Purpose The phosphoinositol-3 kinase (PI3K) pathway is frequently dysregulated in endometrial cancer (EC). Hormonal manipulation leads to response in some patients with EC, but resistance derived from PI3K pathway activation has been documented. Targeting mammalian target of rapamycin (mTOR) may overcome endocrine resistance. We conducted a two-institution phase II trial of everolimus and letrozole in women with recurrent EC. Patients and Methods Patients were considered incurable, had measurable disease, and were treated with up to two prior cytotoxic regimens. Everolimus was administered orally at 10 mg daily and letrozole was administered orally at 2.5 mg daily. Each cycle consisted of 4 weeks of therapy. Patients were treated until progression, toxicity, or complete response (CR). The primary end point was the clinical benefit rate (CBR), which was defined as CR, partial response, or stable disease (≥ 16 weeks) by RECIST 1.0 criteria. Translational studies were performed to correlate biomarkers with response. Results Thirty-eight patients were enrolled (median age, 62 years; range, 24 to 82 years). Thirty-five patients were evaluable for response. The CBR was 40% (14 of 35 patients); the median number of cycles among responders was 15 (range, seven to 29 cycles). The confirmed objective response rate (RR) was 32% (11 of 35 patients; nine CRs and two partial responses; median, 15 cycles; range, eight to 29 cycles). Twenty percent of patients (seven of 35 patients) were taken off treatment after a prolonged CR and at the discretion of the treating clinician. None of the patients discontinued treatment as a result of toxicity. Serous histology was the best predictor of lack of response. Patients with endometrioid histology and CTNNB1 mutations responded well to everolimus and letrozole. Conclusion Everolimus plus letrozole results in a high CBR and RR in patients with recurrent EC. Further development of this combination in recurrent endometrioid EC is under way.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (https://www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point‐in‐time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15537. In addition to this overview, in which are identified ‘Other protein targets’ which fall outside of the subsequent categorisation, there are six areas of focus: G protein‐coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid‐2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC‐IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Purpose Recent studies show that colorectal tumors with high microsatellite instability (MSI-H) have increased immunogenicity and response to immunotherapy compared to microsatellite stable (MSS) tumors. It is not yet clear if MSI-H endometrial cancer (EC) may also benefit from these therapies. It is also unknown whether immune response is equivalent in MSI-H EC with sporadic or inherited Lynch syndrome origins. Experimental Design Multiplexed fluorescent immunohistochemistry (IHC) was used to compare matched MSI-H (n=60) and MSS (n=96) EC specimens by evaluating immune cell populations in tumor and stroma compartments. Sporadic MSI-H and Lynch syndrome-associated (LS) MSI-H EC were also directly compared. Results Increased immune cells were present in stroma of MSI-H EC compared to MSS, including granzyme B+ cells, activated cytotoxic T lymphocytes (CTLs, CD8+granzyme B+), and PD-L1+ cells. Granzyme B+ cells and activated CTLs were also increased in the tumor compartment of MSI-H ECs. Comparing sporadic and LS MSI-H EC showed distinct differences in immune cell populations, indicating that mechanisms underlying microsatellite instability alter immune response. Specifically, LS MSI-H EC showed increased CD8+ cells and activated CTLs in stroma, with reduced macrophages in stroma and tumor compared to sporadic MSI-H. Sporadic MSI-H had increased PD-L1+ macrophages in stroma and tumor compared to LS MSI-H EC. Conclusions MSI-H EC has increased immune cell infiltration compared to MSS EC and the hereditary or sporadic origin of microsatellite instability impacts immune response. Clinical trials to determine the role of immunotherapy in patients with MSI-H EC must evaluate Lynch-related and sporadic MSI-H tumors separately.

Objective-Adiponectin, a protein secreted by adipose cells, is inversely associated with endometrial cancer (EC). Our objective was to assess pre-diagnostic adiponectin levels in relation to risk of EC.Study Design-Prospective nested case-control study within the Nurses' Health Study; cases 146, controls 377. Adiponectin was measured using enzyme-linked immunoabsorbant assay. Logistic regression analyses were performed adjusting for known EC risk factors.Results-Mean age at diagnosis was 64.6 years. Mean interval between blood draw and diagnosis was 7.4 years (range 2-13). There was no difference in median adiponectin (cases 12.9 vs controls 12.9µg/mL; p=0.97). Adiponectin >15ul/mL was not associated with EC risk (RR=0.86 95% CI=0.53-1.39; p=0.48), even among postmenopausal women (OR 0.66, CI 0.29-1.5). Results did not vary by time from blood draw to diagnosis (p for heterogeneity = 0.18).Conclusion-Pre-diagnostic adiponectin was not predictive of EC risk. Further study will better define the relationship between adiponectin and EC.

Metformin is an oral biguanide commonly used for the treatment of type II diabetes and has recently been demonstrated to possess anti-proliferative 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.