This study is being done to answer the following question: What are the effects of a new drug or drugs on ovarian cancer? The pre-study screening may be done to test a sample of tissue for biomarkers to determine participation in the study.

Start Date03 May 2022

Sponsor / Collaborator

Canadian Cancer Trials Group

[+3]

100 Clinical Results associated with Tubulin x AXL

100 Translational Medicine associated with Tubulin x AXL

0 Patents (Medical) associated with Tubulin x AXL

Literatures (Medical) associated with Tubulin x AXL

01 Oct 2022·European Journal of Medicinal Chemistry

Discovery of N-benzylarylamide derivatives as novel tubulin polymerization inhibitors capable of activating the Hippo pathway

Article

Author: Xu, Yan ; Zhang, Wei-Xin ; Song, Jian ; Song, Chun-Hong ; Wang, Sheng-Hui ; Zhang, Sai-Yang ; Fu, Xiang-Jing ; Tian, Xin-Yi ; Zhu, Jun-Xia ; Jin, Cheng-Yun

Novel N-benzylarylamide saderivatives were designed and synthesized, and their antiproliferative activities were explored. Some of 51 target compounds exhibited potent inhibitory activities against MGC-803, HCT-116 and KYSE450 cells with IC₅₀ values in two-digit nanomolar. Compound I-33 (MY-875) displayed the most potent antiproliferative activities against MGC-803, HCT-116 and KYSE450 cells (IC₅₀ = 0.027, 0.055 and 0.067 μM, respectively) and possessed IC₅₀ values ranging from 0.025 to 0.094 μM against other 11 cancer cell lines. Further mechanism studies indicated that compound I-33 (MY-875) inhibited tubulin polymerization (IC₅₀ = 0.92 μM) by targeting the colchicine bingding site of tubulin. Compound I-33 (MY-875) disrupted the construction of the microtubule networks and affected the mitosis in MGC-803 and SGC-7901 cells. In addition, although it acted as a colchicine binding site inhibitor, compound I-33 (MY-875) also activated the Hippo pathway to promote the phosphorylation status of MST and LATS, resulting in the YAP degradation in MGC-803 and SGC-7901 cells. Due to the degradation of YAP, the expression levels of TAZ and Axl decreased. Because of the dual actions on colchicine binding site and Hippo pathway, compound I-33 (MY-875) dose-dependently inhibited cell colony formatting ability, arrested cells at the G2/M phase and induced cells apoptosis in MGC-803 and SGC-7901 cells. Moreover, compound I-33 (MY-875) could regulate the levels of cell cycle and apoptosis regulatory proteins in MGC-803 and SGC-7901 cells. Furthermore, molecular docking analysis suggested that the hydrogen bond and hydrophobic interactions made compound I-33 (MY-875) well bind into the colchicine binding site of tubulin. Collectively, compound I-33 (MY-875) is a novel anti-gastric cancer agent and deserves to be further investigated for cancer therapy by targeting the colchicine binding site of tubulin and activating the Hippo pathway.

01 Nov 2018·Gynecologic OncologyQ2 · MEDICINE

SQ1274, a novel microtubule inhibitor, inhibits ovarian and uterine cancer cell growth

Q2 · MEDICINE

Article

Author: Quinn, Jeanne M ; Hagemann, Andrea R ; Beck, Hollie M ; McCourt, Carolyn ; Lawrence, Julie A ; Mills, Kathryn A ; Guo, Lei ; Roach, S Tanner ; Fuh, Katherine C ; Mutch, David G ; Powell, Matthew A ; Lomonosova, Elena ; Ilivicky, Anna R ; Starks, Courtney M ; Thaker, Premal H

OBJECTIVEPaclitaxel, a microtubule inhibitor, is subject to tumor resistance while treating high-grade serous ovarian and uterine cancer. This study aims to directly compare the effects of SQ1274, a novel microtubule inhibitor that binds to the colchicine-binding site on tubulin, and paclitaxel in high-grade serous ovarian and uterine cancer cell lines both in vitro and in vivo.METHODSWe assessed the sensitivity of ovarian (OVCAR8) and uterine (ARK1) cancer cell lines to SQ1274 and paclitaxel using XTT assays. We used western blot and quantitative real-time PCR to analyze changes in AXL RNA and protein expression by SQ1274 and paclitaxel. Differences in cell-cycle arrest and apoptosis were investigated using flow cytometry. Finally, we treated ovarian and uterine xenograft models with vehicle, paclitaxel, or SQ1274.RESULTSFirst, we demonstrate that SQ1274 has a much lower IC₅₀ than paclitaxel in both ARK1 (1.26 nM vs. 15.34 nM, respectively) and OVCAR8 (1.34 nM vs. 10.29 nM, respectively) cancer cell lines. Second, we show SQ1274 decreases both RNA and protein expression of AXL. Third, we show that SQ1274 causes increased cell-cycle arrest and apoptosis compared to paclitaxel. Finally, we report that SQ1274 more effectively inhibits tumor growth in vivo compared to paclitaxel.CONCLUSIONSSQ1274 presents as a viable alternative to paclitaxel for treating ovarian and uterine cancer. This study supports the development of SQ1274 as a chemotherapeutic to treat ovarian and uterine cancer.

01 Feb 2018·Applied Immunohistochemistry & Molecular MorphologyQ4 · MEDICINE

Identification of New Biomarkers Associated With IDH Mutation and Prognosis in Astrocytic Tumors Using NanoString nCounter Analysis System

Q4 · MEDICINE

Article

Author: Chang, Qing ; Fang, Weigang ; Zheng, Danfeng ; Qi, Xueling ; Zhong, Yanfeng ; Liu, Yan ; Dong, Rongfang ; Zhang, Jing ; Pan, Yi ; Zhang, Ming

Background:Isocitrate dehydrogenase (IDH) mutations have been reported as biomarkers associated with tumorigenesis and prognosis in gliomas. However, genes affected by these mutations are still under investigation. The purpose of this study is to identify new molecular biomarkers associated with IDH mutation and prognosis in astrocytic tumors, which account for the largest proportion of gliomas.Materials and Methods:NanoString analysis was conducted on 40 astrocytic tumors. In total, 69 genes and 6 fusion genes were selected for screening. Quantitative real-time polymerase chain reaction and immunohistochemistry were used to validate the selected discriminatory genes. Kaplan-Meier survival curves and log-rank test were used to analyze the overall survival and progression-free survival.Results:mRNA levels of NTRK3, ERCC1, JAK2, AXL, BCL2, ESR1, HSP90AB1, TUBB3, RET, and ABCG2 were elevated in the IDH mutant group, whereas levels of POSTN and ERBB2 were elevated in the IDH wild-type group. Genes more highly expressed in the better prognosis group included NTRK3, ERCC1, ROS1, ERBB4, BCL2, CDKN2A, AXL, PI3KCA, HSP90AB1, ABCG2, JAK2, and RET. In the worse prognosis group, TIMP1, POSTN, and ERBB2 showed increased expressions. The elevated expression of HSP90AB1 was correlated with IDH mutation, long survival, and secondary glioblastomas. Elevated TIMP1 expression was related to high tumor grade and short patient survival. The results of NanoString were confirmed with quantitative real-time polymerase chain reaction and immunohistochemistry.Conclusions:HSP90AB1 is related to IDH mutation and the expressions of HSP90AB1 and TIMP1 can predict prognosis in astrocytic tumors. The NanoString analysis system is a precise and reliable method to detect mRNA expression in formalin-fixed paraffin-embedded samples.

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