2. Academic Validation
  3. Effects of the Novel PFKFB3 Inhibitor KAN0438757 on Colorectal Cancer Cells and Its Systemic Toxicity Evaluation In Vivo

Effects of the Novel PFKFB3 Inhibitor KAN0438757 on Colorectal Cancer Cells and Its Systemic Toxicity Evaluation In Vivo

  • Cancers (Basel). 2021 Feb 28;13(5):1011. doi: 10.3390/cancers13051011.
Tiago De Oliveira 1,  Tina Goldhardt 1,  Marcus Edelmann 1,  Torben Rogge 2,  Karsten Rauch 2,  Nikola Dobrinov Kyuchukov 1,  Kerstin Menck 3 4,  Annalen Bleckmann 3 4,  Joanna Kalucka 5 6,  Shawez Khan 7,  Jochen Gaedcke 1,  Martin Haubrock 8,  Tim Beissbarth 8,  Hanibal Bohnenberger 9,  Mélanie Planque 10,  Sarah-Maria Fendt 10,  Lutz Ackermann 2,  Michael Ghadimi 1,  Lena-Christin Conradi 1
Affiliations

Affiliations

  • 1 Clinic of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075 Göttingen, Germany.
  • 2 Institute of Organic and Biomolecular Chemistry, Tammannstraβe 2, 37077 Göttingen, Germany.
  • 3 Clinic of Hematology and Medical Oncology, University Medical Center Göttingen, Robert-Koch-Straße 40, 37075 Göttingen, Germany.
  • 4 Department of Medicine Medical Clinic A, University Hospital Münster, Albert-Schweitzer-Campus 1, 48149 Münster, Germany.
  • 5 Department of Biomedicine, Aarhus University, Høegh-Guldbergs Gade 10, DK-Aarhus C, Denmark.
  • 6 Aarhus Institute of Advanced Studies (AIAS), Aarhus University, 8000 Aarhus, Denmark.
  • 7 National Center for Cancer Immune Therapy (CCIT-DK), Department of Oncology, Copenhagen University Hospital, 2730 Herlev, Denmark.
  • 8 Institute of Medical Bioinformatics, University Medical Center Göttingen, Goldschmidtstraße 1, 37077 Göttingen, Germany.
  • 9 Institute of Pathology, University Medical Center Göttingen, Robert-Koch-Straβe 40, 37075 Göttingen, Germany.
  • 10 Laboratory of Cellular Metabolism and Metabolic Regulation, VIB-KU Leuven Center for Cancer Biology, VIB, Herestraat 49, 3000 Leuven, Belgium.
PMID: 33671096 DOI: 10.3390/cancers13051011
Abstract

Background: Despite substantial progress made in the last decades in colorectal Cancer (CRC) research, new treatment approaches are still needed to improve patients' long-term survival. To date, the promising strategy to target tumor angiogenesis metabolically together with a sensitization of CRC to chemo- and/or radiotherapy by PFKFB3 (6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3) inhibition has never been tested. Therefore, initial evaluation and validation of newly developed compounds such as KAN0438757 and their effects on CRC cells are crucial steps preceding to in vivo preclinical studies, which in turn may consolidate new therapeutic targets.

Materials and methods: The efficiency of KAN0438757 to block PFKFB3 expression and translation in human CRC cells was evaluated by immunoblotting and Real-Time PCR. Functional in vitro assays assessed the effects of KAN0438757 on cell viability, proliferation, survival, adhesion, migration and invasion. Additionally, we evaluated the effects of KAN0438757 on matched patient-derived normal and tumor organoids and its systemic toxicity in vivo in C57BL6/N mice.

Results: High PFKFB3 expression is correlated with a worse survival in CRC patients. KAN0438757 reduces PFKFB3 protein expression without affecting its transcriptional regulation. Additionally, a concentration-dependent anti-proliferative effect was observed. The migration and invasion capacity of Cancer cells were significantly reduced, independent of the anti-proliferative effect. When treating colonic patient-derived organoids with KAN0438757 an impressive effect on tumor organoids growth was apparent, surprisingly sparing normal colonic organoids. No high-grade toxicity was observed in vivo.

Conclusion: The PFKFB3 inhibitor KAN0438757 significantly reduced CRC cell migration, invasion and survival. Moreover, on patient-derived Cancer organoids KAN0438757 showed significant effects on growth, without being overly toxic in normal colon organoids and healthy mice. Our findings strongly encourage further translational studies to evaluate KAN0438757 in CRC therapy.

Keywords

KAN0438757; PFKFB3; colon cancer; glycolysis; intestinal organoids; rectal cancer.

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