Exploitation of sulfated glycosaminoglycan status for precision medicine of platinums in triple-negative breast cancer
Exploitation of sulfated glycosaminoglycan status for precision medicine of platinums in triple-negative breast cancer
Abstract Triple negative breast cancer (TNBC) is a subtype of breast cancer lacking targetable biomarkers. TNBC is known to be most aggressive, and when metastatic is often drug resistant and uncurable. Biomarkers predicting response to therapy improve treatment decisions and allow personalized approaches for TNBC patients. This study explores sulfated glycosaminoglycan (sGAG) levels as a predictor of TNBC response to platinum therapy. sGAG levels were quantified in three distinct TNBC tumor models including cell line-derived, patient-derived xenograft (PDX) tumors, and isogenic models deficient in sGAG biosynthesis. The in vivo antitumor efficacy of Triplatin, a sGAG-directed platinum agent, was compared in these models to the clinical platinum agent, carboplatin. We determined that >40% of TNBC PDX tissue microarray samples have high levels of sGAGs. The in vivo accumulation of Triplatin in tumors as well as antitumor efficacy of Triplatin positively correlated with sGAG levels on tumor cells, whereas carboplatin followed the opposite trend. In carboplatin-resistant tumor models expressing high levels of sGAGs, Triplatin decreased primary tumor growth, reduced lung metastases and inhibited metastatic growth in lungs, liver, and ovaries. sGAG levels served as a predictor of Triplatin sensitivity in TNBC. Triplatin may be particularly beneficial in treating patients with chemotherapy-resistant tumors who have evidence of residual disease after standard neoadjuvant chemotherapy. More effective neoadjuvant and adjuvant treatment will likely improve clinical outcome of TNBC. SignificanceTNBC is a heterogenous disease, often defined by the absence of a therapeutic target. Our recent results show sGAGs may provide a viable biomarker for Triplatin in patients with TNBC, producing a significant advantage over carboplatin in this setting. Selective precision medicine agents, such as Triplatin, that are active against chemotherapy-resistant disease and exploit molecular biomarkers like sGAGs may significantly benefit patients in this setting.
Hampton James D.、H.Turner Tia、Harrell J. Chuck、Kraskauskiene Vita、Idowu Michael O.、Puchalapalli Madhavi、Litovchick Larisa、Farrell Nicholas P.、Koblinski Jennifer E.、Gigliotti Pam J.、Hu Bin、Katner Samantha J.、Peterson Erica J.、Dozmorov Mikhail G.、Takabe Kazuaki、Shende Mayuri、Katsuta Eriko、Alzubi Mohammad A.
Department of Biochemistry, Virginia Commonwealth University||Massey Cancer Center, Virginia Commonwealth UniversityDepartment of Pathology, Virginia Commonwealth University||Wright Center for Clinical and Translational ResearchMassey Cancer Center, Virginia Commonwealth University||Department of Pathology, Virginia Commonwealth UniversityMassey Cancer Center, Virginia Commonwealth University||Department of Pathology, Virginia Commonwealth UniversityMassey Cancer Center, Virginia Commonwealth University||Department of Pathology, Virginia Commonwealth UniversityMassey Cancer Center, Virginia Commonwealth University||Department of Pathology, Virginia Commonwealth UniversityMassey Cancer Center, Virginia Commonwealth University||Department of Internal Medicine, Virginia Commonwealth UniversityMassey Cancer Center, Virginia Commonwealth University||Department of Chemistry, Virginia Commonwealth UniversityMassey Cancer Center, Virginia Commonwealth University||Department of Pathology, Virginia Commonwealth UniversityMassey Cancer Center, Virginia Commonwealth University||Department of Pathology, Virginia Commonwealth UniversityMassey Cancer Center, Virginia Commonwealth University||Department of Pathology, Virginia Commonwealth UniversityDepartment of Biochemistry, Chemistry, and Geology, Minnesota State UniversityMassey Cancer Center, Virginia Commonwealth University||Department of Chemistry, Virginia Commonwealth UniversityDepartment of Pathology, Virginia Commonwealth University||Department of Biostatistics, Virginia Commonwealth University,Roswell Park Comprehensive Cancer Center||University at Buffalo, the State University of New YorkMassey Cancer Center, Virginia Commonwealth University||Department of Pathology, Virginia Commonwealth UniversityRoswell Park Comprehensive Cancer CenterDepartment of Pathology, Virginia Commonwealth University
肿瘤学医学研究方法基础医学
Hampton James D.,H.Turner Tia,Harrell J. Chuck,Kraskauskiene Vita,Idowu Michael O.,Puchalapalli Madhavi,Litovchick Larisa,Farrell Nicholas P.,Koblinski Jennifer E.,Gigliotti Pam J.,Hu Bin,Katner Samantha J.,Peterson Erica J.,Dozmorov Mikhail G.,Takabe Kazuaki,Shende Mayuri,Katsuta Eriko,Alzubi Mohammad A..Exploitation of sulfated glycosaminoglycan status for precision medicine of platinums in triple-negative breast cancer[EB/OL].(2025-03-28)[2025-06-15].https://www.biorxiv.org/content/10.1101/2021.05.05.442616.点此复制
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