Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0476089 (endometrial cancer)
 11,379 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ixabepilone demonstrates marked synergistic activity in combination with capecitabine, which served as the rationale for the evaluation of this combination in the clinic. Ixabepilone plus capecitabine is currently approved for patients with locally advanced or metastatic breast cancer (MBC) progressing after treatment with an anthracycline and a taxane; approval was based on the results of two phase III trials comparing the combination with capecitabine monotherapy. An array of preclinical studies in multiple solid tumor types show that ixabepilone demonstrates therapeutic synergy with targeted therapies including trastuzumab, bevacizumab, brivanib, and cetuximab; with immune-modulating agents such as anti-CTLA-4 antibody; and with other chemotherapy drugs such as irinotecan and epirubicin. Notably, experiments in several xenograft models show that ixabepilone provides greater antitumor synergism when combined with bevacizumab than either paclitaxel or nab-paclitaxel combined with bevacizumab. These preclinical findings provide a foundation for ongoing phase II clinical trials using ixabepilone in combination with trastuzumab or lapatinib in HER2-positive breast cancer; with bevacizumab in breast cancer, endometrial cancer, renal cancer, and non-small cell lung cancer (NSCLC); with cetuximab in breast cancer, NSCLC, and pancreatic cancer; and with brivanib, dasatinib, sorafinib, sunitinib, or vorinostat in MBC. Preliminary results from several of these trials suggest that ixabepilone-based combinations have promising anticancer activity.
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PMID:Synergistic activity of ixabepilone plus other anticancer agents: preclinical and clinical evidence. 2178 52

Immune checkpoint inhibitors have shown promising efficacy in multiple cancer types. The recent food and drug administration approval of PD-1 inhibitors for mismatch repair (MMR)-deficient tumors has extended use of these treatments to all cancer types, and programmed death ligand 1 (PD-L1) positivity in tumor tissue has also been shown to predict susceptibility to immunotherapy. Despite these advances, the response to immunotherapy in endometrial cancer remains poorly understood. Here, we describe the case of a patient with MMR-proficient, PD-L1-negative stage IV endometrial cancer who exhibited a strong clinical response to combination PD-1 and CTLA-4 inhibition. She showed deep and durable ongoing partial response to nivolumab and ipilimumab that has persisted after 12 months. This case indicates the potential existence of an endometrial cancer subtype that is sensitive to immune checkpoint blockade based on mechanisms other than those driven by MMR deficiency or PD-L1 positivity. Improved understanding of immunotherapy in advanced endometrial cancer is clearly needed and offers the potential to significantly enhance patient outcomes.
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PMID:Deep and Durable Response With Combination CTLA-4 and PD-1 Blockade in Mismatch Repair (MMR)-proficient Endometrial Cancer. 3024 4

Gynecological malignances include cervical, uterine (sarcoma), ovarian, vaginal, and vulvar cancers are among the most common cancers in women. Advanced and recurrent cases of these malignancies have poor prognosis and hence new types of treatment strategy are ur- gently required. Recent clinical trials have revealed an outstanding anti-tumor effect of im- mune checkpoint inhibitors (anti-cytotoxic T-lymphocyte-associated protein 4 [CTIA-4] anti- body, anti- programmed cell death 1 [PD-1] antibody and/or anti-PD-Li [PD-i ligand 1] antibody) in patients with gynecologic malignancies, especially for ovarian cancer and endo- metrial cancer. Besides, several clinical trials for other gynecologic malignancie's also have started and achieved a certain result in these agents and demonstrated some'candidates of predictive biomarkers of anti-tumor response such as polymerase epsilon (POLE) ultra- mutated or DNA mismatch repair deficiency-mutated genes in endometrial cancer and ovar- ian cancer. In this review, we highlight recent clinical trials that evaluated immune check- point inhibitors against gynecologic malignancies and discuss the clinical perspectives and issues regarding immune checkpoint inhibitors.
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PMID:Immune checkpoint (PD-1 and CTIA-4) signal inhibitors for gynecologic oncology; up to date. 3056 58

Based on clinical outcomes in colorectal cancer, high microsatellite instability (MSI-H) has recently been approved by the Food and Drug Administration (FDA) as a genetic test to select patients for immunotherapy targeting PD-1 and/or CTLA-4 without limitation to cancer type. However, it is unclear whether the MSI-H would broadly alter the tumor microenvironment to confer the therapeutic response of different cancer types to immunotherapy. To fill in this gap, we performed an in silico analysis of tumor immunity among different MSI statuses in five cancer types. We found that consistent with clinical responses to immunotherapy, MSI-H and non-MSI-H samples from colorectal cancer (COAD-READ) exhibited distinct infiltration levels and immune phenotypes. Surprisingly, the immunological difference between MSI-H and non-MSI-H samples was diminished in stomach adenocarcinoma and esophageal carcinoma (STAD-ESCA) and completely disappeared in uterine corpus endometrial carcinoma (UCEC). Regardless of cancer types, the abundance of tumor-infiltrating immune cells, rather than MSI status, strongly associated with the clinical outcome. Since preexisting antitumor immune response in the tumor (hot cancer) is accepted as a prerequisite to the therapeutic response to anti-PD-1/CTLA-4 immunotherapy, our data demonstrate that the impact of MSI varied on immune contexture will lead to the further evaluation of predictive immunotherapy responsiveness based on the universal biomarker of MSI status.
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PMID:Microsatellite instability status differentially associates with intratumoral immune microenvironment in human cancers. 3282 73

Tumor mutation burden (TMB) is an essential biomarker to predict immunotherapy response. TMB measurement was mainly evaluated by whole-exome sequencing (WES), which was costly and difficult to be widely applied. In the present study, we aimed to establish and validate a miRNA signature to predict TMB level in endometrial cancer using The Cancer Genome Atlas (TCGA) database. MiRNA expression and somatic mutation profiles of uterine corpus endometrial carcinoma (UCEC) were downloaded from TCGA database. Total 518 patients with UCEC were randomly classified into training set (n=311) and validation set (n=207). Thirty-five differentially expressed miRNAs between high-TMB and low-TMB group were identified in training set. Least absolute shrinkage and selection operator (LASSO) method was performed to select out 26 miRNAs to establish the optimal signature. The accuracy of the miRNA signature for predicting TMB level was 0.833 for training set, 0.749 for validation set and 0.799 for total set. Moreover, the miRNA signature had significant correlation with immune checkpoints related genes (PD-1, PD-L1, CTLA-4) and mismatch repair related genes (BRCA1, BRCA2, MLH1, MSH6) expression. In conclusion, this miRNA signature could predict TMB level in endometrial cancer and might have some merits in providing guidance for immunotherapy in endometrial cancer.
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PMID:An miRNA signature associated with tumor mutation burden in endometrial cancer. 3314 Nov 68