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      New therapies for advanced, recurrent, and metastatic endometrial cancers

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          Abstract

          Endometrial cancer is the most common gynecologic malignancy in the United States, accounting for 6% of cancers in women. In 2017, an estimated 61,380 women were diagnosed with endometrial cancer, and approximately 11,000 died from this disease. From 1987 to 2008, there was a 50% increase in the incidence of endometrial cancer, with an approximate 300% increase in the number of associated deaths. Although there are many chemotherapeutic and targeted therapy agents approved for ovarian, fallopian tube and primary peritoneal cancers, since the 1971 approval of megestrol acetate for the palliative treatment of advanced endometrial cancer, only pembrolizumab has been Food and Drug Administration (FDA)-approved for high microsatellite instability (MSI-H) or mismatch repair deficient (dMMR) endometrial cancer; this highlights the need for new therapies to treat advanced, recurrent, metastatic endometrial cancer. In this review, we discuss current and emerging treatment options for endometrial cancer, including chemotherapy, targeted therapy, and immunotherapy. The National Cancer Institute (NCI) and others are now focusing their efforts on the design of scientifically rational targeted therapy and immunotherapy trials for specific molecular phenotypes of endometrial cancer. This is essential for the advancement of cancer care for women, which is threatened by a severe enrollment decline of approximately 80% for gynecologic oncology clinical trials.

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          Akt stimulates aerobic glycolysis in cancer cells.

          Cancer cells frequently display high rates of aerobic glycolysis in comparison to their nontransformed counterparts, although the molecular basis of this phenomenon remains poorly understood. Constitutive activity of the serine/threonine kinase Akt is a common perturbation observed in malignant cells. Surprisingly, although Akt activity is sufficient to promote leukemogenesis in nontransformed hematopoietic precursors and maintenance of Akt activity was required for rapid disease progression, the expression of activated Akt did not increase the proliferation of the premalignant or malignant cells in culture. However, Akt stimulated glucose consumption in transformed cells without affecting the rate of oxidative phosphorylation. High rates of aerobic glycolysis were also identified in human glioblastoma cells possessing but not those lacking constitutive Akt activity. Akt-expressing cells were more susceptible than control cells to death after glucose withdrawal. These data suggest that activation of the Akt oncogene is sufficient to stimulate the switch to aerobic glycolysis characteristic of cancer cells and that Akt activity renders cancer cells dependent on aerobic glycolysis for continued growth and survival.
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            Cancer as a metabolic disease

            Emerging evidence indicates that impaired cellular energy metabolism is the defining characteristic of nearly all cancers regardless of cellular or tissue origin. In contrast to normal cells, which derive most of their usable energy from oxidative phosphorylation, most cancer cells become heavily dependent on substrate level phosphorylation to meet energy demands. Evidence is reviewed supporting a general hypothesis that genomic instability and essentially all hallmarks of cancer, including aerobic glycolysis (Warburg effect), can be linked to impaired mitochondrial function and energy metabolism. A view of cancer as primarily a metabolic disease will impact approaches to cancer management and prevention.
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              Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women.

              The positive association between obesity and postmenopausal breast cancer has been attributed, in part, to the fact that estrogen, a risk factor for breast cancer, is synthesized in adipose tissue. Obesity is also associated with high levels of insulin, a known mitogen. However, no prospective studies have directly assessed associations between circulating levels of insulin and/or insulin-like growth factor (IGF)-I, a related hormone, and the risk of breast cancer independent of estrogen level. We conducted a case-cohort study of incident breast cancer among nondiabetic women who were enrolled in the Women's Health Initiative Observational Study (WHI-OS), a prospective cohort of 93,676 postmenopausal women. Fasting serum samples obtained at study entry from 835 incident breast cancer case subjects and from a subcohort of 816 randomly chosen WHI-OS subjects were tested for levels of insulin, glucose, total IGF-I, free IGF-I, insulin-like growth factor binding protein-3, and estradiol. Multivariable Cox proportional hazards models were used to estimate associations between levels of the serologic factors and baseline characteristics (including body mass index [BMI]) and the risk of breast cancer. All statistical tests were two-sided. Results Insulin levels were positively associated with the risk of breast cancer (hazard ratio [HR] for highest vs lowest quartile of insulin level = 1.46, 95% confidence interval [CI] = 1.00 to 2.13, P(trend) = .02); however, the association with insulin level varied by hormone therapy (HT) use (P(interaction) = .01). In a model that controlled for multiple breast cancer risk factors including estradiol, insulin level was associated with breast cancer only among nonusers of HT (HR for highest vs lowest quartile of insulin level = 2.40, 95% CI = 1.30 to 4.41, P(trend) or=30 kg/m(2)) was also associated with the risk of breast cancer among nonusers of HT (HR for BMI >or=30 kg/m(2) vs 18.5 to <25 kg/m(2) = 2.12, 95% CI = 1.26 to 3.58, P(trend) = .003); however, this association was attenuated by adjustment for insulin (P(trend) = .40). These data suggest that hyperinsulinemia is an independent risk factor for breast cancer and may have a substantial role in explaining the obesity-breast cancer relationship.
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                Author and article information

                Contributors
                646-888-4224 , makkerv@mskcc.org
                greena@mskcc.org
                Robert.Wenham@moffitt.org
                mutchd@wustl.edu
                brittany.davidson@duke.edu
                David.Miller@UTSouthwestern.edu
                Journal
                Gynecol Oncol Res Pract
                Gynecol Oncol Res Pract
                Gynecologic Oncology Research and Practice
                BioMed Central (London )
                2053-6844
                2 December 2017
                2 December 2017
                2017
                : 4
                : 19
                Affiliations
                [1 ]ISNI 0000 0001 2171 9952, GRID grid.51462.34, Gynecologic Medical Oncology Service, Department of Surgery, , Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, ; 1275 York Avenue, New York, TX 10065 USA
                [2 ]ISNI 0000 0000 9891 5233, GRID grid.468198.a, Department of Gynecologic Oncology, , H. Lee Moffitt Cancer Center, ; Tampa, FL USA
                [3 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Division of Gynecologic Oncology, , Washington University School of Medicine, ; St Louis, MO USA
                [4 ]ISNI 0000 0004 1936 7961, GRID grid.26009.3d, Division of Gynecologic Oncology, , Duke University Medical Center, Duke Cancer Institute, ; Durham, NC USA
                [5 ]ISNI 0000 0000 9482 7121, GRID grid.267313.2, Division of Gynecologic Oncology, , University of Texas Southwestern Medical Center, ; Dallas, USA
                Article
                56
                10.1186/s40661-017-0056-7
                5712183
                29214032
                b9496217-6f5e-43d6-a04e-de5ff956799e
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 7 August 2017
                : 13 November 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000054, National Cancer Institute;
                Award ID: P30 CA008748
                Categories
                Review
                Custom metadata
                © The Author(s) 2017

                endometrial cancer,targeted therapy,chemotherapy,immunotherapy

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