Synergistic Effect of a HER2 Targeted Thorium-227 Conjugate in Combination with Olaparib in a BRCA2 Deficient Xenograft Model

Abstract

Targeted thorium-227 conjugates (TTCs) represent a novel class of therapeutic radiopharmaceuticals for the treatment of cancer. TTCs consist of the alpha particle emitter thorium-227 complexed to a 3,2-hydroxypyridinone chelator conjugated to a tumor-targeting monoclonal antibody. The high energy and short range of the alpha particles induce potent and selective anti-tumor activity driven by the induction of DNA damage in the target cell. Methods: The efficacy of human epidermal growth factor receptor 2 (HER2)-TTC was tested in combination in vitro and in vivo with the poly ADP ribose polymerase (PARP) inhibitor (PARPi), olaparib, in the human colorectal adenocarcinoma isogenic cell line pair DLD-1 and the knockout variant DLD-1 BRCA2 -/- Results: The in vitro combination effects were determined to be synergistic in DLD-1 BRCA2 -/- and additive in DLD-1 parental cell lines. Similarly, the in vivo efficacy of the combination was determined to be synergistic only in the DLD-1 BRCA2 -/- xenograft model, with statistically significant tumor growth inhibition at a single TTC dose of 120 kBq/kg body weight (bw) and 50 mg/kg bw olaparib (daily, i.p. for 4 weeks), demonstrating comparable tumor growth inhibition to a single TTC dose of 600 kBq/kg bw. Conclusions: This study supports the further investigation of DNA damage response inhibitors in combination with TTCs as a new strategy for the effective treatment of mutation-associated cancers.

Advances in Precision Oncology: Targeted Thorium-227 Conjugates As a New Modality in Targeted Alpha Therapy

“…Importantly, the combination treatment appeared to be well tolerated. 84 These data support further investigation of the combinations of TTCs with specific DDR inhibitors in the BRCA2 -/setting.…”

“…To test this hypothesis, several preclinical studies have been performed where TTCs were combined with DDR inhibitors. [84][85][86] A humanized HER2-targeting IgG1 antibody derived from trastuzumab was conjugated to the 3,2-HOPO chela-tor and subsequently radiolabeled with 227 Th resulting in HER2-TTC. 25 Robust tumor growth inhibition was achieved when HER2-TTC was combined at a subefficacious monotherapy dose of 125 kBq/kg with the poly-ADP ribose polymerase 1/2 (PARP1/2) inhibitor olaparib in the DLD-1 BRCA2 -/xenograft model established from the DLD-1 colorectal cancer cell line with inactivated BRCA2 gene, while no significant tumor inhibition occurred in the xenograft model established from the DLD-1 parental isogenic cell line (Table 2).…”

“…25 Robust tumor growth inhibition was achieved when HER2-TTC was combined at a subefficacious monotherapy dose of 125 kBq/kg with the poly-ADP ribose polymerase 1/2 (PARP1/2) inhibitor olaparib in the DLD-1 BRCA2 -/xenograft model established from the DLD-1 colorectal cancer cell line with inactivated BRCA2 gene, while no significant tumor inhibition occurred in the xenograft model established from the DLD-1 parental isogenic cell line (Table 2). 84 The dosing regimen that combined 125 or 300 kBq/kg HER2-TTC and 50 mg/kg of olaparib resulted in a complete tumor growth inhibition in the DLD-1 BRCA2 -/xenograft model (Table 2). Importantly, the combination treatment appeared to be well tolerated.…”

Targeted α-Therapy in Cancer Management: Synopsis of Preclinical and Clinical Studies

“…107 Synergistic efficacy has also been demonstrated with HER2 targeted 227 Th conjugates in combination with DNA repair inhibitor drug, olaparib (poly ADP ribose polymerase inhibitor) in BRCA2 deficient xenograft tumor models. 108 The same group of investigators have also reported on the potential utility of 227 Th conjugates targeting the fibroblast growth factor receptor 2 (FGFR2), which is overexpressed in many cancers, and in acute myeloid leukemia targeting CD33. 109,110 212 Pb…”

Targeted Alpha Therapy: Current Clinical Applications

“…Furthermore, MSLN targeting 227 Th conjugates have demonstrated synergistic antitumor effect when combined with DNA damage response inhibitors, particularly ATRi and PARPi in preclinical cancer models. 115 a Emitter Selection…”