RAAV-delivered PTEN therapeutics for prostate cancer

Jianzhong Ai,Jia Li,Qin Su,Hong Ma,Qiang Wei,Hong Li,Guangping Gao

doi:10.1016/j.omtn.2021.11.018

Abstract

Effective treatments for prostate cancer (PCa) require further development, and previous studies have reported that PTEN and its downstream target CDKN1B are significantly downregulated in PCa cells compared with normal cells. Therefore, modulation of PTEN and CDKN1B expression might be a promising therapeutic approach for PCa treatment. Expression of PTEN and CDKN1B was verified in specimens from PCa patients and transgenic adenocarcinoma mouse prostate (TRAMP) mice. The effect of PTEN on PCa cell migration, apoptosis, and the cell cycle was analyzed in vitro using a wound-healing assay and flow cytometry. We assessed the ability of intraprostatic and intratumoral injections of recombinant adeno-associated virus (rAAV) 9 expressing Pten or Cdkn1b into TRAMP mice and a subcutaneous tumor xenograft mouse model, respectively, to inhibit PCa progression. PTEN and CDKN1B were significantly downregulated in human and mouse PCa samples, and CDKN1B expression correlated positively with PTEN expression. PTEN overexpression significantly inhibited cell migration and cell-cycle progression and promoted apoptosis in PCa cells by decreasing Ccnd1 expression and increasing that of Cdkn1b. Importantly, treatment with the rAAV9.Pten or rAAV9.Cdkn1b extended the lifespan of TRAMP mice and inhibited the growth rate of tumor xenografts by regulating downstream gene expression. Moreover, neoplasia in treated prostates was significantly diminished compared with that in control prostates, and apoptosis was markedly observed in xenografts treated with Pten or Cdkn1b. These data indicate that rAAV-based PTEN/CDKN1B delivery is promising for the development of novel therapeutics for PCa.

Highlights

Prostate cancer (PCa) is the second most commonly diagnosed cancer and the second leading cause of cancer-related deaths among men in 46 countries.[1]
Decreased expression of CDKN1B in prostate cancer (PCa) samples By mining The Cancer Genome Atlas (TCGA) data, we found that CDKN1B expression was markedly reduced in PCa samples (Figure 2A) and that its expression was positively correlated with Phosphatase and tensin homolog (PTEN) expression (r = 0.4776) (Figure 2B)
Tumor cells can become resistant to this type of treatment due to genomic reprogramming or other causes, whereby androgen-dependent PCa (ADPC) evolves toward castration-resistant PCa (CRPC)

Summary

Introduction

Prostate cancer (PCa) is the second most commonly diagnosed cancer and the second leading cause of cancer-related deaths among men in 46 countries.[1] Drugs for different targets have been developed for the treatment of PCa, including sipuleucel-T,2 abiraterone,[3] enzalutamide,[4] and docetaxel.[5] tumor cell growth and metastasis are not completely inhibited by these therapeutics, and PCa relapse is a major challenge for the effective treatment of PCa. In recent decades, many studies have investigated the underlying mechanism involved in the occurrence and development of PCa, and many innovative drug candidates have been provided,[6,7] though the efficacies of these drugs need to be improved. Novel therapeutics should be developed for effective PCa treatment based on different perspectives

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