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.

22 Mar 2024·Cancer Research

Abstract 5998: Pharmacological inhibition of the LIF-LIFR autocrine loop reveals vulnerability of ovarian cancer to ferroptosis

Author: Chen, Yidong ; Sanchez, Alondra L. Rodriguez ; Konda, Swapna ; Xu, Zhenming ; Yang, Xue ; Sareddy, Gangadhara R. ; Yan, Hui ; Tekmal, Rajeshwar R. ; Venkata, Prabhakar P. ; Nair, Hareesh B. ; Rao, Manjeet ; Singh, Brij B. ; Lai, Zhao ; Santhamma, Bindu ; Drel, Viktor ; Kost, Edward R. ; Curiel, Tyler ; Valente, Philip T. ; Vadlamudi, Ratna K. ; Ebrahimi, Behnam ; Li, Xiaonan ; Viswanadhapalli, Suryavathi ; Gopalam, Rahul ; Pratap, Uday P.

AbstractIntroduction: Of all gynecologic cancers, epithelial ovarian cancer (OCa) stands out with the highest mortality rates. Despite all efforts, 90% of individuals who receive standard surgical and cytotoxic therapy experience disease recurrence. The potential involvement of leukemia inhibitory factor (LIF) and its receptor (LIFR) in the progression of OCa is still obscure. In this study, we examined the mechanisms by which disruption of LIF/LIFR autocrine loops contributes to the cell death of ovarian cancer cells.Methods: The expression profiles of LIF and LIFR were obtained using 24 distinct OCa model cells, comprising both primary and established cell lines. The effects of EC359 on OCa cells were evaluated using reporter assays, colony formation, cell death, and cell viability. Flow cytometry was utilized to analyze lipid peroxidation. The Agilent Seahorse XF Pro Analyzer was used to calculate the extracellular acidification rate (ECAR) and oxygen consumption rate (OCR). Furthermore, flow cytometry was used for the preparation and analysis of lymphocytes. Mechanistic investigations were performed with RT-qPCR and RNA-seq analysis. The efficacy of the LIFR inhibitor EC359 as a targeted therapy was investigated using cell-based xenografts, syngeneic xenografts, patient-derived organoids (PDO), and patient-derived xenograft (PDX) models.Results: Analysis of cancer databases revealed that elevated expression of LIF or LIFR was associated with poor progression-free survival of OCa patients and a predictor of poor response to chemotherapy. Using 24 different primary and established OCa cell lines that represent four subtypes of epithelial OCa, we demonstrated that LIF/LIFR autocrine signaling is active in OCa. Moreover, treatment with EC359, a novel LIFR inhibitor, significantly reduced OCa cell viability and cell survival with an IC50 ranging from 5 to 50 nM. Furthermore, EC359 diminished the stemness of OCa cells. Mechanistic studies using RNA-seq and rescue experiments unveiled that EC359 primarily induced ferroptosis by suppressing the glutathione antioxidant defense system. Using multiple in vitro, ex vivo, and in vivo models including organoids, cell-based xenografts, patient-derived explants, and xenograft tumors, we demonstrated that EC359 dramatically reduced the growth and progression of OCa. Additionally, EC359 therapy considerably improved tumor immunogenicity by robust CD45+ leukocyte tumor infiltration and polarizing tumor-associated macrophages (TAMs) toward M1 phenotype while showing no impact on normal T-, B-, and other immune cells.Conclusions: Collectively, our findings indicate that the LIF/LIFR autocrine loop plays an essential role in OCa progression and that EC359 could be a promising therapeutic agent for OCa.Citation Format: Behnam Ebrahimi, Suryavathi Viswanadhapalli, Uday P. Pratap, Rahul Gopalam, Xue Yang, Prabhakar P. Venkata, Viktor Drel, Bindu Santhamma, Swapna Konda, Xiaonan Li, Alondra L. Rodriguez Sanchez, Hui Yan, Gangadhara R. Sareddy, Zhenming Xu, Brij B. Singh, Philip T. Valente, Yidong Chen, Zhao Lai, Manjeet Rao, Edward R. Kost, Tyler Curiel, Rajeshwar R. Tekmal, Hareesh B. Nair, Ratna K. Vadlamudi. Pharmacological inhibition of the LIF-LIFR autocrine loop reveals vulnerability of ovarian cancer to ferroptosis [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 5998.

22 Mar 2024·Cancer Research

Abstract 4688: EC359, A new therapeutic drug for the treatment of low grade serous ovarian cancer

Author: Ebrahimi, Behnam ; Lyons, Yasmin ; Nair, Hareesh B. ; Santhamma, Bindu ; Viswanadhapalli, Suryavathi ; Vadlamudi, Ratna K. ; Arnold, William Cole ; Kost, Edward R.

AbstractBackground: Ovarian cancer (OCa) is the deadliest of all gynecologic cancers in the United States. About 10% of all cases of serous ovarian cancer have the unusual histology named low-grade serous carcinomas (LGSOC), that has a distinct clinical behavior with a unique molecular landscape. LGSOC is characterized by a younger age at diagnosis, indolent progression, and chemotherapy resistance. BRAF and KRAS mutations occur in 33% and 35% of LGSOC cases, respectively. LGSOC is frequently detected when the malignancy is in advanced stage and LGSOC relapses in about 70% of patients with advanced disease. Therefore, new targeted therapies are required. Since LGSOC uniquely expresses mutations of either BRAF or KRAS, and because Leukemia Inhibitor Factor (LIF) expression is induced by oncogenes such as KRAS, we reason that the LIF/LIFR axis represents a unique target for treating LGSOC. The objective of this study is to test the utility of blocking LIF/LIFR axis using LIFR inhibitor EC359 in treating LGSOC.Methods: The expression of LIF and its receptor LIFR was profiled using multiple established LGSOC cells and primary LGSOC model cells. The effects of EC359 on LGSOC cells were evaluated using cell viability, colony formation, and apoptosis assays. Mechanistic investigations were conducted with Western blotting, reporter assays and RT-qPCR analysis. The in vivo efficacy of LIFR inhibitor EC359 as a targeted therapy was investigated using LGSOC cell-based xenografts.Results: Western blot analysis confirmed expression of LIFR and LIF in established LGSOC and primary LGSOC cells and functional autocrine loop of LIF/LIFR signaling. The treatment with the LIFR inhibitor EC359 significantly reduced LGSOC cell viability, cell survival, and increased apoptosis. The activation of downstream LIFR signaling including STAT3, mTOR, AKT, and p42/44 MAPKs markedly decreased by EC359 treatment. EC359 enhanced the efficacy of trametinib, a currently used medication of LGSOC. EC359+trametinib as a combination therapy showed more efficacy over monotherapy of EC359 or trametinib in reducing cell viability and colony formation. Using cell-based xenograft and PDX models, we demonstrated that the EC359 at 5mg/kg dose significantly reduced the LGSOC xenograft growth compared to the vehicle control.Conclusions: Together, our findings support the existence of LIF/LIFR autocrine loops, and EC359 is a viable treatment option for LGSOC.Citation Format: Yasmin Lyons, William Cole Arnold, Behnam Ebrahimi, Bindu Santhamma, Edward R. Kost, Hareesh B. Nair, Suryavathi Viswanadhapalli, Ratna K. Vadlamudi. EC359, A new therapeutic drug for the treatment of low grade serous ovarian 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 4688.

22 Mar 2024·Cancer Research

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

Author: Romo, Bianca ; Viswanadhapalli, Suryavathi ; Randolph, Lois ; Fuentes, Zenaida ; Vadlamudi, Ratna ; 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.

100 Deals associated with Evestra, Inc.

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Drug(Targets)	Indications	Global Highest Phase

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

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