Exploring Targeted Thorium Conjugate and Small Molecule Combinations: New Effective Treatments for Cancer

Abstract

Targeted Thorium-227 Conjugates (TTCs) represent a novel class of cancer therapy currently in preclinical and clinical development. The TTCs consist of the alpha emitter thorium-227 (227Th) complexed to a 3,2-HOPO chelator conjugated to a tumor specific antibody. The high energy and short range of the alpha-particle induces a potent local irradiation of the tumor with limited damage to surrounding tissue, thus making them beneficial for treatment of cancer.

This thesis describes the preclinical evaluation of TTCs in combination with small molecule DNA damage response (DDR) inhibitors. The overall aim with the combination therapy is to achieve an enhanced effect at lower doses and thereby an increased therapeutic window. The results presented in the thesis summarize in vitro and in vivo studies demonstrating synergistic effects achieved over a range of cancer indications, TTC targets and DDR inhibitors. In sum-mary, this supports the further exploration of combination therapy with TTCs and DDR inhibitors for treatment of dif-ferent cancer indications and investigation of defects in DDR genes as potential biomarkers for treatment with TTCs.