Feed-forward alpha particle radiotherapy ablates androgen receptor-addicted prostate cancer

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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.

Detaljer

Författare
Enheter & grupper
Externa organisationer
  • Memorial Sloan-Kettering Cancer Center
  • Weill Cornell Medical College
  • Johns Hopkins University School of Medicine
  • Tokyo Medical University
  • University of Oxford
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Cancer och onkologi
  • Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci)
Originalspråkengelska
Artikelnummer1629
TidskriftNature Communications
Volym9
Utgivningsnummer1
StatusPublished - 2018 dec 1
PublikationskategoriForskning
Peer review utfördJa