NANODELIVERY OF SPECIFIC GENOME ENGINEERING TOOLS AS A NOVEL THERAPEUTIC APPROACH FOR AGGRESSIVE PROSTATE CANCERS

Prostate cancer is the second most common diagnosed malignancy and the fifth leading cause of cancer mortality in men.

Whilst primary tumours respond well to therapy, tumours in the metastatic setting become inherently resistant to chemotherapy.

Thus, more novel and effective therapeutic approaches are highly needed to treat this lethal disease.The cornerstone treatment for advanced prostate cancer consists of androgen deprivation therapy and docetaxel (DTX). However, both DTX activity and Androgen receptor (AR) signalling are highly interrelated.

On the one hand, it has been shown that DTX is able to inhibit Androgen Receptor (AR) signalling and on the other hand, the activation of AR signaling can induce DTX insensitivity.

In order to break this dependency of DTX effectiveness on AR signaling and ensure efficient treatment for advanced prostate cancer, we propose the selective inhibition of AR deploying CRISPR/Cas9 technology together with DTX.

Both therapeutical approaches will be encapsulated into prostate-specific targeted nanoparticles which will allow the simultaneous delivery of the drug and CRISPR plasmids targeting AR into the tumour site.

The designed state-of-art multi-functional nanoparticles will reprogram and sensitise the prostate tumour to DTX in situ, and will also induce a higher accumulation of the treatment in the tumour while healthy tissues will remain less affected.

Moreover, the use of CRISPR/Cas9 will precisely engineer the prostate cancer cells to express lower levels of AR, contrasting with current anti-AR treatments, which have multiple off-targets.This approach represents an innovative targeted therapy for advanced prostate cancer.

It will allow the administration of lower doses of chemotherapy with consequently reduced toxicity and the potential for longer tolerated treatment periods, whilst improving efficacy by selectively suppressing the molecular pathways causing cancer survival and resistance to treatment.