ORCID Profile
0000-0002-3522-7382
Current Organisations
Dartmouth-Hitchcock Norris Cotton Cancer Center
,
Dartmouth–Hitchcock Medical Center
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Publisher: Springer Science and Business Media LLC
Date: 06-2013
DOI: 10.1007/S10549-013-2604-0
Abstract: Molecular prognostic assays, such as Oncotype DX, are increasingly incorporated into the management of patients with invasive breast carcinoma. BreastPRS is a new molecular assay developed and validated from a meta-analysis of publically available genomic datasets. We applied the assay to matched fresh-frozen (FF) and formalin-fixed paraffin-embedded (FFPE) tumor s les to translate the assay to FFPE. A linear relationship of the BreastPRS prognostic score was observed between tissue preservation formats. BreastPRS recurrence scores were compared with Oncotype DX recurrence scores from 246 patients with invasive breast carcinoma and known Oncotype DX results. Using this series, a 120-gene Oncotype DX approximation algorithm was trained to predict Oncotype DX risk groups and then applied to series of untreated, node-negative, estrogen receptor (ER)-positive patients from previously published studies with known clinical outcomes. Correlation of recurrence score and risk group between Oncotype DX and BreastPRS was statistically significant (P < 0.0001). 59 of 260 (23 %) patients from four previously published studies were classified as intermediate-risk when the 120-gene Oncotype DX approximation algorithm was applied. BreastPRS reclassified the 59 patients into binary risk groups (high- vs. low-risk). 23 (39 %) patients were classified as low-risk and 36 (61 %) as high-risk (P = 0.029, HR: 3.64, 95 % CI: 1.40-9.50). At 10 years from diagnosis, the low-risk group had a 90 % recurrence-free survival (RFS) rate compared to 60 % for the high-risk group. BreastPRS recurrence score is comparable with Oncotype DX and can reclassify Oncotype DX intermediate-risk patients into two groups with significant differences in RFS. Further studies are needed to validate these findings.
Publisher: Elsevier BV
Date: 04-2008
DOI: 10.1053/J.SEMINONCOL.2008.02.003
Abstract: Standard cytotoxic chemotherapy of locally advanced or metastatic breast cancer includes the microtubule-stabilizing taxanes, but like other cytotoxic drugs their effectiveness is compromised by resistance that is either inherent or develops during treatment. Epothilones, which also stabilize microtubules but by a different mechanism, are in clinical development primarily to overcome taxane or multidrug resistance, based on potent preclinical antitumor activity against resistant tumor lines. Ixabepilone is the best-studied epothilone clinically and is active in patients with metastatic breast cancer that has been pretreated with, or had established resistance to, taxanes and/or anthracyclines. In a phase III trial in patients with anthracycline-pretreated or -resistant and taxane-resistant locally advanced or metastatic breast cancer, adding ixabepilone to capecitabine significantly improved progression-free survival and the overall response rate compared with capecitabine alone. The primary toxicities associated with ixabepilone treatment are neuropathy and neutropenia, but both are generally manageable. Other epothilones currently in clinical studies are KOS-862, patupilone, ZK-EPO, BMS-310705, and KOS-1584, which have all shown activity in patients with pretreated or resistant metastatic breast cancer.
Publisher: Cold Spring Harbor Laboratory
Date: 06-10-2022
DOI: 10.1101/2022.10.03.510707
Abstract: Copper is a trace element essential to cellular function with elevated levels implicated in cancer progression. Clinical trials using copper chelators are associated with improved patient survival, however, the molecular mechanisms by which copper depletion inhibits tumor progression are poorly understood. This remains a major hurdle to the clinical translation of copper chelators. Epithelial-mesenchymal transition (EMT) is often exploited by malignant cells to promote growth and metastasis. Transforming growth factor (TGF)- β is a master regulator of EMT and facilitates cancer progression through changes in the tumor and its microenvironment. Herein, we report that a reduction of copper with the chelating agent tetraethylenepentamine (TEPA) inhibited EMT in vitro in three erse cancer cell types human triple-negative breast cancer (TNBC), neuroblastoma (NB), and diffuse intrinsic pontine glioma (DIPG) cell lines. Single-molecule imaging demonstrated EMT markers including Vimentin, β -catenin, ZEB1, and p-SMAD2 had increased expression with copper treatment and this pro-mesenchymal shift was rescued by the addition of TEPA. Moreover, SNAI1, ZEB1, and p-SMAD2 demonstrated increased accumulation in the cytoplasm after treating with TEPA. Transcriptomic analyses revealed a significant downregulation of the EMT pathway, including canonical (TGF- β /SMAD2& ) and non-canonical (TGF- β /PI3K/AKT and TGF- β /RAS/RAF/MEK/ERK) TGF signaling pathways. Matrix metalloproteinases MMP-9 and MMP-14 proteins which activate latent TGF- β complexes were also downregulated by TEPA treatment. These molecular changes are consistent with reduced plasma levels of TGF- β we observed in cancer models treated with TEPA. Importantly, copper chelation reduced metastasis to the lung in a TNBC orthotopic syngeneic mouse model. Our studies suggest copper chelation therapy can be used to inhibit EMT-induced metastasis by targeting TGF- β signalling. Because on-target anti-TGF- β therapies are failing in the clinic, copper chelation presents itself as a potential therapy for targeting TGF- β in cancer.
Publisher: Springer Science and Business Media LLC
Date: 18-04-2019
Location: United States of America
Location: United States of America
Location: United States of America
Location: United States of America
Location: United States of America
Location: United States of America
No related grants have been discovered for Linda Vahdat.