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EP502 Blocking 17b-hydroxysteroid dehydrogenase type 1 in endometrial cancer: a potential novel endocrine therapeutic approach
  1. KMC Cornel1,2,
  2. G Konings2,3,
  3. S Xanthoulea2,3,
  4. B Delvoux3,
  5. MA Skowron4,
  6. L Kooreman1,5,
  7. P Koskimies6,
  8. C Krakstad7,8,
  9. HB Salvesen7,8,
  10. K Kuijk van1,2,
  11. YJ Schrooders1,2,
  12. M Vooijs1,9,
  13. AJ Groot1,9,
  14. MY Bongers1,2,
  15. RF Kruitwagen1,2,
  16. A Romano1,2,
  17. ENITEC (European Network Individualized Treatment Endometrial Cancer)
  1. 1GROW - School for Oncology and Developmental Biology, Maastricht University
  2. 2Gynaecology & Obstetrics
  3. 3GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands
  4. 4Urology, Heinrich Heine University Düsseldorf, Dusseldorf, Germany
  5. 5Pathology, Maastricht University Medical Centre (MUMC), Maastricht, The Netherlands
  6. 6Forendo Pharma Ltd., Turku, Finland
  7. 7Gynaecology & Obstetrics, Haukeland University Hospital
  8. 8Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen, Norway
  9. 9Department of Radiotherapy (MAASTRO), Maastricht University, Maastricht, The Netherlands


Introduction/Background The enzyme type 1 17β-hydroxysteroid dehydrogenase (HSD17B1), responsible for generating active 17β-estradiol (E2) from low-active estrone (E1), is over-expressed in endometrial cancer (EC) thus implicating an increased intra-tissue generation of E2 in this estrogen-dependent condition.

In this study we explored the possibility of inhibiting HSD17B1 and impairing the generation of E2 from E1 in EC using in vitro, in vivo and ex vivo models.

Methodology We generated EC cell lines derived from the well-differentiated endometrial adenocarcinoma Ishikawa cell line and expressing levels of HSD17B1 similar to human tissues. In these cells, HPLC analysis showed that HSD17B1 activity could be blocked by a specific HSD17B1 inhibitor. In vitro, E1 administration elicited colony formation similar to E2, and this was impaired by HSD17B1 inhibition. In vivo, tumours grafted on the chicken chorioallantoic membrane (CAM) demonstrated that E1 upregulated the expression of the estrogen responsive cyclin A similar to E2, which was impaired by HSD17B1 inhibition. Neither in vitro nor in vivo effects of E1 were observed using HSD17B1 negative cells (negative control).

Results Using a patient cohort of 52 primary ECs, we demonstrated the presence of HSD17B1 enzyme activity (ex vivo in tumour tissues, as measured by HPLC), which was inhibited by over 90% in more than 45% of ECs using the HSDβB1 inhibitor. Since drug treatment is generally indicated for metastatic/recurrent and not primary tumour, we next demonstrated the mRNA expression of the potential drug target, HSD17B1, in metastatic lesions using a second cohort of 37 EC patients.

Conclusion In conclusion, HSD17B1 inhibition efficiently blocks the generation of E2 from E1 using various EC models. Further preclinical investigations and HSD17B1 inhibitor development to make candidate compounds suitable for the first human studies are awaited.

Disclosure Nothing to disclose.

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