Inhibition of tumor growth by targeted anti-EGFR/IGF-1R Nanobullets depends on efficient blocking of cell survival pathways

Roy van der Meel, Sabrina Oliveira, Isil Altintas, R. Heukers, Ebel H.E. Pieters, Paul M.P. van Bergen en Henegouwen, Gerrit Storm, Wim E. Hennink, Robbert J. Kok, Raymond M. Schiffelers

Research output: Contribution to journalArticleAcademicpeer-review

15 Citations (Scopus)

Abstract

The clinical efficacy of epidermal growth factor receptor (EGFR)-targeted inhibitors is limited due to resistance mechanisms of the tumor such as activation of compensatory pathways. Crosstalk between EGFR and insulin-like growth factor 1 (IGF-1R) signaling has been frequently described to be involved in tumor proliferation and resistance. One of the attractive features of nanomedicines is the possibility to codeliver agents that inhibit different molecular targets in one nanocarrier system, thereby strengthening the antitumor effects of the individual agents. Additionally, exposure to healthy tissues and related unwanted side-effects can be reduced. To this end, we have recently developed anti-EGFR nanobody (Nb)-liposomes loaded with the anti-IGF-1R kinase inhibitor AG538, which showed promising antiproliferative effects in vitro. In the present study, we have further evaluated the potential of this dual-active nanomedicine in vitro and for the first time in vivo. As intended, the nanomedicine inhibited EGFR and IGF-1R signaling and subsequent activation of downstream cell proliferation and survival pathways. The degree of inhibition induced by the nanomedicine on a molecular level correlated with cytotoxicity in tumor cell proliferation assays and may even be predictive of the response to nanomedicine treatment in tumor xenograft models. Combination therapy with kinase inhibitor-loaded Nb–liposomes is therefore an appealing strategy for inhibiting the proliferation of tumors that are highly dependent on EGFR and IGF-1R signaling
Original languageUndefined
Pages (from-to)3717-3727
JournalMolecular pharmaceutics
Volume10
Issue number10
DOIs
Publication statusPublished - 2013

Keywords

  • IR-90157
  • METIS-301794

Cite this

van der Meel, R., Oliveira, S., Altintas, I., Heukers, R., Pieters, E. H. E., van Bergen en Henegouwen, P. M. P., ... Schiffelers, R. M. (2013). Inhibition of tumor growth by targeted anti-EGFR/IGF-1R Nanobullets depends on efficient blocking of cell survival pathways. Molecular pharmaceutics, 10(10), 3717-3727. https://doi.org/10.1021/mp400212v
van der Meel, Roy ; Oliveira, Sabrina ; Altintas, Isil ; Heukers, R. ; Pieters, Ebel H.E. ; van Bergen en Henegouwen, Paul M.P. ; Storm, Gerrit ; Hennink, Wim E. ; Kok, Robbert J. ; Schiffelers, Raymond M. / Inhibition of tumor growth by targeted anti-EGFR/IGF-1R Nanobullets depends on efficient blocking of cell survival pathways. In: Molecular pharmaceutics. 2013 ; Vol. 10, No. 10. pp. 3717-3727.
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title = "Inhibition of tumor growth by targeted anti-EGFR/IGF-1R Nanobullets depends on efficient blocking of cell survival pathways",
abstract = "The clinical efficacy of epidermal growth factor receptor (EGFR)-targeted inhibitors is limited due to resistance mechanisms of the tumor such as activation of compensatory pathways. Crosstalk between EGFR and insulin-like growth factor 1 (IGF-1R) signaling has been frequently described to be involved in tumor proliferation and resistance. One of the attractive features of nanomedicines is the possibility to codeliver agents that inhibit different molecular targets in one nanocarrier system, thereby strengthening the antitumor effects of the individual agents. Additionally, exposure to healthy tissues and related unwanted side-effects can be reduced. To this end, we have recently developed anti-EGFR nanobody (Nb)-liposomes loaded with the anti-IGF-1R kinase inhibitor AG538, which showed promising antiproliferative effects in vitro. In the present study, we have further evaluated the potential of this dual-active nanomedicine in vitro and for the first time in vivo. As intended, the nanomedicine inhibited EGFR and IGF-1R signaling and subsequent activation of downstream cell proliferation and survival pathways. The degree of inhibition induced by the nanomedicine on a molecular level correlated with cytotoxicity in tumor cell proliferation assays and may even be predictive of the response to nanomedicine treatment in tumor xenograft models. Combination therapy with kinase inhibitor-loaded Nb–liposomes is therefore an appealing strategy for inhibiting the proliferation of tumors that are highly dependent on EGFR and IGF-1R signaling",
keywords = "IR-90157, METIS-301794",
author = "{van der Meel}, Roy and Sabrina Oliveira and Isil Altintas and R. Heukers and Pieters, {Ebel H.E.} and {van Bergen en Henegouwen}, {Paul M.P.} and Gerrit Storm and Hennink, {Wim E.} and Kok, {Robbert J.} and Schiffelers, {Raymond M.}",
note = "ISSN Molecular Pharmaceutics",
year = "2013",
doi = "10.1021/mp400212v",
language = "Undefined",
volume = "10",
pages = "3717--3727",
journal = "Molecular pharmaceutics",
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van der Meel, R, Oliveira, S, Altintas, I, Heukers, R, Pieters, EHE, van Bergen en Henegouwen, PMP, Storm, G, Hennink, WE, Kok, RJ & Schiffelers, RM 2013, 'Inhibition of tumor growth by targeted anti-EGFR/IGF-1R Nanobullets depends on efficient blocking of cell survival pathways' Molecular pharmaceutics, vol. 10, no. 10, pp. 3717-3727. https://doi.org/10.1021/mp400212v

Inhibition of tumor growth by targeted anti-EGFR/IGF-1R Nanobullets depends on efficient blocking of cell survival pathways. / van der Meel, Roy; Oliveira, Sabrina; Altintas, Isil; Heukers, R.; Pieters, Ebel H.E.; van Bergen en Henegouwen, Paul M.P.; Storm, Gerrit; Hennink, Wim E.; Kok, Robbert J.; Schiffelers, Raymond M.

In: Molecular pharmaceutics, Vol. 10, No. 10, 2013, p. 3717-3727.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Inhibition of tumor growth by targeted anti-EGFR/IGF-1R Nanobullets depends on efficient blocking of cell survival pathways

AU - van der Meel, Roy

AU - Oliveira, Sabrina

AU - Altintas, Isil

AU - Heukers, R.

AU - Pieters, Ebel H.E.

AU - van Bergen en Henegouwen, Paul M.P.

AU - Storm, Gerrit

AU - Hennink, Wim E.

AU - Kok, Robbert J.

AU - Schiffelers, Raymond M.

N1 - ISSN Molecular Pharmaceutics

PY - 2013

Y1 - 2013

N2 - The clinical efficacy of epidermal growth factor receptor (EGFR)-targeted inhibitors is limited due to resistance mechanisms of the tumor such as activation of compensatory pathways. Crosstalk between EGFR and insulin-like growth factor 1 (IGF-1R) signaling has been frequently described to be involved in tumor proliferation and resistance. One of the attractive features of nanomedicines is the possibility to codeliver agents that inhibit different molecular targets in one nanocarrier system, thereby strengthening the antitumor effects of the individual agents. Additionally, exposure to healthy tissues and related unwanted side-effects can be reduced. To this end, we have recently developed anti-EGFR nanobody (Nb)-liposomes loaded with the anti-IGF-1R kinase inhibitor AG538, which showed promising antiproliferative effects in vitro. In the present study, we have further evaluated the potential of this dual-active nanomedicine in vitro and for the first time in vivo. As intended, the nanomedicine inhibited EGFR and IGF-1R signaling and subsequent activation of downstream cell proliferation and survival pathways. The degree of inhibition induced by the nanomedicine on a molecular level correlated with cytotoxicity in tumor cell proliferation assays and may even be predictive of the response to nanomedicine treatment in tumor xenograft models. Combination therapy with kinase inhibitor-loaded Nb–liposomes is therefore an appealing strategy for inhibiting the proliferation of tumors that are highly dependent on EGFR and IGF-1R signaling

AB - The clinical efficacy of epidermal growth factor receptor (EGFR)-targeted inhibitors is limited due to resistance mechanisms of the tumor such as activation of compensatory pathways. Crosstalk between EGFR and insulin-like growth factor 1 (IGF-1R) signaling has been frequently described to be involved in tumor proliferation and resistance. One of the attractive features of nanomedicines is the possibility to codeliver agents that inhibit different molecular targets in one nanocarrier system, thereby strengthening the antitumor effects of the individual agents. Additionally, exposure to healthy tissues and related unwanted side-effects can be reduced. To this end, we have recently developed anti-EGFR nanobody (Nb)-liposomes loaded with the anti-IGF-1R kinase inhibitor AG538, which showed promising antiproliferative effects in vitro. In the present study, we have further evaluated the potential of this dual-active nanomedicine in vitro and for the first time in vivo. As intended, the nanomedicine inhibited EGFR and IGF-1R signaling and subsequent activation of downstream cell proliferation and survival pathways. The degree of inhibition induced by the nanomedicine on a molecular level correlated with cytotoxicity in tumor cell proliferation assays and may even be predictive of the response to nanomedicine treatment in tumor xenograft models. Combination therapy with kinase inhibitor-loaded Nb–liposomes is therefore an appealing strategy for inhibiting the proliferation of tumors that are highly dependent on EGFR and IGF-1R signaling

KW - IR-90157

KW - METIS-301794

U2 - 10.1021/mp400212v

DO - 10.1021/mp400212v

M3 - Article

VL - 10

SP - 3717

EP - 3727

JO - Molecular pharmaceutics

JF - Molecular pharmaceutics

SN - 1543-8384

IS - 10

ER -

van der Meel R, Oliveira S, Altintas I, Heukers R, Pieters EHE, van Bergen en Henegouwen PMP et al. Inhibition of tumor growth by targeted anti-EGFR/IGF-1R Nanobullets depends on efficient blocking of cell survival pathways. Molecular pharmaceutics. 2013;10(10):3717-3727. https://doi.org/10.1021/mp400212v