Tall cell carcinoma of the breast with reversed polarity (TCCRP) with mutations in the IDH2 and PIK3CA genes: a case report
MOLECULAR BIOLOGY REPORTS
Authors: Haefliger, Simon; Muenst, Simone; Went, Philip; Bihl, Michel; Dellas, Sophie; Weber, Walter Paul; Vlajnic, Tatjana
Abstract
Tall cell carcinoma with reversed polarity (TCCRP) is a rare breast carcinoma with low malignant potential, initially named "breast tumor resembling the tall cell variant of papillary thyroid carcinoma", which has recently been recognized as a separate entity in the 5th edition of the WHO (World Health Organization) classification of breast tumors. Since the first report of this entity in 2003, more than 40 cases have been reported in the literature. Here, we report another case of this rare tumor in a 60-year-old woman. We performed immunohistochemical analyses and next-generation-sequencing (NGS) using the Oncomine (TM) Comprehensive DNA Panel (Thermo Fisher Scientific). The tumor showed the typical morphological features of TCCRP and a "triple-negative" phenotype. Moreover, we identified pathogenic mutations in the IDH2 (p.R172G) and PIK3CA (p.H1047R) genes. We report a case of TCCRP of the breast showing the characteristic morphologic, immunohistochemical and molecular features of this entity. There is still a limited number of cases with comprehensive molecular analyses reported in the literature. Therefore, we herewith contribute to a better understanding of the morphological and molecular characteristics as well as the clinical behavior of this rare entity.
Structure-based design, synthesis and bioactivity evaluation of macrocyclic inhibitors of mutant isocitrate dehydrogenase 2 (IDH2) displaying activity in acute myeloid leukemia cells
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
Authors: Che, Jinxin; Huang, Feng; Zhang, Mengmeng; Xu, Gaoya; Qu, Bingxue; Gao, Jian; Chen, Binhui; Zhang, Jianjun; Ying, Huazhou; Hu, Yongzhou; Hu, Xiaobei; Zhou, Yubo; Gao, Anhui; Li, Jia; Dong, Xiaowu
Abstract
The enzymes involved in the metabolic pathways in cancer cells have been demonstrated as important therapeutic targets such as the isocitrate dehydrogenase 2 (IDH2). A series of macrocyclic derivatives was designed based on the marketed IDH2 inhibitor AG-221 by using the conformational restriction strategy. The resulted compounds showed moderate to good inhibitory potential against different IDH2-mutant enzymes. Amongst, compound C6 exhibited better IDH2(R140Q) inhibitory potency than AG 221, and showed excellent activity of 2-hydroxyglutarate (2-HG) suppression in vitro and its mesylate displayed good pharmacokinetic profiles. Moreover, C6 performed strong binding mode to IDH2(R140Q) after computational docking and dynamic simulation, which may serve as a good starting point for further development. (C) 2020 Elsevier Masson SAS. All rights reserved.