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Prostate cancer extracellular vesicles as biomarkers for nanomedicine treatment

Periodic Reporting for period 1 - PREVENT (Prostate cancer extracellular vesicles as biomarkers for nanomedicine treatment)

Reporting period: 2015-09-14 to 2017-09-13

Prostate cancer (PC) is one of the deadliest types of cancer in males worldwide. Early stage PC is often curable but many patients develop castration-resistant prostate cancer (CRPC), resulting in lethal end-stage disease. Prostate specific antigen (PSA) plasma levels have been traditionally exploited for diagnosis and prognosis. However, PSA screening is characterized by high variability leading to false-positive outcomes. Advanced therapies are required for the treatment of CRPC, guided by a reliable companion diagnostic test (CDx) for patient selection and to monitor therapeutic efficacy. The aim of this proposal is to co-develop for the first time a nanomedicine combination therapy and a CDx based on extracellular vesicles (EVs) for the treatment of CRPC. I will employ tumor-targeted nanomedicines to deliver more drug to the tumor and reduce side effects when compared to free drug. The treatment comprises microfluidics-prepared lipid nanoparticles (LNPs) containing siRNAs that target essential CRPC genes, combined with LNPs loaded with the cytotoxic anti-cancer agent docetaxel to achieve synergistic therapeutic effects. Regarding the CDx, EVs have created excitement as potential biomarker candidates. EVs are released by cells as means of intercellular communication and can be detected in bodily fluids. The number of EVs and their composition is altered in CRPC, raising opportunities to exploit them in a CDx. As EVs provide a fingerprint of their parental cell, EVs can be considered as liquid biopsies which provide more information than standard biomarker measurements and are much less invasive than prostate biopsies. I will collect blood and urine samples during the preclinical evaluation of the proposed treatment for EV analysis by surface markers, protein content and RNA content. The co-development of a nanomedicine combination treatment for CRPC and a CDx is a rational strategy that has the potential to advance into clinical evaluation and ultimately improve patient survival.
In the four months that the project was active, the following results have been achieved:
- Design and optimization of siRNAs that induce knockdown of wild type and variant androgen receptor
- Formulation of siRNAs in lipid nanoaparticles (LNPs) using microfluidic and inline mixing methods
- Assessment of the therapeutic efficacy of LNPs containing siRNA against the androgen receptor as measured by target gene knockdown and cell viability
Although the project was only active for four months, it is clear that microfluidics- or inline-based production of LNPs is cost-effective, reproducible and straightforward. LNPs are the most clinically advanced delivery siRNA delivery systems, exemplified by Patisiran which is currently in phase III. The stable encapsulation of siRNA that silences both wild type and variant androgen receptor (AR) has considerable potential to impact on prostate cancer treatment. As current AR inhibitors such as enzalutamide and abiraterone inhibit AR signaling by preventing interaction of androgens with the ligand binding domain of the receptor, they are not able to inhibit constitutively active AR variants where the ligand binding domain is spliced out. Castration-resistant prostate cancer is characterized by the expression of AR variants and inhibitors are currently being developed against the DNA binding domain or the N-terminus domain of AR. Continued development of the LNPs with AR siRNA could not only lead to a nanomedicine that would be beneficial inhibition of wild type and varaint AR, but also provides oppertunities to include other drugs in the formulation, such as chemotherapeutics, for combination therapy.