LIF/LIFR oncogenic signaling is a novel therapeutic target in endometrial cancer (original) (raw)
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European Journal of Obstetrics & Gynecology and Reproductive Biology, 2005
Objective: Leukaemia inhibitory factor (LIF) is a pleiotrophic cytokine, which might play an important role in human reproduction and endocrine-responsive tumours. Therefore, the aim of this study was to determine the frequency and tissue distribution of LIF in normal, hyperplastic and malignant endometrium. Study design: Paraffin-fixed endometrial tissue was obtained from normal premenopausal women (n = 15), endometrial hyperplasia (n = 20), endometroid adenocarcinoma (n = 32) and endometrial polyps (n = 9). The LIF expression was demonstrated by immunohistochemical means and evaluated with a semi-quantitative immunoreactive score. The Mann-Whitney U-test was used for statistical evaluation. Results: The lowest expression of LIF was observed in endometrial adenocarcinomas compared to all groups, while endometrial polyps expressed the highest LIF immunostaining. The expression in normal human glandular cells was significantly higher during the late secretory phase than in the proliferative phase. The highest expression of LIF was observed in endometrial polyps. Simple hyperplasia showed a significantly higher LIF expression than proliferative endometrium and adenocarcinoma. Adenomatous hyperplasia (AH) grade I-III had a significantly higher LIF expression than adenocarcinoma. The lowest expression of LIF was observed in adenocarcinoma, being statistically significant compared to all groups. Conclusion: LIF was immunohistochemically demonstrated in normal, hyperplastic and malignant endometrial tissue, suggesting a widespread but complex role for LIF in hyperplastic and malignant endometrial growth regulation. AH I-III also expressed LIF with statistically higher immunostaining than adenocarcinoma. Since AH III can be considered as a precursor of endometrial cancer, LIF could be a marker of cell transformation. #
Emerging therapeutic biomarkers in endometrial cancer
Although clinical trials of molecular therapies targeting critical biomarkers (mTOR, epidermal growth factor receptor/epidermal growth factor receptor 2, and vascular endothelial growth factor) in endometrial cancer show modest effects, there are still challenges that might remain regarding primary/acquired drug resistance and unexpected side effects on normal tissues. New studies that aim to target both genetic and epigenetic alterations (noncoding microRNA) underlying malignant properties of tumor cells and to specifically attack tumor cells using cell surface markers overexpressed in tumor tissue are emerging. More importantly, strategies that disrupt the cancer stem cell/epithelial-mesenchymal transition-dependent signals and reactivate antitumor immune responses would bring new hope for complete elimination of all cell compartments in endometrial cancer. We briefly review the current status of molecular therapies tested in clinical trials and mainly discuss the potential therapeutic candidates that are possibly used to develop more effective and specific therapies against endometrial cancer progression and metastasis.
Molecular therapy as a future strategy in endometrial cancer
Asian Pacific journal of cancer prevention : APJCP, 2013
Of all gynecologic cancers, endometrial cancer is the most common cancer in the US and Europe. In addition, it is presently the second most common gynecologic cancer in the world. As a result of increasing menopausal, obese and tamoxifen use women, the incidence of the cancer seems to be on the increase. Surgery is the major treatment, whereas postoperative radiation therapy in high-intermediate risk patients many prevent locoregional recurrence. Adjuvant chemotherapy can improve progression free survival in advanced or recurrent cancers. Molecular targeted therapies are now a focus of attention including anti-vascular endothelial growth factor (VEGF), mammalian target of rapamycin (mTOR) inhibitor and tyrosine kinase inhibitor (TKI). They may provide useful future strategies for control of endometrial malignancies in developing countries and across the world.
Molecular-targeted therapies and precision medicine for endometrial cancer
The overall survival rate of patients with early-stage endometrial cancer is relatively high; however , there are few treatment options for patients with advanced or recurrent endometrial cancer, and the prognosis of such patients remains poor. Recent progress in molecular-targeted therapies demonstrated that they have the potential to improve the long-term survival of cancer patients with appropriate biomarkers. However, the median progression-free survival of patients who received single-agent molecular-targeted therapy was <5 months, and the development of molecular-targeted therapies for endometrial cancer patients is urgently needed. This review highlights the previous efforts, including antiangiogenesis therapy, PI3K/AKT/mTOR pathway inhibitor treatment and epidermal growth factor receptor inhibitor treatment and reports on ongoing phase 2 clinical trials, including immune checkpoint inhibitor and PARP inhibitor. We also summarized the genetic background of endometrial cancer according to The Cancer Genome Atlas data and considered the theoretical background for future efforts to prolong the survival of patients with refractory endometrial cancer and for other interesting challenges.
Molecular Cancer Therapeutics, 2019
Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a critical role in cancer progression, metastasis, stem cell maintenance, and therapy resistance. Here, we describe a rationally designed first-in-class inhibitor of LIFR, EC359, which directly interacts with LIFR to effectively block LIF/LIFR interactions. EC359 treatment exhibits antiproliferative effects, reduces invasiveness and stemness, and promotes apoptosis in triple-negative breast cancer (TNBC) cell lines. The activity of EC359 is dependent on LIF and LIFR expression, and treatment with EC359 attenuated the activation of LIF/LIFR-driven pathways, including STAT3, mTOR, and AKT. Concomitantly, EC359 was also effective in blocking signaling by other LIFR ligands (CTF1, CNTF, and OSM) that interact at LIF/LIFR interface. EC359 significantly reduced tumor progression in TNBC xenografts and patient-derived xenografts (PDX), and reduced proliferation in patient-derived primary TNBC explants. EC359 exhibits distin...
Current status of molecular‑targeted drugs for endometrial cancer (Review)
Molecular and Clinical Oncology, 2013
Endometrial cancer is a common gynecological malignant tumor in Western countries and its incidence has also been on the increase in Asia. Genetic abnormalities related to onset and progression of malignancy in the endometrial membrane and signaling system have been identified and the developmental mechanism of endometrial cancer is becoming elucidated. The identification of the molecules related to these abnormalities has led to new potential treatment regimens for endometrial cancer, using molecular-targeted drugs. The current chemotherapy for endometrial cancer often causes systemic side effects that require discontinuation of the treatment. Furthermore, a treatment regimen for cancers of rare histological types has not been established. Recent studies on endometrial cancer revealed patterns of genetic disorders that differ among the histological types. Genetic and molecular information that underlie pathological changes and is associated with DNA mismatch repair genes and epigenetic regulation was also identified. Targeting of these mechanisms with molecular-targeted drugs has been performed with the aim of linking treatment to the carcinogenic mechanism at the molecular and genetic levels. However, the response rates with single-agent therapy are generally low and several problems remain unresolved. Trials of combinations of molecular-targeted drugs with currently available treatments and identification of factors determining sensitivity are required to overcome these difficulties.
Recent Advances in Endometrial Cancer
2020
Endometrial cancer is the most common gynecologic malignancy in the United States, with yearly rates continuing to increase. Most women present with early stage disease; however, advanced disease carries a grave prognosis. As a result, novel therapies are currently under investigation for the treatment of endometrial cancer. These advances include a better understanding of the genetic basis surrounding the development of endometrial cancer, novel surgical therapies, and new molecular targets for the treatment of this disease. This review explores the literature regarding these advancements in endometrial cancer.
Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells
British journal of cancer, 2008
In this study, we explore the therapeutic potential of lapatinib a selective inhibitor of both the EGFR and HER2 tyrosine kinases for the treatment of endometrial cancer. The effect of lapatinib on tumour cell growth and receptor activation was studied in a panel of human endometrial cancer cell lines. Candidate molecular markers predicting sensitivity were assessed by baseline gene expression profiling, ELISA, and western blot analyses. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions between chemotherapeutic drugs and lapatinib. Concentration-dependent anti-proliferative effects of lapatinib were seen in all endometrial cancer cell lines tested, but varied significantly between individual cell lines (IC(50) range: 0.052-10.9 micromol). HER2 overexpression or increased expression of EGFR was significantly associated with in vitro sensitivity (P=0.024 or 0.011, respectively). Lapatinib exerts growth inhibition in a PTEN-independent ...
Healthcare
Endometrial cancer (EC) is one of the most common gynecological malignancies in Western countries. Traditionally, loco-reginal dissemination and histological characteristics are the main prognostic factors. Nowadays, molecular and genomic profiling showed exciting results in terms of prognostication. According to the data provided by The Cancer Genome Atlas and other studies, molecular and genomic profiling might be useful in identifying patients al low, intermediate, and high risk of recurrence. However, data regarding the therapeutic value are scant. Several prospective studies are ongoing to identify the most appropriate adjuvant strategy in EC patients, especially for those with positive nodes and low volume disease. The molecular classification has offered the possibility to improve the risk stratification and management of EC. The aim of this review is to focus on the evolution of molecular classification in EC and its impact on the research approach and on clinical management...