Targeting EphA2 in Bladder Cancer Using a Novel Antibody-Directed Nanotherapeutic
Ephrin receptor A2 (EphA2) is a member of the Ephrin/Eph receptor cell-to-cell signaling family of molecules, and it plays a key role in cell proliferation, differentiation, and migration. EphA2 is overexpressed in a broad range of cancers, and its expression is in many cases associated with poor pr...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-10-01
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| Series: | Pharmaceutics |
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| Online Access: | https://www.mdpi.com/1999-4923/12/10/996 |
| _version_ | 1797550398727258112 |
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| author | Walid Kamoun Elden Swindell Christine Pien Lia Luus Jason Cain Minh Pham Irawati Kandela Zhaohua Richard Huang Suresh K. Tipparaju Alexander Koshkaryev Vasileios Askoxylakis Dmitri B. Kirpotin Troy Bloom Mari Mino-Kenudson James D. Marks Alena Zalutskaya Wiam Bshara Carl Morrison Daryl C. Drummond |
| author_facet | Walid Kamoun Elden Swindell Christine Pien Lia Luus Jason Cain Minh Pham Irawati Kandela Zhaohua Richard Huang Suresh K. Tipparaju Alexander Koshkaryev Vasileios Askoxylakis Dmitri B. Kirpotin Troy Bloom Mari Mino-Kenudson James D. Marks Alena Zalutskaya Wiam Bshara Carl Morrison Daryl C. Drummond |
| author_sort | Walid Kamoun |
| collection | DOAJ |
| description | Ephrin receptor A2 (EphA2) is a member of the Ephrin/Eph receptor cell-to-cell signaling family of molecules, and it plays a key role in cell proliferation, differentiation, and migration. EphA2 is overexpressed in a broad range of cancers, and its expression is in many cases associated with poor prognosis. We recently developed a novel EphA2-targeting antibody-directed nanotherapeutic encapsulating a labile prodrug of docetaxel (EphA2-ILs-DTXp) for the treatment of EphA2-expressing malignancies. Here, we characterized the expression of EphA2 in bladder cancer using immunohistochemistry in 177 human bladder cancer samples and determined the preclinical efficacy of EphA2-ILs-DTXp in four EphA2-positive patient-derived xenograft (PDX) models of the disease, either as a monotherapy, or in combination with gemcitabine. EphA2 expression was detected in 80–100% of bladder cancer samples and correlated with shorter patient survival. EphA2 was found to be expressed in tumor cells and/or tumor-associated blood vessels in both primary and metastatic lesions with a concordance rate of approximately 90%. The EphA2-targeted antibody-directed nanotherapeutic EphA2-ILs-DTXp controlled tumor growth, mediated greater regression, and was more active than free docetaxel at equitoxic dosing in all four EphA2-positive bladder cancer PDX models. Combination of EphA2-ILs-DTXp and gemcitabine in one PDX model led to improved tumor growth control compared to monotherapies or the combination of free docetaxel and gemcitabine. These data demonstrating the prevalence of EphA2 in bladder cancers and efficacy of EphA2-ILs-DTXp in PDX models support the clinical exploration of EphA2 targeting in bladder cancer. |
| first_indexed | 2024-03-10T15:28:43Z |
| format | Article |
| id | doaj.art-8d1191f930f84ed890aae26feb4148ee |
| institution | Directory Open Access Journal |
| issn | 1999-4923 |
| language | English |
| last_indexed | 2024-03-10T15:28:43Z |
| publishDate | 2020-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceutics |
| spelling | doaj.art-8d1191f930f84ed890aae26feb4148ee2023-11-20T17:49:03ZengMDPI AGPharmaceutics1999-49232020-10-01121099610.3390/pharmaceutics12100996Targeting EphA2 in Bladder Cancer Using a Novel Antibody-Directed NanotherapeuticWalid Kamoun0Elden Swindell1Christine Pien2Lia Luus3Jason Cain4Minh Pham5Irawati Kandela6Zhaohua Richard Huang7Suresh K. Tipparaju8Alexander Koshkaryev9Vasileios Askoxylakis10Dmitri B. Kirpotin11Troy Bloom12Mari Mino-Kenudson13James D. Marks14Alena Zalutskaya15Wiam Bshara16Carl Morrison17Daryl C. Drummond18Merrimack Pharmaceuticals, Inc., Cambridge, MA 02142, USAMerrimack Pharmaceuticals, Inc., Cambridge, MA 02142, USAMerrimack Pharmaceuticals, Inc., Cambridge, MA 02142, USAMerrimack Pharmaceuticals, Inc., Cambridge, MA 02142, USAMerrimack Pharmaceuticals, Inc., Cambridge, MA 02142, USAMerrimack Pharmaceuticals, Inc., Cambridge, MA 02142, USADevelopmental Therapeutics Core Facility, Northwestern University, Evanston, IL 60208, USAMerrimack Pharmaceuticals, Inc., Cambridge, MA 02142, USAMerrimack Pharmaceuticals, Inc., Cambridge, MA 02142, USAMerrimack Pharmaceuticals, Inc., Cambridge, MA 02142, USAMerrimack Pharmaceuticals, Inc., Cambridge, MA 02142, USAMerrimack Pharmaceuticals, Inc., Cambridge, MA 02142, USAMerrimack Pharmaceuticals, Inc., Cambridge, MA 02142, USAMassachusetts General Hospital, Harvard Medical School, Boston, MA 02115, USADepartments of Anesthesia and Pharmaceutical Chemistry, University of California at San Francisco, San Francisco, CA 94110, USAMerrimack Pharmaceuticals, Inc., Cambridge, MA 02142, USARoswell Park Cancer Institute, Buffalo, NY 14203, USARoswell Park Cancer Institute, Buffalo, NY 14203, USAMerrimack Pharmaceuticals, Inc., Cambridge, MA 02142, USAEphrin receptor A2 (EphA2) is a member of the Ephrin/Eph receptor cell-to-cell signaling family of molecules, and it plays a key role in cell proliferation, differentiation, and migration. EphA2 is overexpressed in a broad range of cancers, and its expression is in many cases associated with poor prognosis. We recently developed a novel EphA2-targeting antibody-directed nanotherapeutic encapsulating a labile prodrug of docetaxel (EphA2-ILs-DTXp) for the treatment of EphA2-expressing malignancies. Here, we characterized the expression of EphA2 in bladder cancer using immunohistochemistry in 177 human bladder cancer samples and determined the preclinical efficacy of EphA2-ILs-DTXp in four EphA2-positive patient-derived xenograft (PDX) models of the disease, either as a monotherapy, or in combination with gemcitabine. EphA2 expression was detected in 80–100% of bladder cancer samples and correlated with shorter patient survival. EphA2 was found to be expressed in tumor cells and/or tumor-associated blood vessels in both primary and metastatic lesions with a concordance rate of approximately 90%. The EphA2-targeted antibody-directed nanotherapeutic EphA2-ILs-DTXp controlled tumor growth, mediated greater regression, and was more active than free docetaxel at equitoxic dosing in all four EphA2-positive bladder cancer PDX models. Combination of EphA2-ILs-DTXp and gemcitabine in one PDX model led to improved tumor growth control compared to monotherapies or the combination of free docetaxel and gemcitabine. These data demonstrating the prevalence of EphA2 in bladder cancers and efficacy of EphA2-ILs-DTXp in PDX models support the clinical exploration of EphA2 targeting in bladder cancer.https://www.mdpi.com/1999-4923/12/10/996bladder cancerEphA2antibody directed nanotherapeuticliposomesimmunoliposomesnanocarrier |
| spellingShingle | Walid Kamoun Elden Swindell Christine Pien Lia Luus Jason Cain Minh Pham Irawati Kandela Zhaohua Richard Huang Suresh K. Tipparaju Alexander Koshkaryev Vasileios Askoxylakis Dmitri B. Kirpotin Troy Bloom Mari Mino-Kenudson James D. Marks Alena Zalutskaya Wiam Bshara Carl Morrison Daryl C. Drummond Targeting EphA2 in Bladder Cancer Using a Novel Antibody-Directed Nanotherapeutic Pharmaceutics bladder cancer EphA2 antibody directed nanotherapeutic liposomes immunoliposomes nanocarrier |
| title | Targeting EphA2 in Bladder Cancer Using a Novel Antibody-Directed Nanotherapeutic |
| title_full | Targeting EphA2 in Bladder Cancer Using a Novel Antibody-Directed Nanotherapeutic |
| title_fullStr | Targeting EphA2 in Bladder Cancer Using a Novel Antibody-Directed Nanotherapeutic |
| title_full_unstemmed | Targeting EphA2 in Bladder Cancer Using a Novel Antibody-Directed Nanotherapeutic |
| title_short | Targeting EphA2 in Bladder Cancer Using a Novel Antibody-Directed Nanotherapeutic |
| title_sort | targeting epha2 in bladder cancer using a novel antibody directed nanotherapeutic |
| topic | bladder cancer EphA2 antibody directed nanotherapeutic liposomes immunoliposomes nanocarrier |
| url | https://www.mdpi.com/1999-4923/12/10/996 |
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