FOXL2

Researchers have shed light on the proteins controlling the development of ovaries in mice before and after birth. This could lead to a better understanding of how female infertility develops. Researchers at the Francis Crick Institute have shed light on the proteins controlling the development of ovaries in mice before and after birth. This could lead to a better understanding of how female infertility develops. Following their research identifying the gene responsible for initiating the development of ovaries in the mouse embryo, the scientists aimed to understand which genes maintain the functions of the ovaries, including producing eggs, after birth. Previous experiments have shown that removing a gene called Foxl2 in female (XX) mice at different points in development has different effects depending on the timing. If removed from embryos, ovaries become abnormal and the adult mice are infertile. If removed from adult mice, their ovaries begin to resemble testes1. In research published today in Science Advances, the team found that, while FOXL2 does play a role during embryonic development, it has the most impact after birth, where the protein regulates the activity of many more genes, including some involved in functions critical for the ovary such as egg development. FOXL2 is a type of protein that physically sits on top of specific regions in DNA ('enhancers') and influences whether and how other (target) genes are read. The researchers used a technique called chromatin proteomics to 'fish out' all of the other proteins that interact with FOXL2 when it is bound to DNA. They found that the number of protein interactions drastically increased in ovaries after birth compared to during embryonic development. Among many others, they identified a protein called USP7, which binds to FOXL2 when it interacts with its DNA targets. Until now, researchers weren't aware of USP7 and FOXL2 interaction or what role USP7 was playing in ovary development. When the researchers removed the Usp7 gene from female mice, they found that the mice couldn't develop ovaries beyond puberty, so were infertile. The team believe USP7 might be needed to stabilise FOXL2 on top of DNA. FOXL2 and USP7 share some common roles in humans. People lacking one copy of the FOXL2 gene can start making eggs but don't develop full ovaries, so have problems with fertility. USP7 mutations can also lead to infertility in people, as well as neurodevelopmental disorders. Genetic testing is key to diagnose problems with sexual development, so researchers hope to find the major genetic causes of infertility and consider how gene editing techniques could help with future treatments. Robin Lovell-Badge, Group Leader of the Stem Cell Biology and Developmental Genetics Laboratory at the Crick, said: "In our research, we've come closer to answers for two major questions regarding development -- what drives ovary development, and how the function of the ovary is maintained. We've found that FOXL2 has very different roles throughout development, and identified another crucial protein, USP7. "The genetic factors underlying female development haven't been as well studied as male development, because many female developmental pathways happen at the same time rather than in an easy-to-follow sequence. Infertility is a big problem worldwide, so shedding light on the key genes and proteins responsible at each stage is vital." Roberta Migale, Postdoctoral Fellow at the Crick and first and co-senior author on the study, said: "This is the first time we've been able to use these approaches to see the interactions that FOXL2, a factor critical for female fertility, establishes with other proteins whilst they are bound to DNA in mouse ovaries. Factors that actively bind to the DNA are more likely to have an impact on the regulation of genes important for the development and function of the ovary. We've identified USP7 through this method and the hope is that many more proteins responsible for ovary development can be found using our approach." A Crick-wide effort, Robin and Roberta worked with several specialist teams, including the Genetic Modification Service, Bioinformatics and Biostatistics, Proteomics, Flow Cytometry, Experimental Histopathology, Light Microscopy, and the Biological Research Facility. The researchers will continue to study the role of the USP7 protein in sexual development.

STAMFORD, Conn., May 30, 2023 (GLOBE NEWSWIRE) -- SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, today announced that it has achieved full enrollment in its Phase 2 trial evaluating nirogacestat, an investigational gamma secretase inhibitor, as a monotherapy in patients with recurrent ovarian granulosa cell tumors (OvGCT). SpringWorks expects to report initial data from the trial in 2024. OvGCT account for approximately 5% of all ovarian cancers and are the most common subtype of ovarian sex cord tumors, representing 70% of all cases. Nearly all OvGCT harbor a mutation in the FOXL2 gene and preclinical studies have demonstrated that OvGCT cell lines are susceptible to gamma secretase inhibition.1,2 “While early-stage OvGCT can be managed with surgery, nearly half of patients experience post-surgical recurrence, and once these tumors recur, there are limited treatment options and no FDA-approved therapies,” said Saqib Islam, Chief Executive Officer of SpringWorks. “We are very pleased to have fully enrolled this trial well ahead of our projections, which we believe is a testament to the high unmet need that remains for patients living with OvGCT who are in need of a rational, targeted, oral therapy to treat their tumors. We look forward to continuing to work closely with our investigators and to reporting initial data from this study next year.” The Phase 2 trial (NCT05348356) is a multi-center, single-arm, open-label study evaluating the efficacy, tolerability, safety, and pharmacokinetics of nirogacestat in recurrent OvGCT. The target enrollment for the study was approximately 40 participants, with people receiving 150mg of nirogacestat twice daily. The study enrolled participants with recurrent OvGCT who had received one or more prior lines of systemic therapy. The primary endpoint of the trial is objective response rate as measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Secondary endpoints include progression-free survival, overall survival, duration of response, safety and tolerability, and quality of life assessments. About Ovarian Granulosa Cell Tumors Ovarian granulosa cell tumors (OvGCT) are a rare ovarian cancer subtype that are usually slow-growing tumors. OvGCT account for approximately 5% of all ovarian cancers and are the most common subtype of ovarian sex cord stromal tumors. At the time of diagnosis, patients typically present with severe abdominal pain, abdominal distension, and abnormal or postmenopausal bleeding alongside a large pelvic or abdominal mass.3 OvGCT are most commonly diagnosed in women during the perimenopausal/early postmenopausal period with a median age of diagnosis of 50 years.3 It is estimated that there are 1,500 to 2,000 new cases diagnosed per year in the U.S., and an estimated prevalence of approximately 10,000-15,000 patients with OvGCT in the U.S.4,5 Prognosis for patients with advanced disease is poor, with a 10-year survival rate of approximately 25%.6 There are currently no FDA-approved therapies for patients with OvGCT. While early-stage disease can be managed with surgery, approximately 45% of patients experience post-surgical recurrence,7 and once these tumors recur, those with advanced disease often receive off-label systemic therapy, including chemotherapy. About Nirogacestat Nirogacestat is an oral, selective, small molecule gamma secretase inhibitor in Phase 3 clinical development for desmoid tumors. SpringWorks is also evaluating nirogacestat as a potential treatment for patients with ovarian granulosa cell tumors and for patients with multiple myeloma as part of several B-cell maturation agent (BCMA) combination therapy regimens in collaboration with leaders in industry and academia. Nirogacestat is an investigational drug for which safety and efficacy have not been established. The U.S. Food and Drug Administration (FDA) has accepted the New Drug Application (NDA) for nirogacestat for the treatment of adults with desmoid tumors, which is being reviewed under the FDA's Real-Time Oncology Review program. The NDA was granted Priority Review designation and has been given a Prescription Drug User Fee Act (PDUFA) action date of August 27, 2023. The FDA also granted Fast Track and Breakthrough Therapy Designations to nirogacestat for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis. In addition, nirogacestat has received Orphan Drug Designation from the FDA for the treatment of desmoid tumors and from the European Commission for the treatment of soft tissue sarcoma. Gamma secretase cleaves multiple transmembrane protein complexes, including Notch, which is believed to play a role in activating pathways that contribute to growth of desmoid and ovarian granulosa cell tumors. Gamma secretase has also been shown to directly cleave membrane-bound BCMA, resulting in the release of the BCMA extracellular domain (ECD) from the cell surface. By inhibiting gamma secretase, membrane-bound BCMA can be preserved, increasing target density while reducing levels of soluble BCMA ECD, which may serve as decoy receptors for BCMA-directed therapies. Nirogacestat’s ability to enhance the activity of BCMA-directed therapies has been observed in preclinical models of multiple myeloma. SpringWorks is evaluating nirogacestat as a BCMA potentiator and has several collaborations with industry-leading BCMA developers to evaluate nirogacestat in combinations across modalities. SpringWorks has also formed research collaborations with Fred Hutchinson Cancer Research Center and Dana-Farber Cancer Institute to further characterize the ability of nirogacestat to modulate BCMA and potentiate BCMA-directed therapies using a variety of preclinical multiple myeloma models. About SpringWorks Therapeutics SpringWorks is a clinical-stage biopharmaceutical company applying a precision medicine approach to acquiring, developing and commercializing life-changing medicines for patients living with severe rare diseases and cancer. SpringWorks has a differentiated targeted oncology pipeline spanning solid tumors and hematological cancers, including two late-stage clinical trials in rare tumor types as well as several programs addressing highly prevalent, genetically defined cancers. SpringWorks’ strategic approach and operational excellence in clinical development have enabled it to rapidly advance its two lead product candidates into late-stage clinical trials while simultaneously entering into multiple shared-value partnerships with innovators in industry and academia to unlock the full potential for its portfolio and create more solutions for patients with cancer. For more information, visit and follow @SpringWorksTx on Twitter and LinkedIn. SpringWorks Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, relating to our business, operations, and financial conditions, including, but not limited to, current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, our development plans, our preclinical and clinical results, as well as relating to other future conditions. Words such as, but not limited to, “look forward to,” “believe,” “expect,” “anticipate,” “estimate,” “intend,” “plan,” “would,” “should” and “could,” and similar expressions or words, identify forward-looking statements. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks relating to: (i) the success and timing of our product development activities, including the initiation and completion of SpringWorks’ clinical trials, (ii) the fact that topline or interim data from a clinical study may not be predictive of the final or more detailed results of such study, or the results of other ongoing or future studies, (iii) the success and timing of our collaboration partners’ ongoing and planned clinical trials, (iv) the timing of our planned regulatory submissions and interactions, including the timing and outcome of decisions made by the U.S. Food and Drug Administration (FDA) and other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies; (v) whether FDA or other regulatory authorities will require additional information or further studies, or may fail or refuse to approve or may delay approval of our drug candidates, (vi) our ability to obtain and maintain regulatory approval of any of our product candidates, (vii) our plans to research, discover and develop additional product candidates, (viii) our ability to maintain adequate patent protection and successfully enforce patent claims against third parties, (ix) our ability to enter into collaborations for the development of new product candidates, (x) our ability to establish manufacturing capabilities, and our and our collaboration partners’ abilities to manufacture our product candidates and scale production, (xi) our ability to meet any specific milestones set forth herein, and (xii) uncertainties and assumptions regarding the impact of the COVID-19 pandemic on SpringWorks’ business, operations, clinical trials, supply chain, strategy, goals and anticipated timelines. Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. Although we believe the expectations reflected in such forward-looking statements are reasonable, we can give no assurance that such expectations will prove to be correct. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. For further information regarding the risks, uncertainties and other factors that may cause differences between SpringWorks’ expectations and actual results, you should review the “Risk Factors” in Item 1A of Part II of SpringWorks’ Quarterly Report on Form 10-Q for the quarter ended March 31, 2023, as well as discussions of potential risks, uncertainties and other important factors in SpringWorks’ subsequent filings. Contacts: Kim Diamond Vice President, Communications and Investor Relations Phone: 203-561-1646 Email: kdiamond@springworkstx.com Samantha Hilson Sandler Senior Director, Investor Relations Phone: 203-461-5501 Email: samantha.sandler@springworkstx.com References 1 Shah SP, Kobel M, Senz J, et al. Mutation of FOXL2 in granulosa-cell tumors of the ovary. N Engl J Med. 2009;360(26):2719–29. doi: 10.1056/NEJMoa0902542. 2 Irusta G, Pazos MC, Abramovich D, De Zúñiga I, Parborell F, Tesone M. Effects of an inhibitor of the γ-secretase complex on proliferation and apoptotic parameters in a FOXL2-mutated granulosa tumor cell line (KGN). Biol Reprod. 2013;89(1):9. doi: 10.1095/biolreprod.113.108100. 3 Dridi M, Chraiet N, Batti R, et al. Granulosa cell tumor of the ovary: A retrospective study of 31 cases and a review of the literature. IntJ Surg Oncol. 2018:1-4. doi:10.1155/2018/4547892. 4 Torre LA, Trabert B, Desantis CE, et al. Ovarian Cancer Statistics, 2018. CA Cancer J Clin. 2018; 68(4): 284–296. doi:10.3322/caac.21456. 5 National Cancer Institute. Cancer of the ovary - cancer stat facts. SEER. Accessed May 2023. 6 Schumer ST, Cannistra SA. Granulosa cell tumor of the ovary. J. Clin Oncol. 2003;21 (6):1180-9. doi: 10.1200/JCO.2003.10.019. 7 Klar M, Plett H, Harter P, et al. Treatment and survival of patients with malignant ovarian sex cord–stromal cell tumours: An analysis of the Arbeitsgemeinschaft für Gynäkologische Onkologie (AGO) study group CORSETT database. J Surg Oncol. 2023; 1-8. doi: 10.1002/jso.27248.

STAMFORD, Conn., Sept. 29, 2022 (GLOBE NEWSWIRE) -- SpringWorks Therapeutics, Inc. (Nasdaq: SWTX), a clinical-stage biopharmaceutical company focused on developing life-changing medicines for patients with severe rare diseases and cancer, today announced that the first patient has been dosed in a Phase 2 trial evaluating nirogacestat, SpringWorks’ investigational gamma secretase inhibitor, as a monotherapy in patients with recurrent ovarian granulosa cell tumors. Ovarian granulosa cell tumors account for approximately 5% of all ovarian cancers and are the most common subtype of ovarian sex cord tumors, representing 70% of all cases. Nearly all ovarian granulosa cell tumors harbor a mutation in the FOXL2 gene and preclinical studies have demonstrated that ovarian granulosa cell tumor cell lines are susceptible to gamma secretase inhibition.1,2 “The science behind this study is exciting because Notch signaling, a key target of gamma secretase inhibitors, is involved in the expression of FOXL2, which is an integral component of granulosa cell development, proliferation, and function,” said Panos Konstantinopoulos, M.D., Ph.D., Director of Gynecological Oncology Translational Research at Dana-Farber Cancer Center and Harvard Medical School and the Principal Investigator of the Phase 2 trial. “Without any FDA-approved therapies, there is a high unmet need for patients with recurrent ovarian granulosa cell tumors and I look forward to evaluating nirogacestat in this important study.” “Over the course of their disease, patients with ovarian granulosa cell tumors may experience severe abdominal pain associated with a large pelvic or abdominal mass, requiring surgery and subsequent systemic therapy,” said Saqib Islam, Chief Executive Officer of SpringWorks. “We are pleased to be developing a much-needed therapy for these patients and are encouraged by this new, meaningful opportunity for nirogacestat.” The Phase 2 trial (NCT05348356) is a multi-center, single-arm, open-label study evaluating the efficacy, tolerability, safety, and pharmacokinetics of nirogacestat in patients with recurrent ovarian granulosa cell tumors. The study will enroll approximately 40 patients who will receive 150mg of nirogacestat twice daily. Eligible patients will have recurrent ovarian granulosa cell tumors and will have received one or more prior lines of systemic therapy. The primary endpoint of the trial is objective response rate as measured by Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Secondary endpoints include progression-free survival, overall survival, duration of response, safety and tolerability, and quality of life assessments. About Ovarian Granulosa Cell Tumors Ovarian granulosa cell tumors (OvGCT) are a rare ovarian cancer subtype that are usually slow-growing tumors. OvGCT account for approximately 5% of all ovarian cancers and are the most common subtype of ovarian sex cord stromal tumors. At the time of diagnosis, patients typically present with severe abdominal pain, abdominal distension, and abnormal or postmenopausal bleeding alongside a large pelvic or abdominal mass.3 OvGCT are most commonly diagnosed in women during the perimenopausal/early postmenopausal period with a median age of diagnosis of 50 years.3 It is estimated that there are 1,500 to 2,000 new cases diagnosed per year in the U.S., and an estimated prevalence of approximately 10,000-15,000 patients with OvGCT in the U.S.4,5 Prognosis for patients with advanced disease is poor, with a 10-year survival rate of approximately 25%.6 There are currently no FDA-approved therapies for patients with OvGCT. Surgery is currently the mainstay of initial treatment, however, the risk of recurrence is high for those with advanced disease and off-label systemic therapy, including chemotherapy, is often used. About Nirogacestat Nirogacestat is an investigational, oral, selective, small molecule gamma secretase inhibitor in Phase 3 clinical development for desmoid tumors and in Phase 2 clinical development for ovarian granulosa cell tumors. Gamma secretase cleaves multiple transmembrane protein complexes, including Notch, which is believed to play a role in activating pathways that contribute to growth of desmoid and ovarian granulosa cell tumors. In addition, gamma secretase has been shown to directly cleave membrane-bound B cell maturation antigen (BCMA), resulting in the release of the BCMA extracellular domain (ECD) from the cell surface. By inhibiting gamma secretase, membrane-bound BCMA can be preserved, increasing target density while reducing levels of soluble BCMA ECD, which may serve as decoy receptors for BCMA-directed therapies. Nirogacestat’s ability to enhance the activity of BCMA-directed therapies has been observed in preclinical models of multiple myeloma. SpringWorks is evaluating nirogacestat as a BCMA potentiator and has eight collaborations with industry-leading BCMA developers to evaluate nirogacestat in combinations across modalities, including with an antibody-drug conjugate, two CAR T cell therapies, three bispecific antibodies and a monoclonal antibody. SpringWorks has also formed research collaborations with Fred Hutchinson Cancer Research Center and Dana-Farber Cancer Institute to further characterize the ability of nirogacestat to modulate BCMA and potentiate BCMA-directed therapies using a variety of preclinical multiple myeloma models. Nirogacestat has received Orphan Drug Designation from the U.S. Food and Drug Administration (FDA) for the treatment of desmoid tumors and from the European Commission for the treatment of soft tissue sarcoma. The FDA also granted Fast Track and Breakthrough Therapy Designations for the treatment of adult patients with progressive, unresectable, recurrent or refractory desmoid tumors or deep fibromatosis. SpringWorks plans to submit a New Drug Application (NDA) to the FDA in the second half of 2022, which will be submitted for review under the FDA’s Real-Time Oncology Review (RTOR) program. About SpringWorks Therapeutics SpringWorks is a clinical-stage biopharmaceutical company applying a precision medicine approach to acquiring, developing and commercializing life-changing medicines for patients living with severe rare diseases and cancer. SpringWorks has a differentiated targeted oncology pipeline spanning solid tumors and hematological cancers, including two potentially registrational clinical trials in rare tumor types as well as several programs addressing highly prevalent, genetically defined cancers. SpringWorks’ strategic approach and operational excellence in clinical development have enabled it to rapidly advance its two lead product candidates into late-stage clinical trials while simultaneously entering into multiple shared-value partnerships with innovators in industry and academia to unlock the full potential for its portfolio and create more solutions for patients with cancer. For more information, visit and follow @SpringWorksTx on Twitter and LinkedIn. SpringWorks Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended, relating to our business, operations, and financial conditions, including, but not limited to, current beliefs, expectations and assumptions regarding the future of our business, future plans and strategies, our development plans, our preclinical and clinical results, the timing of our planned NDA submission for nirogacestat, and our plans for seeking regulatory approval for and making nirogacestat available to desmoid tumor patients, if approved, as well as relating to other future conditions. Words such as, but not limited to, “look forward to,” “believe,” “expect,” “anticipate,” “estimate,” “intend,” “plan,” “would,” “should” and “could,” and similar expressions or words, identify forward-looking statements. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. Any forward-looking statements in this press release are based on management’s current expectations and beliefs and are subject to a number of risks, uncertainties and important factors that may cause actual events or results to differ materially from those expressed or implied by any forward-looking statements contained in this press release, including, without limitation, risks relating to: (i) the success and timing of our product development activities, including the initiation and completion of SpringWorks’ clinical trials, (ii) the fact that topline or interim data from a clinical study may not be predictive of the final or more detailed results of such study, or the results of other ongoing or future studies, (iii) the success and timing of our collaboration partners’ ongoing and planned clinical trials, (iv) the timing of our planned regulatory submissions and interactions, including the NDA for nirogacestat planned for the second half of 2022 and the timing and outcome of decisions made by the U.S. Food and Drug Administration (FDA) and other regulatory authorities, investigational review boards at clinical trial sites and publication review bodies; (v) whether FDA or other regulatory authorities will require additional information or further studies, or may fail or refuse to approve or may delay approval of our drug candidates, including nirogacestat and mirdametinib, (vi) our ability to obtain and maintain regulatory approval of any of our product candidates, (vii) our plans to research, discover and develop additional product candidates, (viii) our ability to enter into collaborations for the development of new product candidates, (ix) our ability to establish manufacturing capabilities, and our and our collaboration partners’ abilities to manufacture our product candidates and scale production, (x) our ability to meet any specific milestones set forth herein, and (xi) uncertainties and assumptions regarding the impact of the COVID-19 pandemic on SpringWorks’ business, operations, clinical trials, supply chain, strategy, goals and anticipated timelines. Except as required by applicable law, we do not plan to publicly update or revise any forward-looking statements contained herein, whether as a result of any new information, future events, changed circumstances or otherwise. Although we believe the expectations reflected in such forward-looking statements are reasonable, we can give no assurance that such expectations will prove to be correct. Accordingly, readers are cautioned not to place undue reliance on these forward-looking statements. For further information regarding the risks, uncertainties and other factors that may cause differences between SpringWorks’ expectations and actual results, you should review the “Risk Factors” in Item 1A of Part I of SpringWorks’ Quarterly Report on Form 10-Q for the quarter ended June 30, 2022, as well as discussions of potential risks, uncertainties and other important factors in SpringWorks’ subsequent filings. Contacts: Kim Diamond Vice President, Communications and Investor Relations Phone: 203-561-1646 Email: kdiamond@springworkstx.com Samantha Hilson Sandler Director, Investor Relations Phone: 203-461-5501 Email: samantha.sandler@springworkstx.com References 1 Shah SP, Kobel M, Senz J, et al. Mutation of FOXL2 in granulosa-cell tumors of the ovary. N Engl J Med. 2009;360(26):2719–29. doi:10.1056/NEJMoa0902542. 2 Irusta G, Pazos MC, Abramovich D, De Zúñiga I, Parborell F, Tesone M. Effects of an inhibitor of the γ-secretase complex on proliferation and apoptotic parameters in a FOXL2-mutated granulosa tumor cell line (KGN). Biol Reprod. 2013;89(1):9. doi:10.1095/biolreprod.113.108100. 3 Dridi M, Chraiet N, Batti R, et al. Granulosa cell tumor of the ovary: A retrospective study of 31 cases and a review of the literature. IntJ Surg Oncol. 2018:1-4. doi:10.1155/2018/4547892. 4 Torre LA, Trabert B, Desantis CE, et al. Ovarian Cancer Statistics, 2018. CA Cancer J Clin. 2018; 68(4): 284–296. doi:10.3322/caac.21456. 5 National Cancer Institute. Cancer of the ovary - cancer stat facts. SEER. Accessed September 2022. 6 Schumer ST, Cannistra SA. Granulosa cell tumor of the ovary. J. Clin Oncol. 2003;21 (6):1180-9. doi:10.1200/JCO.2003.10.019.