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|Ref Type||Journal Article|
|Authors||Alvero AB, Heaton A, Lima E, Pitruzzello M, Sumi N, Yang-Hartwich Y, Cardenas C, Steinmacher S, Silasi DA, Brown D, Mor G|
|Title||TRX-E-002-1 Induces c-Jun-Dependent Apoptosis in Ovarian Cancer Stem Cells and Prevents Recurrence In Vivo.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||Chemoresistance is a major hurdle in the management of patients with epithelial ovarian cancer and is responsible for its high mortality. Studies have shown that chemoresistance is due to the presence of a subgroup of cancer cells with stemness properties and a high capacity for tumor repair. We have developed a library of super-benzopyran analogues to generate potent compounds that can induce cell death in chemoresistant cancer stem cells. TRX-E-002-1 is identified as the most potent analogue and can induce cell death in all chemoresistant CD44(+)/MyD88(+) ovarian cancer stem cells tested (IC50 = 50 nmol/L). TRX-E-002-1 is also potent against spheroid cultures formed from cancer stem cells, chemosensitive CD44(-)/MyD88(-) ovarian cancer cells, and heterogeneous cultures of ovarian cancer cells. Cell death was associated with the phosphorylation and increased levels of c-Jun and induction of caspases. In vivo, TRX-E-002-1 given as daily intraperitoneal monotherapy at 100 mg/kg significantly decreased intraperitoneal tumor burden compared with vehicle control. When given in combination with cisplatin, animals receiving the combination of cisplatin and TRX-E-002-1 showed decreased tumor burden compared with each monotherapy. Finally, TRX-E-002-1 given as maintenance treatment after paclitaxel significantly delayed disease recurrence. Our results suggest that TRX-E-002-1 may fill the current need for better therapeutic options in the control and management of recurrent ovarian cancer and may help improve patient survival. Mol Cancer Ther; 15(6); 1279-90. ©2016 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|TRX-E-002-1||Cantrixil||Cantrixil (TRX-E-002-1) is a super-benzopyran analogue that demonstrates potent anti-proliferation activity through regulation of c-Jun and Mek signaling (PMID: 27196760, PMID: 28013349).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||ovarian cancer||not applicable||Paclitaxel + TRX-E-002-1||Preclinical - Cell line xenograft||Actionable||In a preclinical study, TRX-E-002-1 given as a maintenance treatment after Taxol (paclitaxel) treatment resulted in less tumor recurrence compared to placebo in cell line xenograft models of ovarian cancer (PMID: 27196760).||27196760|
|Unknown unknown||ovarian cancer||not applicable||TRX-E-002-1||Preclinical - Cell line xenograft||Actionable||In a preclinical study, TRX-E-002-1 inhibited proliferation and induced apoptosis in chemoresistant human ovarian cancer cell lines in culture, and reduced tumor size in ovarian cancer cell line xenograft models (PMID: 27196760).||27196760|
|Unknown unknown||ovarian cancer||not applicable||Cisplatin + TRX-E-002-1||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the combination of TRX-E-002-1 and Platinol (cisplatin) synergized to induce cell death in human chemoresistant ovarian cancer cell lines in culture and decreased tumor burden in xenograft models (PMID: 27196760).||27196760|