Combining [177Lu]Lu-DOTA-TOC PRRT with PARP inhibitors to enhance treatment efficacy in small cell lung cancer

Eur J Nucl Med Mol Imaging. 2024 Nov;51(13):4099-4110. doi: 10.1007/s00259-024-06844-1. Epub 2024 Jul 18.

Abstract

Purpose: Small cell lung cancer (SCLC) is a highly aggressive tumor with neuroendocrine origin. Although SCLC frequently express somatostatin receptor type 2 (SSTR2), a significant clinical benefit of SSTR2-targeted radionuclide therapies of SCLC was not observed so far. We hypothesize that combination treatment with a PARP inhibitor (PARPi) could lead to radiosensitization and increase the effectiveness of SSTR2-targeted therapy in SCLC.

Methods: SSTR2-ligand uptake of the SCLC cell lines H69 and H446 was evaluated in vitro using flow cytometry, and in vivo using SPECT imaging and cut-and-count biodistribution. Single-agent (Olaparib, Rucaparib, [177Lu]Lu-DOTA-TOC) and combination treatment responses were determined in vitro via cell viability, clonogenic survival and γH2AX DNA damage assays. In vivo, we treated athymic nude mice bearing H69 or H446 xenografts with Olaparib, Rucaparib, or [177Lu]Lu-DOTA-TOC alone or with combination treatment regimens to assess the impact on tumor growth and survival of the treated mice.

Results: H446 and H69 cells exhibited low SSTR2 expression, i.e. 60 to 90% lower uptake of SSTR2-ligands compared to AR42J cells. In vitro, combination treatment of [177Lu]Lu-DOTA-TOC with PARPi resulted in 2.9- to 67-fold increased potency relative to [177Lu]Lu-DOTA-TOC alone. We observed decreased clonogenic survival and higher amounts of persistent DNA damage compared to single-agent treatment for both Olaparib and Rucaparib. In vivo, tumor doubling times increased to 1.6-fold (H446) and 2.2-fold (H69) under combination treatment, and 1.0 to 1.1-fold (H446) and 1.1 to 1.7-fold (H69) in monotherapies compared to untreated animals. Concurrently, median survival was higher in the combination treatment groups in both models compared to monotherapy and untreated mice. Fractionating the PRRT dose did not lead to further improvement of therapeutic outcome.

Conclusion: The addition of PARPi can markedly improve the potency of SSTR2-targeted PRRT in SCLC models in SSTR2 low-expressing tumors. Further evaluation in humans seems justified based on the results as novel treatment options for SCLC are urgently needed.

Keywords: PARP inhibitors; PRRT; Radioligand therapy; SSTR2; Small cell lung cancer.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Female
  • Humans
  • Lung Neoplasms* / drug therapy
  • Lung Neoplasms* / radiotherapy
  • Mice
  • Mice, Nude
  • Octreotide* / analogs & derivatives
  • Octreotide* / pharmacology
  • Octreotide* / therapeutic use
  • Organometallic Compounds / pharmacology
  • Organometallic Compounds / therapeutic use
  • Poly(ADP-ribose) Polymerase Inhibitors* / pharmacology
  • Poly(ADP-ribose) Polymerase Inhibitors* / therapeutic use
  • Radiopharmaceuticals / pharmacology
  • Radiopharmaceuticals / therapeutic use
  • Receptors, Somatostatin / metabolism
  • Small Cell Lung Carcinoma* / drug therapy
  • Small Cell Lung Carcinoma* / radiotherapy
  • Tissue Distribution
  • Treatment Outcome

Substances

  • Octreotide
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Receptors, Somatostatin
  • lutetium Lu 177 dotatate
  • Organometallic Compounds
  • Radiopharmaceuticals