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Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cases of endometrial cancer have increased in recent years, but the prognosis of patients with this disease has also been improved by combined modality therapy with surgery, radiotherapy and chemotherapy. However, the development of new therapy is required from the perspectives of conservation of fertility and efficacy for recurrent and intractable cancer. New candidate therapeutic agents for endometrial cancer include fourth-generation progestins for inhibition of growth and differentiation of endometrial glands; metformin for reduction of hTERT expression in the endometrium and inhibition of the mTOR pathway by activation of AMPK, with consequent inhibition of the cell cycle; mTOR inhibitors for supressing growth of cancer cells by G1 cell cycle arrest; microRNAs involved in the molecular mechanisms of oncogenesis and progression; and HDAC inhibitors that block the growth of cancer cells by transcriptional elevation of tumor-suppressor genes, cell cycle arrest and induction of apoptosis. In this study, we review the background and early clinical evidence for these agents as new therapeutic candidates for endometrial cancer.
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PMID:New candidate therapeutic agents for endometrial cancer: potential for clinical practice (review). 2329 63

Ten topics were chosen among major clinical research achievements in gynecologic oncology in 2012. For ovarian cancer, comprehensive review of the history of bevacizumab studies was followed by poly adenosine diphosphate [ADP]-ribose polymerase (PARP) inhibitors and other molecular targeted agents such as epidermal growth factor receptor tyrosine kinase inhibitor and AMG 386. For the development of genomic study in gynecologic cancers, BRCA and DICER1 mutations were covered in epithelial and nonepithelial ovarian cancer, respectively. For endometrial cancer, targeted agents including mammalian target of rapamycin (mTOR) inhibitors and bevacizumab were discussed. Radiation therapy "sandwiched" between combination chemotherapy schedules for the treatment of uterine papillary serous carcinoma was also reviewed. Preoperative prediction of lymph node metastasis, definition of low-risk group, and recurrence and survival outcomes of laparoscopic approaches were addressed. For cervical cancer, we reviewed long-term benefit of human papillomavirus test and efficacy of paclitaxel/carboplatin versus paclitaxel/cisplatin in stage IVB, persistent or recurrent disease. In addition, the effect of three dimensional image-based high-dose rate brachytherapy was also reviewed. For vulvar cancer, the diagnostic value of sentinel lymph node biopsy was discussed. For breast cancer, positive results of three outstanding phase III randomized clinical trials, CLEOPATRA, EMILIA, and BOLERO-2 were introduced. Lastly, updates of major practice guidelines were summarized.
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PMID:Major clinical research advances in gynecologic cancer in 2012. 2334 16

Endometrial cancer (EC) is the most commonly diagnosed gynecologic malignancy. Although early-stage EC is effectively treated surgically, commonly without adjuvant therapy, the treatment of high-risk and advanced disease is more complex. Chemotherapy has evolved into an important modality in high-risk early-stage and advanced-stage disease, and in recurrent EC. Multi-institutional trials are in progress to better define optimal adjuvant treatment for subsets of patients, as well as the role of surgical staging in reducing both overuse and underuse of radiation therapy. Understanding and identifying the molecular biology and genetics of EC are central to the development of novel therapies. A number of molecular and genetic events have been observed in ECs, which have enabled us to have a better understanding of the biology and development of the disease. For example, the PTEN/AKT pathway and its downstream targets and the mTOR pathway have been shown to play an important role in EC pathogenesis. This review summarizes the background of the known molecular alterations, and the management of patients with EC.
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PMID:Endometrial cancer: molecular and therapeutic aspects. 2343 42

Heightened mammalian target of rapamycin complex 1 (mTORC1) activity by genetic deletion of its direct inhibitor, Tsc1, is associated with aberrant development and dysfunction of the female reproductive tract in mice. Here, we compared the phenotypes of mice with conditional deletion of Tsc1 in the female reproductive tract by either progesterone receptor (PR)-Cre (Tsc1(PR(d/d))), which inactivates Tsc1 in all major cell types in the uterus (epithelium, stroma and myometrium), or anti-Mullerian hormone type 2 receptor (Amhr2)-Cre (Tsc1(Amhr2(d/d))), which inactivates stromal and myometrial Tsc1. Tsc1(PR(d/d)) and Tsc1(Amhr2(d/d)) females are infertile resulting from oviductal hyperplasia, retention of embryos in the oviduct and implantation failure. In contrast to the appropriate embryonic development after fertilization seen in Tsc1(Amhr2(d/d)) females, embryo development was disrupted in Tsc1(PR(d/d)) females. In addition, uteri in Tsc1(PR(d/d)) and Tsc1(Amhr2(d/d)) females showed epithelial hyperplasia but not endometrial cancer. In conclusion, Tsc1(PR(d/d)) and Tsc1(Amhr2(d/d)) have overlapping yet distinct phenotypes in the context of compartment-specific deletion of Tsc1.
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PMID:Conditional deletion of Tsc1 in the female reproductive tract impedes normal oviductal and uterine function by enhancing mTORC1 signaling in mice. 2347 84

Among female-specific cancers worldwide, endometrial cancer is the third most common after breast cancer and cervical cancer. In addition, it is the most common gynecological cancer in the USA and Europe. The incidence of this disease appears to be increasing. The cause of this increase is multifactorial, but a few possible factors involved are increasing obesity, an aging population leading to more postmenopausal women and greater tamoxifen use. Surgery is generally the primary treatment of this disease and postoperative radiation therapy in some patients with high or intermediate risk may prevent locoregional recurrences. Adjuvant chemotherapy improves progression-free survival in advanced or recurrent cancer. However, overall survival in patients with advanced disease is poor. Hence, better therapy is needed and targeted molecular therapies are emerging as possible treatment candidates. These include molecules that target VEGF, mTOR, tyrosine kinases, human EGF receptors and FGF receptors. Therapies targeting specific molecular features should be evaluated in future strategies in the treatment of endometrial cancer.
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PMID:Targeted endometrial cancer therapy as a future prospect. 2347 24

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.
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PMID:Emerging therapeutic biomarkers in endometrial cancer. 2381 13

Metformin, a drug from the biguanide class, is now one of the most widely used drugs in the treatment of type 2 diabetes. This drug was also used in the treatment of polycystic ovarian syndrome and recent reports indicate the possibility of using this drug in oncology. Latest findings show that metformin has an anticancer effect. Influencing the transduction mechanisms primarily through activation of protein kinase activated by 5'AMP (AMPK) regulates the activity of the AMPK/mTOR signaling pathway. MTOR pathway dysregulation may be a factor in the pathogenesis of various human diseases, especially cancers. Overactivation of mTOR is observed in malignant cells and is associated with their resistance to treatment. It can therefore be concluded that metformin as an inhibitor of mTOR may be a factor that suppresses tumor development. There are also studies showing that metformin prevents the formation of metastases, reducing tumor vasculature and improves the effectiveness of anticancer drugs. The anticancer effect of metformin has been proven in the treatment of colorectal and breast cancer. The current studies reports the positive effects in the treatment of gynecological cancers such as ovarian, endometrial and cervical cancer. Incidence for these tumors in 2009 in Poland was: for ovarian cancer 11.01100000; for endometrial cancer 15.0/100000; for cervical cancer 10.5/100000. Metformin has antitumor activity in monotherapy and also synergistically with other anticancer agents. Metformin has antiproliferative properties; reduces the VEGF levels, causing a reduction in tumor vasculature; causes an increase in progesterone receptor, which increases the response to hormonal therapy; inhibits the expression of glyoxalase I, mediating resistance to chemotherapy; decreases in the concentration of human telomerase; reduces the activity of Akt and Erk kinases, key regulators of metabolism and progression of tumors and also inhibits the formation of metastases.
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PMID:[Metformin--new treatment strategies for gynecologic neoplasms]. 2387 9

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.
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PMID:Molecular therapy as a future strategy in endometrial cancer. 2388 21

Endometrial cancer is the most commonly diagnosed gynecologic malignancy worldwide; yet the tumor microenvironment, especially the fibroblast cells surrounding the cancer cells, is poorly understood. We established four primary cultures of fibroblasts from human endometrial cancer tissues (cancer-associated fibroblasts, CAFs) using antibody-conjugated magnetic bead isolation. These relatively homogenous fibroblast cultures expressed fibroblast markers (CD90, vimentin and alpha-smooth muscle actin) and hormonal (estrogen and progesterone) receptors. Conditioned media collected from CAFs induced a dose-dependent proliferation of both primary cultures and cell lines of endometrial cancer in vitro (175%) when compared to non-treated cells, in contrast to those from normal endometrial fibroblast cell line (51%) (P<0.0001). These effects were not observed in fibroblast culture derived from benign endometrial hyperplasia tissues, indicating the specificity of CAFs in affecting endometrial cancer cell proliferation. To determine the mechanism underlying the differential fibroblast effects, we compared the activation of PI3K/Akt and MAPK/Erk pathways in endometrial cancer cells following treatment with normal fibroblasts- and CAFs-conditioned media. Western blot analysis showed that the expression of both phosphorylated forms of Akt and Erk were significantly down-regulated in normal fibroblasts-treated cells, but were up-regulated/maintained in CAFs-treated cells. Treatment with specific inhibitors LY294002 and U0126 reversed the CAFs-mediated cell proliferation (P<0.0001), suggesting for a role of these pathways in modulating endometrial cancer cell proliferation. Rapamycin, which targets a downstream molecule in PI3K pathway (mTOR), also suppressed CAFs-induced cell proliferation by inducing apoptosis. Cytokine profiling analysis revealed that CAFs secrete higher levels of macrophage chemoattractant protein (MCP)-1, interleukin (IL)-6, IL-8, RANTES and vascular endothelial growth factor (VEGF) than normal fibroblasts. Our data suggests that in contrast to normal fibroblasts, CAFs may exhibit a pro-tumorigenic effect in the progression of endometrial cancer, and PI3K/Akt and MAPK/Erk signaling may represent critical regulators in how endometrial cancer cells respond to their microenvironment.
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PMID:Cancer-associated fibroblasts promote proliferation of endometrial cancer cells. 2392 69

Metformin is an oral biguanide commonly used for the treatment of type II diabetes and has recently been demonstrated to possess antiproliferative properties that can be exploited for the prevention and treatment of a variety of cancers. The mechanisms underlying this effect have not been fully elucidated. Using both in vitro and in vivo models, we examined the effects of metformin on endometrial tumors with defined aberrations in the PI3K/PTEN/mTOR and MAPK signaling pathways to understand metformin mechanism of action and identify clinically useful predictors of response to this agent. In vitro assays of proliferation, cytotoxicity, and apoptosis were used to quantify the effects of metformin on endometrial cancer cell lines with mutations in the PI3K/PTEN/mTOR and MAPK signaling pathways. The in vivo effects of oral metformin on tumor progression were further examined using xenograft mouse models of endometrial cancer. K-Ras localization was analyzed by confocal microscopy using GFP-labeled oncogenic K-Ras and by immunoblot following subcellular fractionation. Metformin inhibited cell proliferation, induced apoptosis, and decreased tumor growth in preclinical endometrial cancer models, with the greatest response observed in cells harboring activating mutations in K-Ras. Furthermore, metformin displaces constitutively active K-Ras from the cell membrane, causing uncoupling of the MAPK signaling pathway. These studies provide a rationale for clinical trials using metformin in combination with PI3K-targeted agents for tumors harboring activating K-Ras mutations, and reveal a novel mechanism of action for metformin.
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PMID:Another surprise from Metformin: novel mechanism of action via K-Ras influences endometrial cancer response to therapy. 2407 15


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