Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer Academic Article uri icon

Overview

MeSH Major

  • Piperazines
  • Poxviridae
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-abl
  • Pyrimidines

abstract

  • Human kallikrein peptidase 2 (hK2) is a prostate specific enzyme whose expression is governed by the androgen receptor (AR). AR is the central oncogenic driver of prostate cancer (PCa) and is also a key regulator of DNA repair in cancer. We report an innovative therapeutic strategy that exploits the hormone-DNA repair circuit to enable molecularly-specific alpha particle irradiation of PCa. Alpha-particle irradiation of PCa is prompted by molecularly specific-targeting and internalization of the humanized monoclonal antibody hu11B6 targeting hK2 and further accelerated by inherent DNA-repair that up-regulate hK2 (KLK2) expression in vivo. hu11B6 demonstrates exquisite targeting specificity for KLK2. A single administration of actinium-225 labeled hu11B6 eradicates disease and significantly prolongs survival in animal models. DNA damage arising from alpha particle irradiation induces AR and subsequently KLK2, generating a unique feed-forward mechanism, which increases binding of hu11B6. Imaging data in nonhuman primates support the possibility of utilizing hu11B6 in man.

publication date

  • December 2018

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC5915579

Digital Object Identifier (DOI)

  • 10.1038/s41467-018-04107-w

PubMed ID

  • 29691406

Additional Document Info

start page

  • 1629

volume

  • 9

number

  • 1