SINGLE DOSE CROSSOVER COMPARATIVE BIOAVAILABILITY STUDY OF ETHINYL ESTRADIOL/ETONOGESTREL VAGINAL RING (DELIVERING 0.015 mg/0.12 mg PER DAY) WORN FOR 21 DAYS IN HEALTHY FEMALE SUBJECTS

Single Dose Crossover Comparative Bioavailability Study of Ethinyl Estradiol/Etonogestrel Vaginal Ring (Delivering 0.015 mg/0.12 mg Per Day) Worn for 21 Days in Healthy Female Subjects

Start Date29 Jul 2023

Sponsor / Collaborator

Evestra, Inc.

100 Clinical Results associated with Evestra, Inc.

0 Patents (Medical) associated with Evestra, Inc.

Literatures (Medical) associated with Evestra, Inc.

21 Apr 2025·Cancer Research

Abstract 1630: Targeting the LIF/LIFR axis reduces the progression of inflammatory breast cancer by promoting ferroptosis

Author: Randolph, Lois ; Mahajan, Megharani ; Romo, Bianca A. ; Santhamma, Bindu ; Viswanadhapalli, Suryavathi ; Ebrahimi, Behnam ; Thomas, Christoforos ; Vadlamudi, Ratna K. ; Fuentes, Zenaida ; Aller, Emily J. ; Nair, Hareesh B.

AbstractBackground:Inflammatory breast cancer (IBC) is a rare subtype of breast cancer affecting 2-4% of the U.S. population. With the incidence being quite low, IBC is responsible for 7% of breast cancer related mortality often affecting younger women. The only currently approved options for treatment are surgical resection, chemotherapy, and radiation. Novel therapeutic targets are desperately needed for the generation of new therapeutics. IBC progression has been linked to growth factor and cytokine signaling abnormalities. In previous studies, the cytokine LIF/LIFR signaling axis has been identified as a crucial pathway in the progression of triple negative breast cancer. However, the role of LIF/LIFR in IBC progression remains unknown. The objective of this study is to test the utility of LIFR and test the effectiveness of LIFR inhibitor at treating IBC.Methods:The utility of using LIFR inhibition as a treatment strategy in IBC was tested using cell survival, apoptosis, and colony formation assays using established IBC cell models (SUM149, SUM190PT, and KPL-4). We have reduced LIFR levels by 70% in IBC cells utilizing two different siRNAs that target LIFR. Western blotting, luciferase reporter assays, RT-qPCR, and lipid peroxidation assays were used to establish the mechanism of EC359 mediated growth suppression of IBC. In vivo treatment of cell-derived xenografts (KPL-4) was used to assess the utility of EC359.Results:All three IBC models exhibited detectable expressions of LIF and LIFR. Reduction of LIFR using siRNA decreased cell survival, colony formation, and invasion capacity of IBC cells relative to cells transfected with control siRNAs. Pharmacological inhibition of LIFR with EC359 effectively reduced cell survival and clonogenic capacity of IBC cells in the low nanomolar range. RT-qPCR tests revealed EC359 markedly decreased the expression of LIFR target genes. Western analyses confirmed that EC359 treatment suppressed downstream LIF/LIFR signaling pathways, including STAT3, AKT, and pS6, and promoted apoptosis. Treatment of cells with the ferroptosis inhibitor Ferrostatin 1 negated the capacity of EC359 to induce cell death. The evaluation of lipid peroxidation in cells via flow cytometry, utilizing the oxidation of BODIPY™ reagent, further confirmed EC359 induction of ferroptosis. Mechanistic investigations demonstrated that EC359 predominantly triggered ferroptosis by inhibiting the glutathione antioxidant defense system through the downregulation of SLC7A11 and GPX4 levels. EC359 (5 mg/kg/day) was effective in reducing the growth of the IBC KPL4 xenograft tumors. Immunohistochemical examinations of tumors validated reduced cell proliferation as assessed by Ki67 staining.Conclusion:Collectively, our research suggests that the inhibition of LIFR promotes ferroptosis-mediated cell death in IBC, and LIFR inhibitors represent a novel therapeutic option for IBC.Citation Format:Bianca A. Romo, Zenaida Fuentes, Lois Randolph, Megharani Mahajan, Emily J. Aller, Behnam Ebrahimi, Bindu Santhamma, Hareesh B. Nair, Christoforos Thomas, Ratna K. Vadlamudi, Suryavathi Viswanadhapalli. Targeting the LIF/LIFR axis reduces the progression of inflammatory breast cancer by promoting ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1630.

21 Apr 2025·Cancer Research

Abstract 5989: Investigating the potential of EC359 in inducing ferroptosis for the treatment of type I and type II endometrial cancers

Author: Mahajan, Megharani R. ; Yang, Xue ; Nair, Hareesh B. ; Ramirez, Paulina ; Viswanadhapalli, Suryavathi ; Aller, Emily J. ; Vadlamudi, Ratna K. ; Ebrahimi, Behnam ; Kost, Edward

AbstractBackground:Over the past decade, the diagnostic and mortality rates of endometrial cancer, the most common malignancy of the female reproductive tract, have risen, highlighting the need for improvements in current therapeutic options. Recent studies suggest that targeting the cellular receptor LIFR with the small molecule inhibitor EC359 could be a potential treatment for endometrial cancers. EC359 has been shown to inhibit the viability and invasion of both Type I and Type II endometrial cancers. However, the underlying mechanisms by which EC359 induces cancer cell death remain unclear. Emerging evidence suggests that LIFR signaling may be linked to ferroptosis. The purpose of this study is to explore the potential of EC359 to induce ferroptosis as a therapeutic strategy for Type I and Type II endometrial cancers.Methods:The effects of EC359 on multiple established and primary endometrial cancer cells were evaluated using colony formation, MTT based cell viability and apoptosis assays. Mechanistic investigations were performed with Western blot, RT-qPCR, transmission electron microscopy (TEM) evaluation, and Flow Cytometry analysis. Patient-derived xenograft (PDX) models were used for preclinical evaluation of EC359.Results:EC359 was efficient in reducing cell viability and promoting programmed cell death in both Type I and Type II endometrial cancer cells. We have demonstrated that the ability of EC359 to reduce cell viability is markedly diminished when ferroptosis is inhibited by pharmacological agents like Ferrostatin 1. EC359 primarily induced ferroptosis by suppressing the glutathione antioxidant defense system, as demonstrated by mechanistic investigations using Western blot analysis. Accordingly, the viability of endometrial cancer cells is restored by the addition of extracellular cystine. Further, EC359 treatment resulted in the reduction of critical anti-ferroptosis proteins. Flow cytometry analyses confirmed that EC359 treatment resulted in an increase in lipid peroxidation and TEM investigations revealed the induction of mitochondrial death through ferroptosis. Additionally, EC359 substantially inhibited the progression of tumors in both Type I and II endometrial cancer PDX models.Conclusion:In conclusion, our data indicate that EC359 is a potent inducer of ferroptosis in endometrial cancer cells and has the potential to be used as an additional tool in current endometrial cancer treatment regimens.Citation Format:Emily J. Aller, Xue Yang, Megharani R. Mahajan, Behnam Ebrahimi, Paulina Ramirez, Hareesh B. Nair, Edward Kost, Ratna K. Vadlamudi, Suryavathi Viswanadhapalli. Investigating the potential of EC359 in inducing ferroptosis for the treatment of type I and type II endometrial cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5989.

22 Mar 2024·Cancer Research

Abstract 5986: Significance of LIF/LIFR axis in the progression of inflammatory breast cancer

Author: Romo, Bianca ; Fuentes, Zenaida ; Vadlamudi, Ratna ; Randolph, Lois ; Viswanadhapalli, Suryavathi ; Nair, Hareesh ; Santhamma, Bindu ; Thomas, Christoforos

AbstractBackground: Inflammatory breast cancer (IBC) is a rare form of locally progressed breast cancer. Even though it is uncommon, IBC accounts for 7% of breast cancer deaths. There is a critical need for novel therapeutic targets to develop new therapeutics. IBC is more common in young women. Altered levels of growth factors, and cytokine signaling are suspected to play a role in the progression of IBC. Leukemia inhibitory factor (LIF) is the most pleiotropic member of the interleukin-6 family of cytokines. LIF and its receptor LIFR have been linked to the progression of many cancers including triple negative breast cancer. We recently developed a first-in-class inhibitor targeting LIFR named EC359. However, the role of the LIF/LIFR axis in IBC progression remains unknown. In this study, we examined the significance of LIFR and the effectiveness of LIFR inhibitor EC359 in treating IBC.Methods: The effect of LIFR inhibitor EC359 on cell survival, colony formation, and apoptosis was evaluated using three well-established IBC model cells (SUM149, SUM190PT, and KPL4). Mechanistic studies were conducted using Western blotting, CRISPR KO, reporter assays, and RT-qPCR. KPL4 cell-based xenografts were used to test the efficacy of EC359 in vivo.Results: Our results using Western blotting confirmed increased expression of LIF and LIFR in IBC cells compared to normal and ER+ breast cancer cells. Treatment with EC359 significantly decreased IBC cell viability, long term colony formation ability with an IC50 of ~10-20 nM. Similarly, knock out of LIFR significantly reduced the progression of IBC model cells in cell viability and colony formation assays. Further EC359 treatment promoted apoptosis of IBC cells. Mechanistic studies confirmed that EC359 treatment substantially reduced LIF/LIFR downstream signaling including STAT3, AKT, and mTOR signaling. We also tested the utility of EC359 in treating IBC in vivo using KPL4 xenografts. EC359 (5mg/kg/day) is highly efficacious in reducing IBC xenograft tumor growth in vivo. IHC analyses of tumors confirmed decreased cell proliferation as measured by Ki67 staining.Conclusion: Collectively, these studies demonstrated the therapeutic benefit of using EC359 to target the LIF/LIFR axis and opened the door for the development of new treatment approaches.Citation Format: Bianca Romo, Zenaida Fuentes, Lois Randolph, Bindu Santhamma, Hareesh Nair, Christoforos Thomas, Ratna Vadlamudi, Suryavathi Viswanadhapalli. Significance of LIF/LIFR axis in the progression of inflammatory breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5986.

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The statistics for drugs in the Pipeline is the current organization and its subsidiaries are counted as organizations,Early Phase 1 is incorporated into Phase 1, Phase 1/2 is incorporated into phase 2, and phase 2/3 is incorporated into phase 3

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Drug(Targets)	Indications	Global Highest Phase

Trimegestone/Estratriol ( ER x PR )	Contraception More	Phase 2
EVE135	Atrophic Vaginitis More	Preclinical
EVE132	Uterine Fibroids More	Preclinical
EC914 ( LIFR )	Prostatic Cancer More	Preclinical
EC-625 ( ERRs )	Contraception More	Preclinical

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