Cargando…

The Novel Anti-cMet Antibody seeMet 12 Potentiates Sorafenib Therapy and Radiotherapy in a Colorectal Cancer Model

RATIONAL: cMet is abnormally regulated in gastrointestinal cancer, and is associated with increased invasiveness of the disease and poor overall survival. There are indications that targeted therapy against cMet, alone or in combination with additional cancer therapies, can help improve treatment ou...

Descripción completa

Detalles Bibliográficos
Autores principales: Spiegelberg, Diana, Mortensen, Anja Charlotte Lundgren, Palupi, Kartika Dyah, Micke, Patrick, Wong, Julin, Vojtesek, Borivoj, Lane, David Philip, Nestor, Marika
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516085/
https://www.ncbi.nlm.nih.gov/pubmed/33014851
http://dx.doi.org/10.3389/fonc.2020.01717
_version_ 1783586935146545152
author Spiegelberg, Diana
Mortensen, Anja Charlotte Lundgren
Palupi, Kartika Dyah
Micke, Patrick
Wong, Julin
Vojtesek, Borivoj
Lane, David Philip
Nestor, Marika
author_facet Spiegelberg, Diana
Mortensen, Anja Charlotte Lundgren
Palupi, Kartika Dyah
Micke, Patrick
Wong, Julin
Vojtesek, Borivoj
Lane, David Philip
Nestor, Marika
author_sort Spiegelberg, Diana
collection PubMed
description RATIONAL: cMet is abnormally regulated in gastrointestinal cancer, and is associated with increased invasiveness of the disease and poor overall survival. There are indications that targeted therapy against cMet, alone or in combination with additional cancer therapies, can help improve treatment outcome. Thus, in the present study we investigated the therapeutic efficacy of a novel cMet-targeting antibody therapy in gastrointestinal cancer models, and assessed potential augmenting effects in combination with tyrosine kinase inhibitor (TKI) targeted therapy or radiotherapy. METHODS: Three different cMet-targeting antibodies were first characterized with respect to antigen binding and effects on cell viability in vitro. The best performing candidate seeMet 12 was then further assessed for effects on colorectal cancer cell growth, proliferation and migration. Combinations with the TKI-inhibitor sorafenib or external beam radiotherapy were then evaluated for potential additive or synergistic effects in vitro using monolayer- and multicellular tumor spheroid assays. Finally, the combination of seeMet 12 and radiotherapy was evaluated in vivo in a proof-of-concept colorectal cancer xenograft study. RESULTS: Dose-dependent therapeutic effects were demonstrated for all three cMet-targeting antibodies. Monotherapy using seeMet 12 resulted in impaired cellular migration/proliferation and reduced tumor spheroid growth. Moreover, seeMet 12 was able to potentiate therapeutic effects in vitro for both sorafenib and radiotherapy treatments. Finally, the in vivo therapy study demonstrated promising results, where a combination of seeMet 12 and fractionated radiotherapy increased median survival by 79% compared to radiotherapy alone, and tripled maximum survival. CONCLUSION: The novel anti-cMet antibody seeMet 12 demonstrated therapeutic effects in cMet positive gastrointestinal cancer cells in vitro. Moreover, the addition of seeMet 12 augmented the effects of sorafenib and radiotherapy. An in vivo proof-of-concept study of seeMet 12 and radiotherapy further validated the results. Thus, cMet-targeted therapy should be further explored as a promising approach to increase therapeutic effects, circumvent treatment resistance, and reduce side effects.
format Online
Article
Text
id pubmed-7516085
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-75160852020-10-02 The Novel Anti-cMet Antibody seeMet 12 Potentiates Sorafenib Therapy and Radiotherapy in a Colorectal Cancer Model Spiegelberg, Diana Mortensen, Anja Charlotte Lundgren Palupi, Kartika Dyah Micke, Patrick Wong, Julin Vojtesek, Borivoj Lane, David Philip Nestor, Marika Front Oncol Oncology RATIONAL: cMet is abnormally regulated in gastrointestinal cancer, and is associated with increased invasiveness of the disease and poor overall survival. There are indications that targeted therapy against cMet, alone or in combination with additional cancer therapies, can help improve treatment outcome. Thus, in the present study we investigated the therapeutic efficacy of a novel cMet-targeting antibody therapy in gastrointestinal cancer models, and assessed potential augmenting effects in combination with tyrosine kinase inhibitor (TKI) targeted therapy or radiotherapy. METHODS: Three different cMet-targeting antibodies were first characterized with respect to antigen binding and effects on cell viability in vitro. The best performing candidate seeMet 12 was then further assessed for effects on colorectal cancer cell growth, proliferation and migration. Combinations with the TKI-inhibitor sorafenib or external beam radiotherapy were then evaluated for potential additive or synergistic effects in vitro using monolayer- and multicellular tumor spheroid assays. Finally, the combination of seeMet 12 and radiotherapy was evaluated in vivo in a proof-of-concept colorectal cancer xenograft study. RESULTS: Dose-dependent therapeutic effects were demonstrated for all three cMet-targeting antibodies. Monotherapy using seeMet 12 resulted in impaired cellular migration/proliferation and reduced tumor spheroid growth. Moreover, seeMet 12 was able to potentiate therapeutic effects in vitro for both sorafenib and radiotherapy treatments. Finally, the in vivo therapy study demonstrated promising results, where a combination of seeMet 12 and fractionated radiotherapy increased median survival by 79% compared to radiotherapy alone, and tripled maximum survival. CONCLUSION: The novel anti-cMet antibody seeMet 12 demonstrated therapeutic effects in cMet positive gastrointestinal cancer cells in vitro. Moreover, the addition of seeMet 12 augmented the effects of sorafenib and radiotherapy. An in vivo proof-of-concept study of seeMet 12 and radiotherapy further validated the results. Thus, cMet-targeted therapy should be further explored as a promising approach to increase therapeutic effects, circumvent treatment resistance, and reduce side effects. Frontiers Media S.A. 2020-09-11 /pmc/articles/PMC7516085/ /pubmed/33014851 http://dx.doi.org/10.3389/fonc.2020.01717 Text en Copyright © 2020 Spiegelberg, Mortensen, Palupi, Micke, Wong, Vojtesek, Lane and Nestor. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Spiegelberg, Diana
Mortensen, Anja Charlotte Lundgren
Palupi, Kartika Dyah
Micke, Patrick
Wong, Julin
Vojtesek, Borivoj
Lane, David Philip
Nestor, Marika
The Novel Anti-cMet Antibody seeMet 12 Potentiates Sorafenib Therapy and Radiotherapy in a Colorectal Cancer Model
title The Novel Anti-cMet Antibody seeMet 12 Potentiates Sorafenib Therapy and Radiotherapy in a Colorectal Cancer Model
title_full The Novel Anti-cMet Antibody seeMet 12 Potentiates Sorafenib Therapy and Radiotherapy in a Colorectal Cancer Model
title_fullStr The Novel Anti-cMet Antibody seeMet 12 Potentiates Sorafenib Therapy and Radiotherapy in a Colorectal Cancer Model
title_full_unstemmed The Novel Anti-cMet Antibody seeMet 12 Potentiates Sorafenib Therapy and Radiotherapy in a Colorectal Cancer Model
title_short The Novel Anti-cMet Antibody seeMet 12 Potentiates Sorafenib Therapy and Radiotherapy in a Colorectal Cancer Model
title_sort novel anti-cmet antibody seemet 12 potentiates sorafenib therapy and radiotherapy in a colorectal cancer model
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7516085/
https://www.ncbi.nlm.nih.gov/pubmed/33014851
http://dx.doi.org/10.3389/fonc.2020.01717
work_keys_str_mv AT spiegelbergdiana thenovelanticmetantibodyseemet12potentiatessorafenibtherapyandradiotherapyinacolorectalcancermodel
AT mortensenanjacharlottelundgren thenovelanticmetantibodyseemet12potentiatessorafenibtherapyandradiotherapyinacolorectalcancermodel
AT palupikartikadyah thenovelanticmetantibodyseemet12potentiatessorafenibtherapyandradiotherapyinacolorectalcancermodel
AT mickepatrick thenovelanticmetantibodyseemet12potentiatessorafenibtherapyandradiotherapyinacolorectalcancermodel
AT wongjulin thenovelanticmetantibodyseemet12potentiatessorafenibtherapyandradiotherapyinacolorectalcancermodel
AT vojtesekborivoj thenovelanticmetantibodyseemet12potentiatessorafenibtherapyandradiotherapyinacolorectalcancermodel
AT lanedavidphilip thenovelanticmetantibodyseemet12potentiatessorafenibtherapyandradiotherapyinacolorectalcancermodel
AT nestormarika thenovelanticmetantibodyseemet12potentiatessorafenibtherapyandradiotherapyinacolorectalcancermodel
AT spiegelbergdiana novelanticmetantibodyseemet12potentiatessorafenibtherapyandradiotherapyinacolorectalcancermodel
AT mortensenanjacharlottelundgren novelanticmetantibodyseemet12potentiatessorafenibtherapyandradiotherapyinacolorectalcancermodel
AT palupikartikadyah novelanticmetantibodyseemet12potentiatessorafenibtherapyandradiotherapyinacolorectalcancermodel
AT mickepatrick novelanticmetantibodyseemet12potentiatessorafenibtherapyandradiotherapyinacolorectalcancermodel
AT wongjulin novelanticmetantibodyseemet12potentiatessorafenibtherapyandradiotherapyinacolorectalcancermodel
AT vojtesekborivoj novelanticmetantibodyseemet12potentiatessorafenibtherapyandradiotherapyinacolorectalcancermodel
AT lanedavidphilip novelanticmetantibodyseemet12potentiatessorafenibtherapyandradiotherapyinacolorectalcancermodel
AT nestormarika novelanticmetantibodyseemet12potentiatessorafenibtherapyandradiotherapyinacolorectalcancermodel