Integrative transcriptomics analysis for uterine leiomyosarcoma identifies aberrant activation of cell cycle-dependent kinases and their potential therapeutic significance.

Purpose: Uterine leiomyosarcoma is among the most aggressive gynecological malignancies. No effective treatment strategies have been established. This study aimed to identify novel therapeutic targets for uterine leiomyosarcoma based on transcriptome analysis and assess the preclinical efficacy of novel drug candidates. Experimental Design: Transcriptome analysis was carried out using fresh-frozen samples of six uterine leiomyosarcomas and three myomas. The Ingenuity Pathway Analysis was then used to identify potential therapeutic target genes for uterine leiomyosarcoma. Moreover, our results were validated using three independent datasets, including 40 uterine leiomyosarcomas. Then, the inhibitory effects of several selective inhibitors for the candidate genes were examined using the SK-UT-1, SK-LMS-1, and SKN cell lines. Results: We identified 512 considerably dysregulated genes in uterine leiomyosarcoma compared with myoma. The Ingenuity Pathway Analysis showed that the function of several genes, including CHEK1 and PLK1, were predicted to be activated in uterine leiomyosarcoma. Through an in vitro drug screening, PLK1 or CHEK1 inhibitors (BI 2536 or prexasertib) were found to exert a superior anti-cancer effect against cell lines at low nanomolar concentrations and induced cell cycle arrest. In SK-UT-1 tumor-bearing mice, BI 2536 monotherapy demonstrated a marked tumor regression. Moreover, the prexasertib and cisplatin combination therapy also reduced tumorigenicity and prolonged survival. Conclusion: We identified the upregulated expression of PLK1 and CHEK1; their kinase activity was considered to be activated in uterine leiomyosarcoma. BI 2536 and prexasertib demonstrate a significant anti-cancer effect; thus, cell cycle-related kinases may represent a promising therapeutic strategy for treating uterine leiomyosarcoma.

Tipping Growth Inhibition into Apoptosis by Combining Treatment with MDM2 and WIP1 Inhibitors in p53WT Uterine Leiomyosarcoma

As there is no optimal therapeutic strategy defined for women with advanced or recurrent uLMS, there is an urgent need for the discovery of novel, targeted approaches. One such area of interest is the pharmacological inhibition of the MDM2-p53 interaction with small-molecular-weight MDM2 inhibitors. Growth inhibition and cytotoxic assays were used to evaluate uLMS cell line responses to MDM2 inhibitors as single agents and in combination, qRT-PCR to assess transcriptional changes and Caspase-Glo 3/7 assay to detect apoptosis. RG7388 and HDM201 are potent, selective antagonists of the MDM2-p53 interaction that can effectively stabilise and activate p53 in a dose-dependent manner. GSK2830371, a potent and selective WIP1 phosphatase inhibitor, was shown to significantly potentiate the growth inhibitory effects of RG7388 and HDM201, and significantly increase the mRNA expression of p53 transcriptional target genes in a p53WT cell line at a concentration that has no growth inhibitory effects as a single agent. RG7388, HDM201 and GSK2830371 failed to induce apoptosis as single agents; however, a combination treatment tipped cells into apoptosis from senescence. These data present the possibility of MDM2 and WIP1 inhibitor combinations as a potential treatment option for p53WT uLMS patients that warrants further investigation.

Diagnostic Accuracy of Ultrasound in Differentiation Uterine Leiomyosarcoma from Uterine Leiomyoma: A Systematic Review

Background: Uterine leiomyosarcoma is a rare malignant pathology of smooth muscle of uterus which is mostly asymptomatic with a wide range of late onset of symptoms such as post-menopausal bleeding and severe abdominal pelvic pain and abnormal vaginal discharge. Uterine leiomyosarcoma characteristically has structural and clinical similarities with giant uterine leiomyoma because both originate from the smooth muscle cells of the uterus. The diagnosis of uterine leiomyosarcoma through ultrasound is very different difficult due to indistinguishable sonographic features of uterine leiomyoma and leiomyosarcoma but there are certain sonological features which can prove the reliability of ultrasound as the diagnostic tool for differentiating uterine leiomyosarcoma from uterine leiomyoma. Aim: To access the accuracy of ultrasound in differentiating uterine leiomyosarcoma from uterine leiomyoma. Methods: An electronic database search was performed (PubMed, Science direct, Google Scholar) with the data range from 2000 to 2021. All studies included in the research was in English language. Articles which had descriptive studies related to sonographic features of uterine leiomyosarcoma and uterine leiomyoma. Results: Total 15 articles were found regarding the prevalence, clinical manifestation and sonographic findings of uterine leiomyosarcoma and uterine leiomyoma ,10 articles were included in the introduction and technique where as 6 articles were selected for systemic review with the sample size ranging from 20-200 in all different articles and age criteria of the participant in the selected articles was above 40 years with most candidates were investigated in the post menopause period. Conclusion: We identified certain sonographic patterns that can accurately differentiate uterine leiomyoma sarcoma from uterine leiomyoma with moderate sensitivity and specificity. Keywords: Transvaginal ultrasonography, leiomyoma, leiomyosarcoma

Isolated metastasis of uterine leiomyosarcoma to the pancreas: clinical observation

The article presents a clinical case of successful surgical treatment of a patient with isolated metastasis of uterine leiomyosarcoma to the head of the pancreas 3 years after the removal of the primary tumor. A pancreatectomy with immunohistochemical examination was performed. The patient was examined 6 months after the operation. There are no signs of a relapse of the disease.