Oral Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Co-targeting BET, CBP, and p300 inhibits neuroendocrine signalling in androgen receptor-null prostate cancer (#31)

Nicholas Choo 1 , Shivakumar Keerthikumar 1 2 3 , Susanne Ramm 3 4 , Daisaku Ashikari 1 5 , Kaylene J Simpson 3 4 6 , Renea A Taylor 2 3 7 8 , Gail P Risbridger 1 2 3 8 , Mitchell G Lawrence 1 2 3 8
  1. Department of Anatomy and Developmental Biology, Biomedicine Discovery Institute , Monash University, Clayton, Victoria, Australia
  2. Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  3. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
  4. Victorian Centre for Functional Genomics, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  5. Department of Urology, Nihon University School of Medicine, Tokyo, Japan
  6. Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, Victoria, Australia
  7. Department of Physiology, Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia
  8. Cabrini Institute, Cabrini Health, Malvern, Victoria, Australia

Diverse phenotypes of castration-resistant prostate cancer (CRPC), including neuroendocrine disease, have differing sensitivity to drug treatment. The efficacy of BET and CBP/p300 inhibitors in prostate cancer is attributed, at least in part, to their ability to decrease androgen receptor (AR) signalling. However, the activity of BET and CBP/p300 inhibitors in prostate cancers that lack the AR is unclear. Therefore, our goal was to use patient-derived models to investigate the response of AR-null tumours to BET and CBP/p300 inhibition.

We performed immunohistochemical staining of BRD4, CBP, and p300 in 170 prostate cancer patient-derived xenografts (PDX) from the MURAL and Movember GAP1 consortium. We next treated diverse prostate cancer organoids in a high-content assay, as well as PDXs with neuroendocrine pathology, with NEO2734, a first-in-class dual inhibitor of BET and CBP/p300 proteins in phase 1 trials for CRPC. RNAseq analysis was performed on these tumours collected after acute and long-term NEO2734 treatment to investigate transcriptional responses.

Across large cohorts of PDXs, BRD4, CBP, and p300 were co-expressed in AR-positive and AR-null prostate cancer. NEO2734 reduced the growth of both AR-positive and AR-null organoids, as measured by multiple independent readouts of viability, size and composition, and caused consistent transcriptional downregulation of cell cycle pathways. In neuroendocrine models, NEO2734 treatment reduced ASCL1 levels and other neuroendocrine markers, and reduced tumour growth in vivo.

These results show that epigenome-targeted inhibitors cause decreased growth and phenotype-dependent disruption of lineage regulators in neuroendocrine prostate cancer, warranting further development of compounds with this activity in the clinic.