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Patient-derived models of abiraterone- and enzalutamide-resistant prostate cancer reveal sensitivity to ribosome-directed therapy

Authors Lawrence, Obinata, Sandhu et al.

Review Date August 2018

Citation Eur Urol. 2018. pii: S0302-2838(18)30445-7.

Background

Patient derived xenografts (PDX) have become a valuable tool for medical research to investigate the biology of human cancers in the laboratory, and to test novel therapies on curtailing tumour growth. Primary tumours studied in this setting remain faithful to their genomic identity and recapitulate the tumour microenvironment, making them fertile preclinical models.

PDX for prostate cancer are not widely described as they are more difficult to grow than some other tumours. However a team of researchers have successfully established PDX models of advanced prostate cancer, derived from metastatic castration-resistant prostate cancer (CRPC). CRPC is extremely challenging to treat because despite initial responsiveness to androgen deprivation therapy (ADT), these aggressive cancers develop pathways of resistance and typically maintain androgen receptor (AR) signalling. Clinical and genomic tumour heterogeneity add a further layer of complexity for treating these advanced cancers.

Aim

To establish and characterise new PDX models from patients with metastatic CRPC and to evaluate the anti-tumour efficacy of a panel of candidate drugs.

Methods

Four new PDX models were derived from two patients with CRPC resistant to conventional ADT (direct AR inhibitors, abiraterone and enzalutamide) and standard chemotherapy. Established PDX models were subjected to DNA and RNA sequencing, and preclinical drug testing.

Results

Genomic sequencing of the established PDX models confirmed that they recapitulated their primary tumours and that they possessed heterogeneity typical of CRPC. As expected these castration-resistant PDXs were generally responsive to androgens. Varying mechanisms of castration-resistance were uncovered in the different PDX models, including novel AR mutations and structural rearrangements of the AR gene, and in one model a transition to an AR independent phenotype.

Based on gene pathways enriched in the PDX models, candidate drugs were identified and first tested using ex vivo explant and organoid approaches. Therapies that were evaluated included inhibitors of AR-signalling, DNA repair, cell-cycle, MYC signalling and protein synthesis. Dual treatment using two inhibitors of ribosome function (protein synthesis), CX-5461 and CX-6258, led to promising and universal signs of anti-tumour efficacy across the models. These drugs were then tested on two PDX tumours in vivo, and shown to significantly reduce tumour volume after two weeks of treatment.

Conclusion

CRPCs exhibit diverse mechanisms of castration-resistance. Combination therapy using drug inhibitors of ribosome biogenesis (RNA polymerase I transcription inhibitor – CX-5461) and ribosome function (pan-PIM kinase inhibitor – CX-6258) to suppress protein synthesis, effectively inhibited tumour growth in the preclinical setting.

Points to Note

1. The authors note that the use of only four PDXs from soft tissue metastases is a study limitation, and a reflection of the challenges in establishing viable PDX models for prostate cancer research.

2. Anti-tumour efficacy was determined by measuring tumour volume after two weeks of treatment in vivo; however the long-term efficacy and survival analyses weren’t included.

3. These results suggest that the unchecked proliferation found in CRPC is driven by high rates of protein synthesis, and blocking such pathways may provide therapeutic benefit.

4. Drugs to target ribosome function are currently under clinical trial for other cancers, including breast and blood. Clinical trials for their evaluation in advanced prostate cancer are justified.


Website: https://www.ncbi.nlm.nih.gov/pubmed/30049486

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