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Old 05-18-2014, 02:15 PM   #1
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Post Profiling of signaling pathways in live tumor cells to assess drug mechanism of actio

Profiling of signaling pathways in live tumor cells to assess drug mechanism of action: A method to predict drug efficacy in a patient.

Abstract No:
Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with the 2014 ASCO Annual Meeting but not presented at the Meeting, can be found online only.

Author(s): Lance G. Laing, Ian A. MacNeil, Benjamin E. Rich, Edward Greeno; Celcuity LLC, Medina, MN; University of Minnesota, Minneapolis, MN
Abstract Disclosures


Background: This work reports a dynamic real time analysis of live cells to detect drug attenuation of cell signaling related to the MOA of a targeted therapy. The assay employs an impedance biosensor to detect cellular changes in close proximity to a nanoelectrode caused by specific pathway perturbation. When applied to live patient diseased cells ex vivo, this approach holds great promise to determine a priori whether a targeted drug therapy will clinically benefit that patient. If the targeted therapy is not functional in the patientís cells ex vivo, then it is not likely to function as intended in the patient. Methods: To demonstrate the utility of the assay, HER2+ and ER+/HER2- live breast cancer cell samples (both cell lines and primary cells from fresh tumor specimens) were tested with 6 targeted breast cancer therapies and specific pathway stimulating ligands corresponding to each drug target. Real time signaling impedance profiles were generated for each live cell sample under 3 different conditions: 1) buffer only (C); 2) addition of targeted therapy followed by ligand (CDF); and 3) cells exposed only to the pathway ligand (CF). In the first test series, 20 HER2+ breast cancer cell lines were exposed to lapatinib (an ErbB receptor disrupter). In another test series, 10 ER+/HER2- breast cancer cell lines were tested with 4 standard therapies, letrozole, tamoxifen, fulvestrant, and everolimus, with endocrine (ERa) or PI3K (mTOR) stimulation . This test series was repeated using 10 different ER+/HER2- breast cancer primary cell samples derived from fresh tumor specimens. Changes in cell signaling activity for the C, CDF, and CF samples were measured. Results: In each test series, the cell lines and primary cell samples demonstrated wide variation of signaling stimulation (delta low-high = 500%). Each drug also demonstrated a wide variation in ability to attenuate pathway signaling (ranging from <5% to >70%). These results were completely concordant with immuno-capture results evaluating pathway members. Conclusions: The results confirm the assayís ability to detect broad sensitivity differences to pathway stimulation and drug attenuation thereof in individual cell samples.
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