Genetic blockade of the insulin-like growth factor 1 receptor for human malignancy

Yasushi Adachi, Choon Taek Lee, David P. Carbone

Research output: Contribution to journalReview articleResearchpeer-review

16 Citations (Scopus)

Abstract

Growth factor receptor signals, including insulin-like growth factor (IGF)-1 receptor (IGF-1R), are required for carcinogenesis and tumour progression in many-human malignancies. The concept of targeting specific tumorigenic receptors has been validated by successful clinical application of multiple new drugs, including trastuzumab and gefitinib. In this paper, we review strategies of the genetic blockade of IGF-1/IGF-1R that validate this receptor as a promising anticancer target. Adenoviruses efficiently transduce malignant epithelial cells in culture and are useful for such target validation and potentially also as clinical therapeutics. To block IGF-1R signalling, we constructed adenoviruses expressing antisense IGF-1R and two truncated IGF-1R (482 and 950 amino acids long, IGF-1R/482st and IGF-1R/950st, respectively) that function as dominant negative inhibitors (IGF-1R/dn). The truncated receptors were also cloned into tetracycline regulated expression vectors to study the effects of modulating this pathway without the use of viral vectors. Blocking for IGF-1R suppressed tumorigenicity both in vitro and invivo and effectively blocked both IGF-1 and IGF-2-induced activation of Akt-1. IGF-1R/dn expression increased radiation- and chemotherapy-induced apoptosis and these combination therapies with chemotherapy were very effective against tumours in mice. In an intraperitoneal dissemination mouse model, blockade of IGF-1R reduced dissemination and prolonged survival times. IGF-1R/482st was more effective than IGF-1R/950st due to its bystander effect. These studies confirm the validity of IGF-1R as a therapeutic target and genetic blockade as a potential strategy for several malignancies, including lung, colon and pancreatic carcinoma.

Original languageEnglish
Pages (from-to)177-192
Number of pages16
JournalNovartis Foundation Symposium
Volume262
StatePublished - 1 Dec 2004

Fingerprint

Somatomedin Receptors
Somatomedins
Neoplasms
Adenoviridae
Bystander Effect
Drug Therapy
Growth Factor Receptors

Cite this

@article{48f6b1d3b89c4540aa138dee3119c56e,
title = "Genetic blockade of the insulin-like growth factor 1 receptor for human malignancy",
abstract = "Growth factor receptor signals, including insulin-like growth factor (IGF)-1 receptor (IGF-1R), are required for carcinogenesis and tumour progression in many-human malignancies. The concept of targeting specific tumorigenic receptors has been validated by successful clinical application of multiple new drugs, including trastuzumab and gefitinib. In this paper, we review strategies of the genetic blockade of IGF-1/IGF-1R that validate this receptor as a promising anticancer target. Adenoviruses efficiently transduce malignant epithelial cells in culture and are useful for such target validation and potentially also as clinical therapeutics. To block IGF-1R signalling, we constructed adenoviruses expressing antisense IGF-1R and two truncated IGF-1R (482 and 950 amino acids long, IGF-1R/482st and IGF-1R/950st, respectively) that function as dominant negative inhibitors (IGF-1R/dn). The truncated receptors were also cloned into tetracycline regulated expression vectors to study the effects of modulating this pathway without the use of viral vectors. Blocking for IGF-1R suppressed tumorigenicity both in vitro and invivo and effectively blocked both IGF-1 and IGF-2-induced activation of Akt-1. IGF-1R/dn expression increased radiation- and chemotherapy-induced apoptosis and these combination therapies with chemotherapy were very effective against tumours in mice. In an intraperitoneal dissemination mouse model, blockade of IGF-1R reduced dissemination and prolonged survival times. IGF-1R/482st was more effective than IGF-1R/950st due to its bystander effect. These studies confirm the validity of IGF-1R as a therapeutic target and genetic blockade as a potential strategy for several malignancies, including lung, colon and pancreatic carcinoma.",
author = "Yasushi Adachi and Lee, {Choon Taek} and Carbone, {David P.}",
year = "2004",
month = "12",
day = "1",
language = "English",
volume = "262",
pages = "177--192",
journal = "Novartis Foundation Symposium",

}

Genetic blockade of the insulin-like growth factor 1 receptor for human malignancy. / Adachi, Yasushi; Lee, Choon Taek; Carbone, David P.

In: Novartis Foundation Symposium, Vol. 262, 01.12.2004, p. 177-192.

Research output: Contribution to journalReview articleResearchpeer-review

TY - JOUR

T1 - Genetic blockade of the insulin-like growth factor 1 receptor for human malignancy

AU - Adachi, Yasushi

AU - Lee, Choon Taek

AU - Carbone, David P.

PY - 2004/12/1

Y1 - 2004/12/1

N2 - Growth factor receptor signals, including insulin-like growth factor (IGF)-1 receptor (IGF-1R), are required for carcinogenesis and tumour progression in many-human malignancies. The concept of targeting specific tumorigenic receptors has been validated by successful clinical application of multiple new drugs, including trastuzumab and gefitinib. In this paper, we review strategies of the genetic blockade of IGF-1/IGF-1R that validate this receptor as a promising anticancer target. Adenoviruses efficiently transduce malignant epithelial cells in culture and are useful for such target validation and potentially also as clinical therapeutics. To block IGF-1R signalling, we constructed adenoviruses expressing antisense IGF-1R and two truncated IGF-1R (482 and 950 amino acids long, IGF-1R/482st and IGF-1R/950st, respectively) that function as dominant negative inhibitors (IGF-1R/dn). The truncated receptors were also cloned into tetracycline regulated expression vectors to study the effects of modulating this pathway without the use of viral vectors. Blocking for IGF-1R suppressed tumorigenicity both in vitro and invivo and effectively blocked both IGF-1 and IGF-2-induced activation of Akt-1. IGF-1R/dn expression increased radiation- and chemotherapy-induced apoptosis and these combination therapies with chemotherapy were very effective against tumours in mice. In an intraperitoneal dissemination mouse model, blockade of IGF-1R reduced dissemination and prolonged survival times. IGF-1R/482st was more effective than IGF-1R/950st due to its bystander effect. These studies confirm the validity of IGF-1R as a therapeutic target and genetic blockade as a potential strategy for several malignancies, including lung, colon and pancreatic carcinoma.

AB - Growth factor receptor signals, including insulin-like growth factor (IGF)-1 receptor (IGF-1R), are required for carcinogenesis and tumour progression in many-human malignancies. The concept of targeting specific tumorigenic receptors has been validated by successful clinical application of multiple new drugs, including trastuzumab and gefitinib. In this paper, we review strategies of the genetic blockade of IGF-1/IGF-1R that validate this receptor as a promising anticancer target. Adenoviruses efficiently transduce malignant epithelial cells in culture and are useful for such target validation and potentially also as clinical therapeutics. To block IGF-1R signalling, we constructed adenoviruses expressing antisense IGF-1R and two truncated IGF-1R (482 and 950 amino acids long, IGF-1R/482st and IGF-1R/950st, respectively) that function as dominant negative inhibitors (IGF-1R/dn). The truncated receptors were also cloned into tetracycline regulated expression vectors to study the effects of modulating this pathway without the use of viral vectors. Blocking for IGF-1R suppressed tumorigenicity both in vitro and invivo and effectively blocked both IGF-1 and IGF-2-induced activation of Akt-1. IGF-1R/dn expression increased radiation- and chemotherapy-induced apoptosis and these combination therapies with chemotherapy were very effective against tumours in mice. In an intraperitoneal dissemination mouse model, blockade of IGF-1R reduced dissemination and prolonged survival times. IGF-1R/482st was more effective than IGF-1R/950st due to its bystander effect. These studies confirm the validity of IGF-1R as a therapeutic target and genetic blockade as a potential strategy for several malignancies, including lung, colon and pancreatic carcinoma.

UR - http://www.scopus.com/inward/record.url?scp=16544381674&partnerID=8YFLogxK

M3 - Review article

VL - 262

SP - 177

EP - 192

JO - Novartis Foundation Symposium

JF - Novartis Foundation Symposium

ER -