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The Therapeutic Challenge of Targeting HER2 in Endometrial Cancer.

ABSTRACT: Endometrial cancer is the most common gynecologic cancer in the United States, diagnosed in more than 50,000 women annually. While the majority of women present with low-grade tumors that are cured with surgery and adjuvant radiotherapy, a significant subset of women experience recurrence and do not survive their disease. A disproportionate number of the more than 8,000 annual deaths attributed to endometrial cancer are due to high-grade uterine cancers, highlighting the need for new therapies that target molecular alterations specific to this subset of tumors. Numerous correlative scientific investigations have demonstrated that the HER2 (ERBB2) gene is amplified in 17%-33% of carcinosarcoma, uterine serous carcinoma, and a subset of high-grade endometrioid endometrial tumors. In breast cancer, this potent signature has directed women to anti-HER2-targeted therapies such as trastuzumab and lapatinib. In contrast to breast cancer, therapy with trastuzumab alone revealed no responses in women with recurrent HER2 overexpressing endometrial cancer, suggesting that these tumors may possess acquired or innate trastuzumab resistance mechanisms. This review explores the literature surrounding HER2 expression in endometrial cancer, focusing on trastuzumab and other anti-HER2 therapy and resistance mechanisms characterized in breast cancer but germane to endometrial tumors. Understanding resistance pathways will suggest combination therapies that target both HER2 and key oncogenic escape pathways in endometrial cancer.This review summarizes the role of HER2 in endometrial cancer, with a focus on uterine serous carcinoma. The limitations to date of anti-HER2 therapy in this disease site are examined, and mechanisms of drug resistance are outlined based on the experience in breast cancer. Potential opportunities to overcome inherent resistance to anti-HER2 therapy in endometrial cancer are detailed, offering opportunities for further clinical study with the goal to improve outcomes in this challenging disease.

SUBMITTER: Diver EJ

PROVIDER: S-EPMC4571805 | biostudies-literature | 2015 Sep

REPOSITORIES: biostudies-literature

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The Therapeutic Challenge of Targeting HER2 in Endometrial Cancer.

Diver Elisabeth J EJ Foster Rosemary R Rueda Bo R BR Growdon Whitfield B WB

The oncologist 20150622 9

<h4>Unlabelled</h4>Endometrial cancer is the most common gynecologic cancer in the United States, diagnosed in more than 50,000 women annually. While the majority of women present with low-grade tumors that are cured with surgery and adjuvant radiotherapy, a significant subset of women experience recurrence and do not survive their disease. A disproportionate number of the more than 8,000 annual deaths attributed to endometrial cancer are due to high-grade uterine cancers, highlighting the need ...[more]

PMID: 26099744

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Project description:BackgroundONC201 is a dopamine receptor D2 (DRD2) antagonist that inhibits tumor growth in preclinical models through ClpP activation to induce integrated stress response pathway and mitochondrial events related to inhibition of cell growth, which is being explored in clinical trials for solid tumors and hematological malignancies. In this study, we investigated the anti-tumorigenic effect of ONC201 in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer.MethodsCell proliferation was assessed by MTT and colony formation assays. Cell cycle and apoptosis were evaluated by Cellometer. Invasion capacity was tested using adhesion, transwell and wound healing assays. LKB1fl/flp53fl/fl mouse model of endometrial cancer were fed a control low fat diet versus a high fat diet to mimic diet-induced obesity. Following tumor onset, mice were treated with placebo or ONC201. Metabolomics and lipidomics were used to identify the obesity-dependent effects of ONC201 in the mouse endometrial tumors. DRD2 expression was analyzed by immunohistochemistry in human endometrioid and serous carcinoma specimens. DRD2 mRNA expression from the Cancer Genome Atlas (TCGA) database was compared between the four molecular subtypes of endometrial cancer.ResultsIncreasing DRD2 expression in endometrial cancer was significantly associated with grade, serous histology and stage, as well as worse progression free survival and overall survival. Higher expression of DRD2 mRNA was found for the Copy Number High (CNH) subtype when compared to the other subtypes. ONC201 inhibited cell proliferation, induced cell cycle G1 arrest, caused cellular stress and apoptosis and reduced invasion in endometrial cancer cells. Diet-induced obesity promoted endometrial tumor growth while ONC201 exhibited anti-tumorigenic efficacy in the obese and lean LKB1fl/fl/p53fl/fl mice. Metabolomic analysis demonstrated that ONC201 reversed the obesity-driven upregulation of lipid biosynthesis and reduced protein biosynthesis in obese and lean mice.ConclusionONC201 has anti-tumorigenic effects in endometrial cancer cells and a transgenic mouse model of endometrial cancer, and DRD2 expression was documented in both human serous and endometrioid endometrial cancer. These studies support DRD2 antagonism via ONC201 as a promising therapeutic strategy for endometrial cancer that has already demonstrated pharmacodynamic activity and clinical benefit in both serous and endometrioid endometrial cancer patients.

Dataset Information

The Therapeutic Challenge of Targeting HER2 in Endometrial Cancer.

Publications

The Therapeutic Challenge of Targeting HER2 in Endometrial Cancer.

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