Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Synergistic Antitumor Effects of 177Lu-Octreotide Combined with an ALK Inhibitor in a High-Risk Neuroblastoma Xenograft Model

Arman Romiani
,
Daniella Pettersson
,
Nishte Rassol
,
Klara Simonsson
,
Hana Bakr
,
Dan Emil Lind
,
Aniko Kovacs
ORCID logo ,
Johan Spetz
,
Ruth H Palmer
ORCID logo ,
Bengt Hallberg
ORCID logo ,
Khalil Helou
ORCID logo ,
Eva Forssell-Aronsson
* ORCID logo
Version 1 : Received: 4 March 2024 / Approved: 5 March 2024 / Online: 5 March 2024 (13:05:37 CET)

How to cite: Romiani, A.; Pettersson, D.; Rassol, N.; Simonsson, K.; Bakr, H.; Lind, D.E.; Kovacs, A.; Spetz, J.; Palmer, R.H.; Hallberg, B.; Helou, K.; Forssell-Aronsson, E. Synergistic Antitumor Effects of 177Lu-Octreotide Combined with an ALK Inhibitor in a High-Risk Neuroblastoma Xenograft Model. Preprints 2024, 2024030251. https://doi.org/10.20944/preprints202403.0251.v1 Romiani, A.; Pettersson, D.; Rassol, N.; Simonsson, K.; Bakr, H.; Lind, D.E.; Kovacs, A.; Spetz, J.; Palmer, R.H.; Hallberg, B.; Helou, K.; Forssell-Aronsson, E. Synergistic Antitumor Effects of 177Lu-Octreotide Combined with an ALK Inhibitor in a High-Risk Neuroblastoma Xenograft Model. Preprints 2024, 2024030251. https://doi.org/10.20944/preprints202403.0251.v1

Abstract

Neuroblastoma (NB) is a childhood cancer with heterogeneous characteristics, posing challenges to effective treatment. NBs express somatostatin receptors that facilitates the use of somatostatin analogs (SSTAs) as tumor-seeking agents for diagnosis and therapy. High-risk (HR) NBs often have gain-of-function mutations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK). Despite intensive multimodal treatment, survival rates remain below 40% for children with HR-NB. The aim of this work was to investigate the combined effect of the SSTA 177Lu-octreotide with the ALK inhibitor lorlatinib. Mice bearing human HR-NB CLB-BAR tumors were treated with lorlatinib, 177Lu-octreotide, combination of these pharmaceuticals or saline (control). Tumor volume was monitored and tumor samples were evaluated for cleaved caspase-3 and expression of 84 human genes involved in apoptosis. Combination treatment with 177Lu-octreotide and lorlatinib demonstrated synergistic antitumor effects. Increased number of cleaved caspase 3-positive cells was observed in tumors from mice treated with 177Lu-octreotide alone and in combination with lorlatinib. Modulation of Bcl-2 family gene expression was observed only in the presence of both 177Lu-octreotide and lorlatinib, with BID downregulated and HRK upregulated on days 2 and 7, respectively. The data suggests that ALK signaling pathway inhibition may contribute to radiosensitization in radionuclide therapy with 177Lu-octreotide.

Keywords

Neurobastoma; Radionuclide therapy; Apoptosis; Somatostatin analog; Radiosensitization; Combination therapy

Subject

Medicine and Pharmacology, Oncology and Oncogenics

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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