remain elusive. Acid sphingomyelinase (SMPD1) facilitates the conversion of SM to CER, functioning as a key enzymatic driver of CER-mediated signalling. Objectives: Herein, we aim to evaluate the role of SMPD1-driven sphingolipid metabolism in pancreatic carcinogenesis. Design: A targeted quantitative analysis of the plasma metabolome was conducted involving patients with pancreatic ductal adenocarcinoma (PDAC, n=202) and matched control subjects (n=204). Multiplex immunohistochemistry was performed on resected PDAC (n=122) to identify expression of SMPD1 with tumour and immune cell markers. CRISPR/Cas9 driven Smpd1-deleted murine cell lines were generated and subsequently assessed for their carcinogenic potential in vitro. The effects of Smpd1 deletion on tumour formation were evaluated using both syngeneic orthotopic and metastatic murine models. Results: Here, we demonstrate that tumour cell-autonomous expression of SMPD1, in pancreatic ductal adenocarcinoma (PDAC), is associated with poorer patients’ outcomes. Smpd1 ablation in murine PDAC cells resulted in reduced proliferation and migration in vitro and decreased metastases and tumour burden in vivo. Integrated transcriptomic, metabolomic and proteomic studies revealed that SMPD1 abrogation impairs Kras ^G12D oncogenic signalling and, thus, reduces tumour burden. Reduced plasma membrane interaction of Kras ^G12D was associated with SMPD1-dependent sphingolipid metabolism. Notably, the SMPD1 inhibitor (ARC39) potently synergised with the Kras ^G12D inhibitor (MRTX1133). Conclusion: In summary, SMPD1 regulated plasma membrane sequestration of Kras ^G12D represents a potential therapeutic target within the Kras signalling pathway for intractable PDAC.