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      Evaluation of Hedgehog Pathway Inhibitors as a Therapeutic Option for Uterine Leiomyosarcoma Using the Xenograft Model

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          Abstract

          Uterine leiomyosarcoma (LMS) contributes to a significant proportion of uterine cancer deaths. It is a rare and high-risk gynecological cancer. LMS is challenging to the treatment due to the resistance of several therapies. The activation of the Hedgehog (HH) pathway has been reported in several types of female cancers. Uterine LMS presents an upregulation of the crucial HH signaling pathway members such as SMO and GLI1. Although targeting the HH pathway exhibited a potent inhibitory effect on the phenotype of uterine LMS in vitro, the effect of the HH inhibitors on LMS growth in vivo has not been identified. The present study aimed to assess the effect of Hedgehog pathway inhibitors (SMO-LDE225 and GLI-Gant61) as a therapeutic option in the xenograft model of uterine LMS. The results demonstrated that LDE225 treatment did not show any inhibitory effect on LMS tumor growth; however, treatment with GLI inhibitor (Gant61) induced a remarkable tumor regression with a significant decrease in Ki67 expression, compared to control ( p < 0.01). Moreover, administration of Gant61 decreased the expression of GLI1, GLI target genes BMP4 and c-MYC ( p < 0.05), indicating that the HH pathway is implicated in the LMS experimental model. In conclusion, our studies demonstrate for the first time that GLI inhibitor (Gant61), but not SMO inhibitor (LDE225), shows a potent inhibitory effect on LMS tumor growth and concomitantly suppresses the expression of GLI1- and GLI-targeted genes using the xenograft model of uterine LMS.

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          Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial.

          Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. We investigated the effect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy. This phase 3 study was done in 72 institutions, across 13 countries. Patients with angiogenesis inhibitor-naive, metastatic soft-tissue sarcoma, progressing despite previous standard chemotherapy, were randomly assigned by an interactive voice randomisation system in a 2:1 ratio in permuted blocks (with block sizes of six) to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Patients, investigators who gave the treatment, those assessing outcomes, and those who did the analysis were masked to the allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00753688. 372 patients were registered and 369 were randomly assigned to receive pazopanib (n=246) or placebo (n=123). Median progression-free survival was 4·6 months (95% CI 3·7-4·8) for pazopanib compared with 1·6 months (0·9-1·8) for placebo (hazard ratio [HR] 0·31, 95% CI 0·24-0·40; p<0·0001). Overall survival was 12·5 months (10·6-14·8) with pazopanib versus 10·7 months (8·7-12·8) with placebo (HR 0·86, 0·67-1·11; p=0·25). The most common adverse events were fatigue (60 in the placebo group [49%] vs 155 in the pazopanib group [65%]), diarrhoea (20 [16%] vs 138 [58%]), nausea (34 [28%] vs 129 [54%]), weight loss (25 [20%] vs 115 [48%]), and hypertension (8 [7%] vs 99 [41%]). The median relative dose intensity was 100% for placebo and 96% for pazopanib. Pazopanib is a new treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma after previous chemotherapy. GlaxoSmithKline. Copyright © 2012 Elsevier Ltd. All rights reserved.
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            The mechanisms of Hedgehog signalling and its roles in development and disease.

            The cloning of the founding member of the Hedgehog (HH) family of secreted proteins two decades ago inaugurated a field that has diversified to encompass embryonic development, stem cell biology and tissue homeostasis. Interest in HH signalling increased when the pathway was implicated in several cancers and congenital syndromes. The mechanism of HH signalling is complex and remains incompletely understood. Nevertheless, studies have revealed novel biological insights into this system, including the function of HH lipidation in the secretion and transport of this ligand and details of the signal transduction pathway, which involves Patched 1, Smoothened and GLI proteins (Cubitus interruptus in Drosophila melanogaster), as well as, in vertebrates, primary cilia.
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              Uterine sarcomas: a review.

              Uterine sarcomas are rare tumors that account for 3% of uterine cancers. Their histopathologic classification was revised by the World Health Organization (WHO) in 2003. A new staging system has been recently designed by the International Federation of Gynecology and Obstetrics (FIGO). Currently, there is no consensus on risk factors for adverse outcome. This review summarizes the available clinicopathological data on uterine sarcomas classified by the WHO diagnostic criteria. Medline was searched between 1976 and 2009 for all publications in English where the studied population included women diagnosed of uterine sarcomas. Since carcinosarcomas (malignant mixed mesodermal tumors or MMMT) are currently classified as metaplastic carcinomas, leiomyosarcomas remain the most common uterine sarcomas. Exclusion of several histologic variants of leiomyoma, as well as "smooth muscle tumors of uncertain malignant potential," frequently misdiagnosed as sarcomas, has made apparent that leiomyosarcomas are associated with poor prognosis even when seemingly confined to the uterus. Endometrial stromal sarcomas are indolent tumors associated with long-term survival. Undifferentiated endometrial sarcomas exhibiting nuclear pleomorphism behave more aggressively than tumors showing nuclear uniformity. Adenosarcomas have a favorable prognosis except for tumors showing myometrial invasion or sarcomatous overgrowth. Adenofibromas may represent well-differentiated adenosarcomas. The prognosis of carcinosarcomas (which are considered here in a post-script fashion) is usually worse than that of grade 3 endometrial carcinomas. Immunohistochemical expression of Ki67, p53, and p16 is significantly higher in leiomyosarcomas and undifferentiated endometrial sarcomas than in endometrial stromal sarcomas. Evaluation of H&E stained sections has been equivocal in the prediction of behavior of uterine sarcomas. Immunohistochemical studies of oncoproteins as well as molecular analysis of non-random translocations will undoubtedly lead to an accurate and prognostically relevant classification of these rare tumors.
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                Author and article information

                Contributors
                yangq@bsd.uchicago.edu
                Journal
                Reprod Sci
                Reprod Sci
                Reproductive Sciences
                Springer International Publishing (Cham )
                1933-7191
                1933-7205
                12 October 2021
                12 October 2021
                March 2022
                : 29
                : 3
                : 781-790
                Affiliations
                [1 ]GRID grid.185648.6, ISNI 0000 0001 2175 0319, Department of Surgery, , University of Illinois at Chicago, ; Chicago, IL USA
                [2 ]GRID grid.411074.7, ISNI 0000 0001 2297 2036, Laboratório de Ginecologia Estrutural e Molecular - LIM 58, Disciplina de Ginecologia, , Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo, HCFMUSP, ; Sao Paulo, Brazil
                [3 ]GRID grid.185648.6, ISNI 0000 0001 2175 0319, Department of Pathology, , University of Illinois at Chicago, ; Chicago, IL USA
                [4 ]GRID grid.7269.a, ISNI 0000 0004 0621 1570, Clinical Pharmacy Department, , Faculty of Pharmacy, Ain Shams University, ; Cairo, Egypt
                [5 ]GRID grid.170205.1, ISNI 0000 0004 1936 7822, Department of Obstetrics and Gynecology, , University of Chicago, ; Chicago, IL USA
                Article
                731
                10.1007/s43032-021-00731-y
                8863774
                34642915
                722c8da3-d638-4f77-903e-208308ff68c5
                © The Author(s) 2021

                Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001807, Fundação de Amparo à Pesquisa do Estado de São Paulo;
                Award ID: FAPESP 2017/24448-1
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;
                Award ID: RO1 HD094378
                Award ID: RO1 ES028615
                Award ID: U54 MD007602
                Award Recipient :
                Funded by: National Institutes of Health (US)
                Award ID: RO1HD094380
                Award Recipient :
                Categories
                Gynecologic Oncology: Original Article
                Custom metadata
                © Society for Reproductive Investigation 2022

                uterine leiomyosarcoma,hedgehog signaling,smo inhibitor,gli inhibitor

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