Martini-Klinik

Primary sclerosing cholangitis (PSC) is an immune-mediated disease of the biliary tract for which no prognosis-improving therapies are yet available. PSC is characterized by genetic risk factors, alterations in the microbiome and pathological immune activation leading to the development of biliary fibrosis. Cholangiocytes play an active role in the inflammatory processes, as they interact directly with the microbiome and immune cells. The concomitant chronic inflammatory bowel disease has a distinct phenotype and causes a reciprocal modulation of intestinal and hepatic disease activity via changes in the intestinal barrier and the enterohepatic circulation of bile acids. While the currently available drugs and endoscopic treatment options are only symptomatically effective, new pharmacologic therapies are under clinical evaluation. In this review, we aim to provide an insight into the current understanding of the pathogenesis of PSC and new therapeutic developments.

Sulforaphane (SFN) is a phytoderived compound abundant in cruciferous plants that possesses a broad spectrum of anticancer properties. We showed that SFN-induced caspase-mediated apoptosis in grade IV bone metastasis-derived androgen-insensitive PC-3 (IC50 = 4.2 μM), and lymph node metastasis-derived androgen-sensitive LNCaP (IC50 = 2.8 μM) prostate adenocarcinoma cells. SFN-mediated cardiotoxic side effects were tested in a preclinical in vitro model that enables the study simultaneously of the impact of drugs on cancer cell death and contractile properties of engineered heart tissues generated from human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM EHT). Thereby, SFN exposure induced PC-3 cell death without affecting the contractile force of hiPSC-CM EHT. Interestingly, the irregular beating pattern of hiPSC-CM EHT observed in the presence of PC-3 coculture was normalized compared to vehicle treatment. Overall, this in vitro coculture model of hiPSC-CM EHT and cancer cells could facilitate the study of cardiotoxic cancer drug side-effects.

Marine triterpene glycosides are known to exhibit significant anticancer activity. We investigated pacificusoside C and cucumariosides C1 and C2 isolated from a sea star Solaster pacificus in prostate cancer models with varying drug resistance and in non-cancerous cells in vitro. Cucumarioside C1 showed selectivity comparable to cisplatin, whereas the other compounds were less selective. Cucumarioside C1 induced apoptosis and enhanced cytotoxic effects of cisplatin, carboplatin, docetaxel, and cabazitaxel, making it a potential candidate for combination therapy. All three glycosides were active in docetaxel-resistant cells and were neither inhibitors nor substrates of P-glycoprotein, indicating P-glycoprotein-independent activity. To explore the mechanism of anticancer activity of cucumarioside C1, we performed functional kinome profiling of treated 22Rv1 cells, predicting activation of kinases involved in stress response and survival (IKKα, IKKβ, IKKε), necroptosis (MLKL), metabolism (GCN2, PDK1), cytoskeletal dynamics (RHOK), mitophagy (PINK1), apoptosis and cell cycle regulation (PITSLRE), and immune modulation (COT). Notably, only MAP kinases p38 and ERK1/2 were predicted to be specifically inhibited, that was further validated by Western blotting. These findings may potentially explain previously reported anticancer effects of cucumarioside C1 and related marine glycosides. To our knowledge, this is the first study to report triterpene glycosides' effects on the kinome of cancer cells.

Zusammenfassung Morbus Hirschsprung (MH) ist eine angeborene Entwicklungsstörung des enterischen Nervensystems (ENS), die durch das Fehlen von Ganglienzellen in einem distalen Darmsegment – meist im Rektosigmoid – gekennzeichnet ist. Die fehlende Peristaltik führt zu einer funktionellen Obstruktion und verursacht in der Neonatalperiode typischerweise einen verzögerten Mekoniumabgang, ein geblähtes Abdomen und Erbrechen. Standardmäßig wird das aganglionäre Segment chirurgisch reseziert und der gesunde Darmabschnitt an den Analkanal angeschlossen („Pull-through“-Operation). Trotz initialer Erfolge treten häufig Langzeitkomplikationen wie chronische Obstipation, Stuhlinkontinenz und M.-Hirschsprung-assoziierte Enterokolitis auf, was den Bedarf an innovativen Behandlungsoptionen unterstreicht. In den letzten Jahren rücken insbesondere Organoide und zellbasierte Therapien in den Fokus der Forschung. Intestinale Organoide, häufig aus patienteneigenen Biopsien oder induzierten pluripotenten Stammzellen (iPSC) generiert und mit enterischen Neuralleistenzellen (ENCC) versehen, erlauben ein patientenspezifisches Modell, um MH-spezifische Pathomechanismen und mögliche Gentherapien (z. B. über CRISPR/Cas9) zu untersuchen. Gleichzeitig werden verschiedene Ansätze zur Reinnervation mittels Zelltherapie erprobt: Durch Transplantation von ENS-Vorläuferzellen in das aganglionäre Darmsegment könnten funktionelle Ganglienstrukturen neu gebildet und somit die Motilität kausal verbessert werden. Tierexperimentelle Studien zeigten bereits erste Erfolge, darunter eine partielle Wiederherstellung der Peristaltik. Die technische und biologische Komplexität solcher Verfahren – etwa die Skalierung der Zellzahlen, die exakte Integration der neuralen Zellen und die langfristige Sicherheit – sind jedoch noch nicht abschließend gelöst. Dennoch eröffnen diese Forschungsfelder vielversprechende Perspektiven: In einem Zeitraum von etwa 5 bis 10 Jahren könnten organoidbasierte Diagnostik – etwa zur funktionellen Charakterisierung von Patientenorganoiden oder zum In-vitro-Test pharmakologischer Substanzen – sowie zelltherapeutische Interventionen die konventionelle Operation ergänzen oder bei bestimmten Hochrisikogruppen sogar ersetzen. Klinische Studien werden zeigen müssen, ob sich durch eine gezielte, auf die Ursache abzielende Therapie die Prognose, insbesondere hinsichtlich chronischer Obstipation und Enterokolitisrisiko, langfristig verbessert. Die enge Zusammenarbeit von Grundlagenforschung und Klinik wird hier entscheidend sein, um neue Therapieoptionen in die pädiatrische Praxis zu überführen und den Betroffenen eine nachhaltige Verbesserung der Lebensqualität zu ermöglichen.

[18F]CTT1057 is a highly selective prostate-specific membrane antigen (PSMA)-targeted PET radiotracer for prostate cancer (PCa) detection. This prospective study (GuideView, NCT04838626) evaluates the imaging efficacy of [18F]CTT1057 PET to detect PSMA-positive lesions against histopathology in patients with newly diagnosed, untreated, high-risk PCa. Methods: Between September 7, 2021, and October 26, 2023, 201 patients planned for radical prostatectomy were screened and 195 patients were enrolled. Of these, 184 patients received a median of 355 MBq (range, 195-400 MBq) of [18F]CTT1057 and underwent PET/CT 90 min (±30 min) later. Three masked central independent readers evaluated the images. Coprimary endpoints were patient-level sensitivity (including primary tumor and pelvic lymph nodes) and region-level specificity (including pelvic lymph nodes only) for detection of PSMA-positive lesions, using histopathology as the standard of truth. The lower-bound 95% CI needed to surpass 50% for patient-level sensitivity and 70% for region-level specificity. Success was defined as at least 2 of 3 central readers meeting these criteria. Secondary endpoints included the patient-level and region-level positive predictive value and accuracy, region-level sensitivity, inter- and intrareader variability, detection rate of distant metastasis, pharmacokinetics, and safety and tolerability assessments. Results: Of the 184 patients who received [18F]CTT1057, 172 patients were evaluable for efficacy. Among these, a median of 19 lymph nodes (interquartile range, 13.0-28.5 lymph nodes) were dissected per patient. Both coprimary endpoints were met, with lower bounds of 95% CIs surpassing the success criteria for all 3 readers for both patient-level sensitivity (range, 86.8%-90.0%; lower-bound 95% CI, 80.7%-84.5%) and region-level specificity (97.1%; lower-bound 95% CI, 92.7%). Interreader variability Fleiss κ was 63.9%; intrareader reproducibility Cohen κ was 89.4%-100%. [18F]CTT1057 had a favorable safety profile. Conclusion: GuideView confirmed the imaging efficacy of [18F]CTT1057 for the detection of PSMA-positive lesions, with high patient-level sensitivity and region-level specificity. Substantial interreader variability and almost perfect intrareader reproducibility suggest that [18F]CTT1057 findings are robust and reliable. [18F]CTT1057 will contribute to expanding access to PSMA PET imaging to properly diagnose and treat patients with PCa.

Pharmacotherapy of older patients requires special attention to drug interactions, based on an increase in morbidity and elevated need for polypharmacy. Especially for drugs with a narrow therapeutic index, interactions may require dose adjustments, discontinuation or switching of co-medication. These interactions are frequently based on pharmacokinetic alterations of drug metabolism via the cytochrome P450 (CYP) enzyme system, mainly via CYP3A4. This isoform is involved in the metabolism of about half of therapeutically applied drugs, including many agents commonly used in patients with prostate cancer. As a consequence, an impressive decrease in plasma levels of coadministered drugs has to be expected during the use of the potent CYP3A4 inducers apalutamide as well as enzalutamide, in contrast to the mild CYP3A4 inducer darolutamide. Abiraterone is classified as a moderate inhibitor of the CYP2D6 isozyme, which catalyses the biotransformation of fewer drugs. As a consequence, abiraterone's spectrum of interaction has to be interpreted differently. As pharmacotherapy approaches, it is helpful to understand the drug biotransformation pathways in more detail, in order to assess the extent of possible interactions that may necessitate the intensification of therapeutic monitoring, or dose modification or any therapeutic switch in time.