دورية أكاديمية
A Novel Brain-Permeant Chemotherapeutic Agent for the Treatment of Brain Metastasis in Triple-Negative Breast Cancer.
| العنوان: | A Novel Brain-Permeant Chemotherapeutic Agent for the Treatment of Brain Metastasis in Triple-Negative Breast Cancer. |
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| المؤلفون: | Deng J; Department of Neurosurgery, Stanford University, Stanford, California.; Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China., Chernikova SB; Department of Neurosurgery, Stanford University, Stanford, California., Wang Y; Department of Neurosurgery, Stanford University, Stanford, California.; Department of Neurosurgery, West China Hospital, Sichuan University, Chengdu, China., Rodriguez ML; Quadriga BioSciences, Inc., Los Altos, California., Andersen SJ; Department of Neurosurgery, Stanford University, Stanford, California., Umeh-Garcia MC; Department of Neurosurgery, Stanford University, Stanford, California., Godfrey BO; Department of Neurosurgery, Stanford University, Stanford, California., Ahmadian SS; Department of Pathology, Stanford University, Stanford, California., Fischer WN; Quadriga BioSciences, Inc., Los Altos, California., Koller KJ; Quadriga BioSciences, Inc., Los Altos, California., Jandeleit B; Quadriga BioSciences, Inc., Los Altos, California., Ringold GM; Quadriga BioSciences, Inc., Los Altos, California., Gephart MH; Department of Neurosurgery, Stanford University, Stanford, California. mghayden@stanford.edu. |
| المصدر: | Molecular cancer therapeutics [Mol Cancer Ther] 2021 Nov; Vol. 20 (11), pp. 2110-2116. Date of Electronic Publication: 2021 Oct 11. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Association for Cancer Research, Inc Country of Publication: United States NLM ID: 101132535 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-8514 (Electronic) Linking ISSN: 15357163 NLM ISO Abbreviation: Mol Cancer Ther Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Philadelphia, PA : American Association for Cancer Research, Inc., c2001- |
| مواضيع طبية MeSH: | Antineoplastic Agents/*therapeutic use , Triple Negative Breast Neoplasms/*drug therapy, Animals ; Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; Humans ; Mice ; Neoplasm Metastasis |
| مستخلص: | Development of metastases to central nervous system (CNS) is an increasing clinical issue following the diagnosis of advanced breast cancer. The propensity to metastasize to CNS varies by breast cancer subtype. Of the four breast cancer subtypes, triple-negative breast cancers (TNBC) have the highest rates of both parenchymal brain metastasis and leptomeningeal metastasis (LM). LM is rapidly fatal due to poor detection and limited therapeutic options. Therapy of TNBC brain metastasis and LM is challenged by multifocal brain metastasis and diffuse spread of LM, and must balance brain penetration, tumor cytotoxicity, and the avoidance of neurotoxicity. Thus, there is an urgent need for novel therapeutic options in TNBCs CNS metastasis. QBS10072S is a novel chemotherapeutic that leverages TNBC-specific defects in DNA repair and LAT1 (L-amino acid transporter type 1)-dependent transport into the brain. In our study, activity of QBS10072S was investigated in vitro with various cell lines including the human TNBC cell line MDA-MB-231 and its brain-tropic derivative MDA-MB-231-BR3. QBS10072S was preferentially toxic to TNBC cells. The efficacy of QBS10072S against brain metastasis and LM was tested using a model of brain metastasis based on the internal carotid injection of luciferase-expressing tumor cells into NuNu mice. The compound was well tolerated, delayed tumor growth and reduced leptomeningeal dissemination, resulting in significant extension of survival. Given that current treatments for LM are palliative with only few studies reporting a survival benefit, QBS10072S is planned to be investigated in clinical trials as a therapeutic for TNBC LM. SIGNIFICANCE: TNBC brain metastasis often involves dissemination into leptomeninges. Treatment options for TNBC leptomeningeal metastasis are limited and are mostly palliative. Our study demonstrates significant efficacy of the brain-penetrating agent QBS10072S against TNBC brain metastasis and leptomeningeal spread. (©2021 The Authors; Published by the American Association for Cancer Research.) |
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| معلومات مُعتمدة: | K08 NS091527 United States NS NINDS NIH HHS; R43 CA174129 United States CA NCI NIH HHS; R44 CA174129 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Antineoplastic Agents) |
| تواريخ الأحداث: | Date Created: 20211012 Date Completed: 20220325 Latest Revision: 20220503 |
| رمز التحديث: | 20231215 |
| مُعرف محوري في PubMed: | PMC8571036 |
| DOI: | 10.1158/1535-7163.MCT-21-0140 |
| PMID: | 34635566 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1538-8514 |
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| DOI: | 10.1158/1535-7163.MCT-21-0140 |