Targeting hedgehog signaling in pancreatic ductal adenocarcinoma.

Delphine Quatannens, Yannick Verhoeven, Peter Van Dam, Filip Lardon, Hans Prenen, Geert Roeyen, Marc Peeters, Evelien L J Smits, Jonas Van Audenaerde

Journal: Pharmacology & therapeutics 2022;236():108107

PMID: 34999181

Full Text on Elsevier Science View on PubMed

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer related death. The urgent need for effective therapies is highlighted by the lack of adequate targeting. In PDAC, hedgehog (Hh) signaling is known to be aberrantly activated, which prompted the pathway as a possible target for effective treatment for PDAC patients. Unfortunately, specific targeting of upstream molecules within the Hh signaling pathway failed to bring clinical benefit. This led to the ongoing debate on Hh targeting as a therapeutic treatment for PDAC patients. Additionally, concurrent non-canonical activation routes also result in translocation of Gli transcription factors into the nucleus. Therefore, different downstream targets of the Hh signaling pathway were identified and evaluated in preclinical and clinical research. In this review we summarize the variety of Hh signaling antagonists in different preclinical models of PDAC. Furthermore, we discuss published and ongoing clinical trials that evaluated Hh antagonists and point out the current hurdles and future perspectives in the light of redesigning Hh-targeting therapies for the treatment of PDAC patients.

Address: Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium. Electronic address: [email protected].; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium. Electronic address: [email protected].; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Unit of Gynecologic Oncology, University Hospital Antwerp (UZA), Antwerp, Belgium. Electronic address: [email protected].; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium. Electronic address: [email protected].; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Department of Oncology, University Hospital Antwerp (UZA), Antwerp, Belgium. Electronic address: [email protected].; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Department of Hepatobiliary Transplantation and Endocrine Surgery, University Hospital Antwerp (UZA), Antwerp, Belgium. Electronic address: [email protected].; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Department of Oncology, University Hospital Antwerp (UZA), Antwerp, Belgium. Electronic address: [email protected].; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium. Electronic address: [email protected].; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium. Electronic address: [email protected].

DOI: 10.1016/j.pharmthera.2022.108107

Link outs

Free resources

Medical:

https://medlineplus.gov/pancreaticcancer.html

Subscription / membership required

Full Text Sources:

MeSH Terms: Carcinoma, Pancreatic Ductal, Hedgehog Proteins, Humans, Pancreatic Neoplasms, Signal Transduction, Zinc Finger Protein GLI1