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PARP1-targeted fluorescence molecular endoscopy as novel tool for early detection of esophageal dysplasia and adenocarcinoma.
Marcazzan, Sabrina; Braz Carvalho, Marcos J; Nguyen, Nghia T; Strangmann, Julia; Slotta-Huspenina, Julia; Tenditnaya, Anna; Tschurtschenthaler, Markus; Rieder, Jonas; Proaño-Vasco, Andrea; Ntziachristos, Vasilis; Steiger, Katja; Gorpas, Dimitris; Quante, Michael; Kossatz, Susanne.
Afiliación
  • Marcazzan S; II. Medizinische Klinik, TUM School of Medicine and Health, Klinikum Rechts der Isar at Technical University of Munich, Munich, 81675, Germany.
  • Braz Carvalho MJ; Institute of Biological and Medical Imaging, Helmholtz Zentrum München, 85764 Neuherberg, Germany and Chair of Biological Imaging at the Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany.
  • Nguyen NT; Clinical Radiology, Medical School OWL, Bielefeld University, Bielefeld, 33615, Germany.
  • Strangmann J; II. Medizinische Klinik, TUM School of Medicine and Health, Klinikum Rechts der Isar at Technical University of Munich, Munich, 81675, Germany.
  • Slotta-Huspenina J; Department of Nuclear Medicine, TUM School of Medicine and Health, Klinikum Rechts der Isar at Technical University of Munich, Munich, 81675, Germany.
  • Tenditnaya A; Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany.
  • Tschurtschenthaler M; Department of Medicine II (Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, 79106, Germany.
  • Rieder J; Institute of Pathology, TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany.
  • Proaño-Vasco A; Institute of Biological and Medical Imaging, Helmholtz Zentrum München, 85764 Neuherberg, Germany and Chair of Biological Imaging at the Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany.
  • Ntziachristos V; Central Institute for Translational Cancer Research (TranslaTUM), TUM School of Medicine and Health, Technical University of Munich, Munich, 81675, Germany.
  • Steiger K; Division of Translational Cancer Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, 69120, Germany.
  • Gorpas D; Chair of Translational Cancer Research and Institute of Experimental Cancer Therapy, TUM School of Medicine and Health, Klinikum rechts der Isar at Technical University of Munich, Munich, 81675, Germany.
  • Quante M; Department of Medicine II (Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, 79106, Germany.
  • Kossatz S; Department of Medicine II (Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, 79106, Germany.
J Exp Clin Cancer Res ; 43(1): 53, 2024 Feb 21.
Article en En | MEDLINE | ID: mdl-38383387
ABSTRACT

BACKGROUND:

Esophageal cancer is one of the 10 most common cancers worldwide and its incidence is dramatically increasing. Despite some improvements, the current surveillance protocol with white light endoscopy and random untargeted biopsies collection (Seattle protocol) fails to diagnose dysplastic and cancerous lesions in up to 50% of patients. Therefore, new endoscopic imaging technologies in combination with tumor-specific molecular probes are needed to improve early detection. Herein, we investigated the use of the fluorescent Poly (ADP-ribose) Polymerase 1 (PARP1)-inhibitor PARPi-FL for early detection of dysplastic lesions in patient-derived organoids and transgenic mouse models, which closely mimic the transformation from non-malignant Barrett's Esophagus (BE) to invasive esophageal adenocarcinoma (EAC).

METHODS:

We determined PARP1 expression via immunohistochemistry (IHC) in human biospecimens and mouse tissues. We also assessed PARPi-FL uptake in patient- and mouse-derived organoids. Following intravenous injection of 75 nmol PARPi-FL/mouse in L2-IL1B (n = 4) and L2-IL1B/IL8Tg mice (n = 12), we conducted fluorescence molecular endoscopy (FME) and/or imaged whole excised stomachs to assess PARPi-FL accumulation in dysplastic lesions. L2-IL1B/IL8Tg mice (n = 3) and wild-type (WT) mice (n = 2) without PARPi-FL injection served as controls. The imaging results were validated by confocal microscopy and IHC of excised tissues.

RESULTS:

IHC on patient and murine tissue revealed similar patterns of increasing PARP1 expression in presence of dysplasia and cancer. In human and murine organoids, PARPi-FL localized to PARP1-expressing epithelial cell nuclei after 10 min of incubation. Injection of PARPi-FL in transgenic mouse models of BE resulted in the successful detection of lesions via FME, with a mean target-to-background ratio > 2 independently from the disease stage. The localization of PARPi-FL in the lesions was confirmed by imaging of the excised stomachs and confocal microscopy. Without PARPi-FL injection, identification of lesions via FME in transgenic mice was not possible.

CONCLUSION:

PARPi-FL imaging is a promising approach for clinically needed improved detection of dysplastic and malignant EAC lesions in patients with BE. Since PARPi-FL is currently evaluated in a phase 2 clinical trial for oral cancer detection after topical application, clinical translation for early detection of dysplasia and EAC in BE patients via FME screening appears feasible.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esófago de Barrett / Neoplasias Esofágicas / Adenocarcinoma Límite: Animals / Humans Idioma: En Revista: J Exp Clin Cancer Res Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Esófago de Barrett / Neoplasias Esofágicas / Adenocarcinoma Límite: Animals / Humans Idioma: En Revista: J Exp Clin Cancer Res Año: 2024 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido