Background:The mechanisms by which stress hormones impact triple-negative breast cancer (TNBC) etiology and treatment are unclear. We have previously shown that stress hormones, cortisol, and catecholamines induce rapid DNA damage and impact DNA repair in NIH 3T3 fibroblasts. This study investigates whether stress hormones increase DNA damage in breast cancer cells and if this impacts drug efficacy.Methods:We first screened a panel of 39 breast cancer cell lines for expression of adrenergic and glucocorticoid receptors and examined if stress hormones induce DNA damage and alter cell cycle regulation in vitro. A TNBC xenograft model was used to assess the impact of restraint stress on tumour growth and chemosensitivity to paclitaxel.Results:We found that stress hormones induced DNA damage, phosphorylation of ATR, which was accompanied by an up-regulation of the G1 cell kinase inhibitor p21 and a cell cycle halt of TNBCs in the G1 phase. p21 knockdown abrogated G1 arrest by stress hormones. We also demonstrated that stress significantly decreased efficacy of paclitaxel.Conclusion:We describe a novel mechanism through which stress hormones can induce drug resistance to paclitaxel, which may have profound implications for treating drug resistance in patients with TNBC.
Clinically relevant biomarkers exist in blood and body fluids in extremely low concentrations, are masked by high abundance high molecular weight proteins, and often undergo degradation during collection and transport due to endogenous and exogenous proteinases. Nanoparticles composed of a N-isopropylacrylamide hydrogel core shell functionalized with internal affinity baits are a new technology that can address all of these critical analytical challenges for disease biomarker discovery and measurement. Core-shell, bait containing, nanoparticles can perform four functions in one step, in solution, in complex biologic fluids (e.g. blood or urine): a) molecular size sieving, b) complete exclusion of high abundance unwanted proteins, c) target analyte affinity sequestration, and d) complete protection of captured analytes from degradation. Targeted classes of protein analytes sequestered by the particles can be concentrated in small volumes to effectively amplify (up to 100 fold or greater depending on the starting sample volume) the sensitivity of mass spectrometry, western blotting, and immunoassays. The materials utilized for the manufacture of the particles are economical, stable overtime, and remain fully soluble in body fluids to achieve virtually 100 percent capture of all solution phase target proteins within a few minutes.
This nonrandomized phase I/II trial assessed the efficacy/tolerability of imatinib plus panitumumab in patients affected by metastatic colorectal cancer (mCRC) after stratification to treatment by selection of activated imatinib drug targets using reverse-phase protein array (RPPA). mCRC patients presenting with a biopsiable liver metastasis were enrolled. Allocation to the experimental and control arms was established using functional pathway activation mapping of c-Kit, PDGFR, and c-Abl phosphorylation by RPPA. The experimental arm received run-in escalation therapy with imatinib followed by panitumumab. The control arm received panitumumab alone. Seven patients were enrolled in the study. For three of the seven patients, sequential pre- and post-treatment biopsies were used to evaluate the effect of the therapeutic compounds on the drug targets and substrates. A decrease in the activation level of the drug targets and downstream substrates was observed in two of three patients. Combination therapy increased the activation of the AKT-mTOR pathway and several receptor tyrosine kinases. This study proposes a novel methodology for stratifying patients to personalized treatment based on the activation level of the drug targets. This workflow provides the ability to monitor changes in the signaling pathways after the administration of targeted therapies and to identify compensatory mechanisms.
TPS11123 Background: The objective of this prospective pilot study was to determine if treatment selected by molecular profiling (MP) of metastatic breast cancer (MBC) tumors at time of disease progression provides greater clinical benefit than empiric treatment selection. Methods: Eligible pts had MBC, ≥ 3 prior lines of therapy, and > 6 wks - < 6 months time to progression on last treatment prior to study entry. Fresh core biopsy samples were taken from the metastatic site for MP. Analysis by IHC, FISH, DNA microarray and reverse phase protein microarray (RPMA) a quantitative protein pathway activation mapping technique using laser capture micro dissected tumor cells was done, with results in ≤14 days reviewed by a Treatment Selection Committee. The primary objective was to compare the progression-free survival (PFS) using a MP selected treatment regimen to the preceding PFS. Clinical benefit for the pt is defined by PFS ratio (PFS on MP selected therapy/PFS on prior therapy) is ≥ 1.3, (JCO,28:4877-83:2010). N= 25 was determined (exact single-stage design for phase II studies, type I error rate of 5% [one-sided], power of 90%). MP selected therapy would warrant further investigation if ≥ 35% of the pts demonstrate a PFS ratio of ≥ 1.3. Results: Three U.S. sites enrolled 25 evaluable pts who were treated based on MP results. Pts were heavily pretreated with 4 -11 prior therapies (median 7.24). Ten pts (40%) met or exceeded the PFS ratio of 1.3. The most common targets used in drug treatment selection were TOPO1, TS, ER/PR, TOP2A, HER2. Sixty percent of pts’ samples had activation of drug targets determined by RPMA in 3 major clusters: pan-HER-AKT; EGFR/SRC/ERK/mTOR; IGFR/RAF/MEK/PLK1. Days on MP selected treatments range from 9 - 816+. 3 pts continue on treatment for 199, 254 and 816 days. Conclusions: This study demonstrates the feasibility of a highly multiplexed genomic and proteomic MP study for treatment selection in a timely fashion. Patient-specific target driven treatment selection based on MP of a metastatic lesion provided clinical benefit for 10 of 25 heavily pretreated MBC pts. Thus, this approach merits further investigation in future studies. Funded by The Side-Out Foundation. Clinical trial information: NCT01074814.
A cohort consisting of asymptomatic health care workers (HCW) donated temporal serum samples following infection with SARS-CoV-2. Analysis shows that all asymptomatic HCW had neutralizing antibodies, that these antibodies persist for at least 60 days, and that anti-spike RBD IgG levels were correspondingly durable over the same time period.
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