DioTree is passionately dedicated to developing innovative treatment for high grade serous ovarian cancer (HGSOC), one of the deadliest human cancers with an extremely poor prognosis. Our groundbreaking approach involves the development of a first-of-its-kind small molecule technology designed to target and inhibit the enzyme DIO3, which drives ovarian cancer progression. We are committed to advancing the frontiers of cancer treatment and making a positive impact on the lives of those affected by this devastating disease.
Ovarian cancer, which is the fourth most common cancer in women and the leading cause of death among tumors in the female reproductive system, currently lacks an effective treatment option beyond chemotherapy and surgery. Although PARP inhibitors have been developed, they are only effective for about 15% of cases, namely for women carrying the BRCA mutation. Annually, more than 300,000 new cases are diagnosed worldwide, 75% of which will not survive the disease.
Our company aims to target all ovarian cancer patients, including those who are non-carriers of the BRCA mutation or resistant to platinum-based chemotherapy. Our innovative drugs, which are "first-in-class" compounds designed to suppress the DIO3 enzyme, have potential applications beyond ovarian cancer, as DIO3 is expressed in other aggressive tumors such as lung, breast, colon, and pancreatic cancers. The target market size could potentially reach millions of cancer patients. Our product is expected to be integrated into the cancer treatment algorithm either as a combination therapy with chemotherapy drugs or as a maintenance therapy for patients who do not respond satisfactorily to current treatment options.
The company's innovative technology involves a series of small molecules that were jointly developed by the co-founder of the company, Prof. Bernard Lerer from Hadassah Medical Center and Prof. Govindasamy Mugesh from Indian Institute of Science.
Those Molecules specifically target the DIO3 enzyme which is highly expressed in various aggressive cancers, including high grade serous ovarian cancer (HGSOC). DIO3 is an attractive target for inhibition since it is responsible for breaking down thyroid hormones, including the biological hormone T3. Because T3 has anti-cancer functions, many tumors express this enzyme, thereby facilitating the division of cancer cells. Our team is the first to generate a series of novel small molecules for DIO3 inhibition, and we are proud to have been granted patent protection in the US and Europe (EP3119768B1; US10435365B2).
Here are some of our key findings:
We have established that ovarian cancer is DIO3-dependent in both cells and mice models.
Using the 'best hit' DIO3 inhibitors, we have achieved high efficacy in both ovarian cancer cells and mice models.
We have confirmed a high safety profile through toxicology experiments.
With these exciting results, we are confident that our technology has the potential to make a significant impact in the fight against cancer
Targeting the DIO3 enzyme using first-in-class inhibitors effectively suppresses tumor growth: a new paradigm in ovarian cancer treatment
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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DIO3, the thyroid hormone inactivating enzyme, promotes tumorigenesis and metabolic reprogramming in high grade serous ovarian cancer
High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy with a need for better understanding the disease pathogenesis. The biologically active thyroid hormone, T3, is considered a tumor suppressor by promoting cell differentiation and mitochondrial respiration. Tumors evolved a strategy to avoid these anticancer actions by expressing the T3 catabolizing enzyme, Deiodinase type 3 (DIO3). This stimulates cancer proliferation and aerobic glycolysis (Warburg effect). We identified DIO3 expression in HGSOC cell lines, tumor tissues from mice and human patients, fallopian tube (FT) premalignant lesion and secretory cells of normal FT, considered the disease site-of-origin. Stable DIO3 knockdown (DIO3-KD) in HGSOC cells led to increased T3 bioavailability and demonstrated induced apoptosis and attenuated proliferation, migration, colony formation, oncogenic signaling, Warburg effect and tumor growth in mice. Proteomics analysis further indicated alterations in an array of cancer-relevant proteins, the majority of which are involved in tumor suppression and metabolism. Collectively this study establishes the functional role of DIO3 in facilitating tumorigenesis and metabolic reprogramming, and proposes this enzyme as a promising target for inhibition in HGSOC.
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