Patient-derived Models of Abiraterone- and Enzalutamide-resistant Prostate Cancer Reveal Sensitivity to Ribosome-directed Therapy

Eur Urol. 2018 Nov;74(5):562-572. doi: 10.1016/j.eururo.2018.06.020. Epub 2018 Jul 23.

Abstract

Background: The intractability of castration-resistant prostate cancer (CRPC) is exacerbated by tumour heterogeneity, including diverse alterations to the androgen receptor (AR) axis and AR-independent phenotypes. The availability of additional models encompassing this heterogeneity would facilitate the identification of more effective therapies for CRPC.

Objective: To discover therapeutic strategies by exploiting patient-derived models that exemplify the heterogeneity of CRPC.

Design, setting, and participants: Four new patient-derived xenografts (PDXs) were established from independent metastases of two patients and characterised using integrative genomics. A panel of rationally selected drugs was tested using an innovative ex vivo PDX culture system.

Intervention: The following drugs were evaluated: AR signalling inhibitors (enzalutamide and galeterone), a PARP inhibitor (talazoparib), a chemotherapeutic (cisplatin), a CDK4/6 inhibitor (ribociclib), bromodomain and extraterminal (BET) protein inhibitors (iBET151 and JQ1), and inhibitors of ribosome biogenesis/function (RNA polymerase I inhibitor CX-5461 and pan-PIM kinase inhibitor CX-6258).

Outcome measurements and statistical analysis: Drug efficacy in ex vivo cultures of PDX tissues was evaluated using immunohistochemistry for Ki67 and cleaved caspase-3 levels. Candidate drugs were also tested for antitumour efficacy in vivo, with tumour volume being the primary endpoint. Two-tailed t tests were used to compare drug and control treatments.

Results and limitations: Integrative genomics revealed that the new PDXs exhibited heterogeneous mechanisms of resistance, including known and novel AR mutations, genomic structural rearrangements of the AR gene, and a neuroendocrine-like AR-null phenotype. Despite their heterogeneity, all models were sensitive to the combination of ribosome-targeting agents CX-5461 and CX-6258.

Conclusions: This study demonstrates that ribosome-targeting drugs may be effective against diverse CRPC subtypes including AR-null disease, and highlights the potential of contemporary patient-derived models to prioritise treatment strategies for clinical translation.

Patient summary: Diverse types of therapy-resistant prostate cancers are sensitive to a new combination of drugs that inhibit protein synthesis pathways in cancer cells.

Keywords: Abiraterone; Androgen receptor; Castration-resistant prostate cancer; Enzalutamide; Explant; Neuroendocrine prostate cancer; Organoid; Patient-derived xenograft; Prostate cancer; Ribosome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Androstenes / pharmacology*
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Azepines / pharmacology*
  • Benzothiazoles / pharmacology*
  • Drug Resistance, Neoplasm*
  • Humans
  • Indoles / pharmacology*
  • Male
  • Mice, Inbred NOD
  • Mice, SCID
  • Molecular Targeted Therapy
  • Naphthyridines / pharmacology*
  • Phenylthiohydantoin / analogs & derivatives*
  • Phenylthiohydantoin / pharmacology
  • Prostatic Neoplasms, Castration-Resistant / drug therapy*
  • Prostatic Neoplasms, Castration-Resistant / enzymology
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Proto-Oncogene Proteins c-pim-1 / antagonists & inhibitors
  • Proto-Oncogene Proteins c-pim-1 / metabolism
  • RNA Polymerase I / antagonists & inhibitors
  • RNA Polymerase I / genetics
  • RNA Polymerase I / metabolism
  • Ribosomes / drug effects*
  • Ribosomes / enzymology
  • Ribosomes / genetics
  • Time Factors
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Androstenes
  • Antineoplastic Agents
  • Azepines
  • Benzothiazoles
  • CX 5461
  • CX-6258
  • Indoles
  • MDV 3100
  • Naphthyridines
  • Phenylthiohydantoin
  • Proto-Oncogene Proteins c-pim-1
  • proto-oncogene proteins pim
  • RNA Polymerase I
  • abiraterone