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Emerging role of insulin-like growth factor receptor inhibitors in oncology

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Emerging role of insulin-like growth factor receptor inhibitors in oncology:

early clinical trial results and future directions
A Gualberto1,2 and M Pollak3
1Clinical Department, Pfizer Oncology, New London, CT, USA; 2Department of Pathology, Brown University Alpert School of Medicine, Providence, RI, USA and 3Department of Oncology, McGill University, Montreal, Quebec, Canada

Preclinical evidence that targeting the insulin-like growth factor receptor (IGF-IR) is effective in cancer treatment
has been accumulating for almost two decades. Efforts to develop drugs began in the late 1990s, and initial data
from clinical trials were reported in 2006. The biological rationale for IGF-IR targeting has potential relevance
to many tumor types, and early results have justifiedn expanded programs to evaluate IGF-IR-targeting agents
in many areas of clinical need. More than two dozen drug candidates have been developed and clinical trials are
underway for at least 12 of these. Early clinical trials reveal an acceptable safety profile together with pharmacodynamic
evidence that the receptor can be successfully targeted. It is premature to draw conclusions regarding
efficacy, but well-documented instances of single-agent activity were noted during phase I evaluations, and
recent evidence from a phase II study suggests that co-administration of an anti-IGF-IR antibody with
chemotherapy for non-small-cell lung cancer improves objective response rate and progression-free survival.With
more than 70 trials involving a variety of drug candidates underway, the IGF-IR is becoming one of the most
intensively investigated molecular targets in oncology.

Early results justify the continuation of ongoing research across a broad range of cancer indications.
Oncogene advance online publication, 6 July 2009;
Keywords: insulin-like growth factor-I receptor inhibitors;
clinical trials; targeted therapies

Research on insulin-like growth factors (IGFs) and their receptors in cancer biology has been ongoing for over
20 years (Myal et al., 1984; Pollak et al., 1987; Arteaga et al., 1989). Model systems provided evidence for
important roles in neoplasia. Examples include genetic alterations that reduce ligand levels (Pollak et al., 2001,
2004; Baserga et al., 2003; Majeed et al., 2005; Hartog et al., 2007; Sachdev and Yee, 2007; Samani et al., 2007;
Chitnis et al., 2008; Weroha and Haluska, 2008; Yuen and Macaulay, 2008; Pollak, 2008a) as well as knockdown
methods (Wu et al., 2003). One important theme that emerged from this work was the notion that
multiple oncogenes require the presence of the insulinlike growth factor receptor (IGF-IR) to achieve cellular
transformation (Sell et al., 1993; Martin et al., 2006); another was that that IGF-I signaling confers resistance
to many antineoplastic therapies (Wiseman et al., 1993; Lu et al., 2001). Interest in IGF-IR targeting increased
with the publication of evidence linking IGF-I signaling with the onset of neoplasia. Examples include evidence
for associations between circulating IGF-I and cancer risk (Chan et al., 1998), between IGF-I and mammographic
breast density (Diorio et al., 2005), between growth rate in adolescence (which is IGF-I mediated)
and cancer risk (Ahlgren et al., 2004), and the observation that IGF-II overexpression was among the
most common molecular derangements in colorectal cancer (Zhang et al., 1997).
Earlier review articles (Baserga et al., 2003; Pollak et al., 2004; Hartog et al., 2007; Sachdev and Yee, 2007;
Samani et al., 2007; Chitnis et al., 2008; Weroha and Haluska, 2008; Yuen and Macaulay, 2008; Pollak,
2008a) have summarized IGF-IR biology, its relevance to neoplasia and the preclinical evaluation of drug
candidates targeting the IGF-IR. Recent studies have provided further evidence that IGF-IR inhibition can be
useful in attenuating the malignant behavior of cancers in which KRAS (Klinakis et al., 2009) or EGF receptor
family members (Buck et al., 2008; Huang et al., 2009) play important roles in pathophysiology.
Close to 30 drug candidates targeting the IGF-IR are being investigated (Baserga et al., 2003; Pollak et al.,
2004; Yee, 2006; Hartog et al., 2007; Sachdev and Yee, 2007; Samani et al., 2007; Tao et al., 2007; Chitnis et al.,
2008; Feng and Dimitrov, 2008; Rodon et al., 2008; Yuen and Macaulay, 2008; Pollak, 2008a, b). Here, we
focus specifically on the available clinical trial and translational research data concerning 12 of these
compounds currently in clinical trials. The large number of trials planned and in progress provide important
opportunities for the incorporation of ‘companion’

Received 11 March 2009; revised 14 May 2009; accepted 23 May 2009 studies that will provide serum and tissue samples for Correspondence: Dr M Pollak, Segal Cancer Centre, McGill
University, 3755, Chemin de la Cote Sainte-Catherine, Room E-763, Montreal, Quebec, Canada H3T 1E2.
Oncogene (2009), 1–13
& 2009 Macmillan Publishers Limited All rights reserved 0950-9232/09 $32.00
analysis of patterns of gene expression, activation of
signaling pathways, circulating growth factor levels, and
genetic variation in the germline and within neoplastic
tissue that may predict response.

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