Targeting the DIO3 enzyme using first-in-class inhibitors effectively suppresses tumor growth: a new paradigm in ovarian cancer treatment

  • Oncogene. 2021 Nov;40(44):6248-6257. doi: 10.1038/s41388-021-02020-z.
Dotan Moskovich  1  2 ,  Yael Finkelshtein  1  2 ,  Adi Alfandari  1  2 ,  Amit Rosemarin  1  2 ,  Tzuri Lifschytz  3 ,  Avivit Weisz  4 ,  Santanu Mondal  5 ,  Harinarayana Ungati  5 ,  Aviva Katzav  4 ,  Debora Kidron  4  6 ,  Govindasamy Mugesh  5 ,  Martin Ellis  1  6 ,  Bernard Lerer  3 ,  Osnat Ashur-Fabian  7  8
Affiliations
  • 1. Translational Oncology Laboratory, Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel.
  • 2. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 3. Biological Psychiatry Laboratory Hadassah - Hebrew University Medical Center, Jerusalem, Israel.
  • 4. Department of Pathology, Meir Medical Center, Kfar Saba, Israel.
  • 5. Department of Inorganic and Physical Chemistry, Indian Institute of Science, Bangalore, India.
  • 6. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
  • 7. Translational Oncology Laboratory, Hematology Institute and Blood Bank, Meir Medical Center, Kfar-Saba, Israel. [email protected].
  • 8. Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. [email protected].
PMID: 34556811 DOI: 10.1038/s41388-021-02020-z
Abstract

The enzyme iodothyronine deiodinase type 3 (DIO3) contributes to Cancer proliferation by inactivating the tumor-suppressive actions of thyroid hormone (T3). We recently established DIO3 involvement in the progression of high-grade serous ovarian Cancer (HGSOC). Here we provide a link between high DIO3 expression and lower survival in patients, similar to common Disease markers such as Ki67, PAX8, CA-125, and CCNE1. These observations suggest that DIO3 is a logical target for inhibition. Using a DIO3 mimic, we developed original DIO3 inhibitors that contain a core of dibromomaleic anhydride (DBRMD) as scaffold. Two compounds, PBENZ-DBRMD and ITYR-DBRMD, demonstrated attenuated cell counts, induction in Apoptosis, and a reduction in cell proliferation in DIO3-positive HGSOC cells (OVCAR3 and KURAMOCHI), but not in DIO3-negative normal ovary cells (CHOK1) and OVCAR3 depleted for DIO3 or its substrate, T3. Potent tumor inhibition with a high safety profile was further established in HGSOC xenograft model, with no effect in DIO3-depleted tumors. The antitumor effects are mediated by downregulation in an array of pro-cancerous proteins, the majority of which known to be repressed by T3. To conclude, using small molecules that specifically target the DIO3 enzyme we present a new treatment paradigm for ovarian Cancer and potentially Other DIO3-dependent malignancies.

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