Targeting EphA2 in Bladder Cancer Using a Novel Antibody-Directed Nanotherapeutic
Walid Kamoun1, Elden Swindell1, Christine Pien1
1Merrimack Pharmaceuticals, Inc., Cambridge, MA 02142, USA.
Abstract:
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.
Insights
Ephrin receptor A2 (EphA2) is highly expressed in bladder cancer, correlating with poor prognosis. A novel nanotherapeutic targeting EphA2 demonstrated significant preclinical efficacy in bladder cancer models, supporting its clinical investigation.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Ephrin receptor A2 (EphA2) is a key cell signaling molecule implicated in cancer progression.
- EphA2 overexpression is linked to poor prognosis in various malignancies.
- Targeting EphA2 presents a potential therapeutic strategy for cancer treatment.
Purpose of the Study:
- To characterize EphA2 expression in human bladder cancer samples.
- To evaluate the preclinical efficacy of a novel EphA2-targeted nanotherapeutic (EphA2-ILs-DTXp) in bladder cancer patient-derived xenograft (PDX) models.
- To assess the combination therapy of EphA2-ILs-DTXp with gemcitabine.
Main Methods:
- Immunohistochemistry was used to assess EphA2 expression in 177 bladder cancer samples.
- Preclinical efficacy studies were conducted in four EphA2-positive bladder cancer PDX models.
- EphA2-ILs-DTXp was tested as monotherapy and in combination with gemcitabine.
Main Results:
- EphA2 expression was detected in 80-100% of bladder cancer samples and correlated with reduced patient survival.
- EphA2-ILs-DTXp demonstrated superior tumor growth control and regression compared to free docetaxel in all tested PDX models.
- Combination therapy with EphA2-ILs-DTXp and gemcitabine showed enhanced tumor growth control.
Conclusions:
- EphA2 is prevalent in bladder cancer and associated with adverse outcomes.
- The EphA2-targeted nanotherapeutic EphA2-ILs-DTXp exhibits significant preclinical anti-tumor activity in bladder cancer.
- These findings support the clinical evaluation of EphA2-targeted therapies for bladder cancer treatment.
