A novel exosome based therapeutic intervention against neuroendocrine prostate cancer
Sharanjot Saini1,2, Amritha Sreekumar3, Sandip Nathani3
1Department of Biochemistry and Molecular Biology, Augusta University, 1410 Laney Walker Boulevard, Augusta, GA, 30912, USA. ssaini@augusta.edu.
Abstract:
Neuroendocrine prostate cancer (NEPC) is a highly lethal variant of castration-resistant prostate cancer (CRPC) with poor survival rates. Current treatment options for NEPC are limited to highly toxic platinum drugs highlighting the urgent need for new therapies. This study aimed to develop a novel therapeutic approach using engineered exosomes against NEPC. Exosomes were modified to target CEACAM5, an NEPC surface antigen, by attaching CEACAM5 antibodies to HEK293T exosomes. These exosomes were loaded with drugs inhibiting EZH2 and the androgen receptor (AR) as recent research shows a persistent role of AR in NEPC wherein it plays a concerted role with EZH2 in driving neuronal gene programs. In vitro experiments with NEPC cell lines demonstrated that CEACAM5-targeted exosomes were specifically taken up by NEPC cells, leading to reduced cellular viability and decreased expression of neuronal markers. Further in vivo tests using a NEPC patient-derived xenograft model (LuCaP145.1) showed significant tumor regression in mice treated with engineered exosomes compared to control mice receiving IgG-labeled exosomes. These results suggest that CEACAM5-engineered exosomes hold promise as a targeted therapy for NEPC. Importantly, our exosome engineering strategy is versatile and can be adapted to target various surface antigens in prostate cancer and other diseases.
Insights
Engineered exosomes targeting CEACAM5 show promise for treating neuroendocrine prostate cancer (NEPC). This novel therapy reduced tumor growth in preclinical models, offering a potential new treatment for this aggressive disease.
Area of Science:
- Oncology
- Nanomedicine
- Biotechnology
Background:
- Neuroendocrine prostate cancer (NEPC) is an aggressive variant of castration-resistant prostate cancer (CRPC) with limited therapeutic options.
- Current treatments for NEPC, primarily platinum drugs, are highly toxic and have poor survival outcomes.
- There is an urgent need for novel, targeted therapies for NEPC.
Purpose of the Study:
- To develop and evaluate engineered exosomes as a targeted therapeutic strategy for NEPC.
- To investigate the efficacy of exosomes engineered to target the NEPC surface antigen CEACAM5.
- To assess the combined inhibition of EZH2 and the androgen receptor (AR) within targeted exosomes.
Main Methods:
- HEK293T exosomes were modified to target CEACAM5 by attaching specific antibodies.
- Exosomes were loaded with drugs targeting EZH2 and the androgen receptor (AR).
- In vitro studies utilized NEPC cell lines, and in vivo studies employed a patient-derived xenograft model (LuCaP145.1).
Main Results:
- CEACAM5-targeted exosomes demonstrated specific uptake by NEPC cells in vitro.
- Engineered exosomes significantly reduced NEPC cell viability and suppressed neuronal marker expression.
- In vivo studies showed significant tumor regression in mice treated with engineered exosomes compared to controls.
- The exosome engineering approach proved versatile for targeting various antigens.
Conclusions:
- CEACAM5-engineered exosomes represent a promising targeted therapy for NEPC.
- This novel exosome-based strategy offers a potential new avenue for treating aggressive prostate cancer.
- The adaptable exosome engineering platform can be applied to other cancer types and diseases.
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