Abstract 750: Nanoliposomal targeting of Ephrin receptor A2 (EphA2): Clinical translation

Autor: Dmitri B. Kirpotin, Lia Luus, Walid S. Kamoun, Tad Kornaga, Daryl C. Drummond, James D. Marks, Alexey Lugovskoy, Minh T. Pham, Lihui Xu, Shinji Oyama, Carl Morrisson, Theresa Feng, Melissa Geddie, Monica L. Murphy
Rok vydání: 2016
Předmět:
Zdroj: Cancer Research. 76:750-750
ISSN: 1538-7445
0008-5472
Popis: Ephrin receptor A2 (EphA2) is part of the Ephrin family of cell-cell junction proteins highly overexpressed in several solid tumors, and is associated with poor prognosis. We developed a novel EphA2-targeted docetaxel nanoliposome, leveraging organ specificity through enhanced permeability effect and cellular specificity through EphA2 targeting. The goal of the study was to develop the diagnostic framework enabling the clinical implementation of EphA2-based exclusion criteria in future MM-310 trials. We used qFACS and an in vitro assay for liposome (Ls)-cell interaction to identify the minimum number of EphA2 receptors to enable antibody-mediated internalization of Ls. We developed an IHC assay able to differentiate EphA2 - vs + cell lines. We characterized EphA2 staining pattern in tumor samples of various indications and developed a scoring algorithm that allows selection of patients in early clinical trials. While non targeted Ls do not associate with cells in vitro, there is a strong correlation between EphA2 expression and EphA2-Ls cell association independent of the cell line origin. We used the non-targeted Ls to determine the extent of non-specific binding that can be achieved (∼340 Ls/cell) and used partitioning to determine the minimum number of EphA2 receptors necessary to mediate targeting (∼3000 receptors/cell). We have developed and validated a qIHC assay for EphA2 (precision ∼90%, linearity 0.8 and reproducibility ∼5%). We stained a set of ∼200 tumor samples from various indications. EphA2 was found to be expressed in tumor cells, tumor-associated myofibroblasts, and tumor-associated blood vessels. Using an inclusive cutoff of 10%, EphA2 prevalence was found to range from 50% to 100% in the tumor types evaluated. No significant difference in staining was seen between metastasis and primary tumors in matched samples. In summary, we developed a diagnostic framework for prospective selection of EphA2+ patients for MM-310 trials based on a mechanistic single cell cut-off, and a clinical-grade IHC assay. Cancer CellsTumor associated myofibroblastsTumor associated blood vesselsEphA2 Overall ScoreBladder19/20 (95%)0/20 (0%)16/20 (80%)19/20 (95%)Gastric18/20 (90%)3/20 (15%)17/20 (85%)20/20 (100%)Head & Neck16/19 (84%)0/19 (0%)9/19 (47%)19/19 (100%)Lung24/41 (58%)1/41 (2.4%)24/41 (58%)28/41 (68%)Lung-FNA7/9 (78%)––7/9 (78%)Ovarian10/18 (55%)7/18 (39%)17/18 (95%)17/18 (95%)Pancreatic15/19 (79%)0/19 (0%)11/19 (58%)17/19 (89%)Prostate7/23 (27%)7/23 (27%)9/23 (28%)12/23 (52%)TNBC6/77 (7%)0/77 (0%)34/77 (44%)37/77 (48%) Citation Format: Walid S. Kamoun, Shinji Oyama, Tad Kornaga, Theresa Feng, Lia Luus, Minh T. Pham, Dmitri B. Kirpotin, James D. Marks, Melissa Geddie, Lihui Xu, Alexey A. Lugovskoy, Monica Murphy, Carl Morrisson, Daryl C. Drummond. Nanoliposomal targeting of Ephrin receptor A2 (EphA2): Clinical translation. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 750.
Databáze: OpenAIRE
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