The development of anticancer drugs remains slow and costly. Use of predictive biomarkers has been postulated to not only accelerate this process but also increase the odds of drug approval (1). Despite concerns about the validation of the insulin-like growth factor receptor type I (IGF-IR) as an important target for anticancer drugs, many drugs targeting this receptor are currently being evaluated in clinical trials (2). IGF-IR is highly expressed on many human cancers, with its ligands IGF1 and IGF2 also being commonly overexpressed in many malignancies (3). IGF1 increases cancer-cell proliferation in vitro, and importantly knockout of IGF-IR makes nonmalignant cells highly resistant to oncogenic transformation (4). Clinical evidence for the validity of this target is also now emerging, with early evidence of antitumor activity in patients with Ewing's sarcoma, adrenocortical carcinoma (ACC), and non-small cell lung (NSCLC) carcinoma (58).

Both small molecule inhibitors and therapeutic antibodies blocking IGF-IR are in clinical development, with the former also often targeting the insulin receptor (IR). This edition of Molecular Cancer Therapeutics includes an important report detailing a comprehensive preclinical evaluation of predictive biomarkers for h10H5 (Genentech, South San Francisco, CA), a humanized monoclonal antibody to IGF-IR (9). The identification of such biomarkers remains arguably the most important issue in development of drugs targeting IGF-IR. Previous studies have reported on the expression of IGF1-R, phospho-IGF-IR, insulin receptor substrates-1 (IRS1), and -2 (IRS2), and predictive gene expression signatures (1013). This report describes a detailed assessment of certain elements of the pathway, including an evaluation of the receptor and its ligands, and its proximal and distal signaling proteins with expression array profiles, focusing exclusively on breast and colorectal cancer (CRC) models. The authors conclude that for sensitivity to h10H5, IGF-IR overexpression is necessary but not sufficient, requiring between 1,300 to 10,000 receptors per cell for sensitivity. These data also indicate that IGF2, IRS1, and IRS2 protein expression may be important for patient selection, supporting previously published findings.

Other studies suggest that IGF-IR expression correlates with response to IGF-IR blockade (10). IGF1, IGF2, and IGF-IR were also highly expressed in sarcoma cell lines sensitive to the tyrosine kinase inhibitor BMS 536924, whereas those resistant to this drug expressed high levels of IGF binding protein-3 (IGFBP-3) and -6 (IGFBP-6), and of epidermal growth factor receptor (EGFR; ref. 11). Studies of an IGF-IR tyrosine kinase inhibitor, NVP-AEW541, reported high levels of IGF-IR in all breast cancer cell lines evaluated with a high level of IRS1-I in the most sensitive of the cells (13). Zha and colleagues report differences in predictors of sensitivity for breast cancer and CRC cell lines, with IGF-IR mRNA expression being more predictive in breast cancer than in CRC (9). Furthermore, a 60-gene predictive expression signature was identified for the CRC cell lines with no predictive signature being identified for the breast cancer cell lines. Further studies led to IRS1 and IRS2 being shown to also be important in assessing likelihood of response. The authors also described a significant correlation between IGF-IR expression and signaling, and estrogen receptor (ER) function, supporting an evaluation of these agents in this subgroup of breast cancers.

Despite the substantial number of experiments reported in this report, however, the authors may not have fully dissected the complexity of the IGF-IR pathway. IGF-IR ligands can also bind IR, although with lower affinity than IGF-IR (2). The role of IR or of the IGFBPs as mediators of drug resistance has not been evaluated here. Furthermore, the relationships between IGF-IR phosphorylation, IGF-IR overexpression, and IRS1 and IRS2 were not clear from this work. Finally, although the authors identify ER-positive breast cancer as an important area for future research, the significance of IGF-IR being previously implicated as an important target in triple-negative and HER2-positive breast cancer is not addressed (14).

The authors suggest ways in which the predictive biomarkers identified in their preclinical experiments can be deployed in clinical trials, proposing the prospective treatment of different cohorts of ER-positive breast cancer patients positive or negative for IGF-IR staining by immunohistochemistry. One important issue with these studies in patients with metastatic cancer is that they usually use the evaluation of IGF-IR expression on archival tumor tissue, frequently acquired many years before. To resolve this problem, immunofluorescence studies of IGF-IR expression on circulating tumor cells (CTC), in addition to analysis of archival tumor tissue, could be undertaken as we have previously described (15), although further studies correlating IGF-IR expression in tumor biopsies and CTC taken from the same patient at the same time are required to clinically qualify this approach. This technique also allows an evaluation of the effect of the therapeutic agent on the number of IGF-IR-positive and IGF-IR-negative cancer cells detected by the assay. The preliminary clinical qualification of such predictive biomarkers should commence during phase I evaluation of these agents, with a focus on detailed evaluation in cohort expansions at higher drug dose levels across histological tumor types expressing the target of interest.

Drs. C.P. Carden, L.R. Molife, and J.S. de Bono have been involved in conducting trials of IGF-1R inhibitors sponsored by Pfizer Oncology and OSI Pharmaceuticals. Dr. J.S. de Bono has served as a consultant for Merck, AstraZeneca, Novartis, Genentech, Amgen, and GlaxoSmithKline.

1
Carden
CP
,
Banerji
U
,
Kaye
SB
,
Workman
P
,
de Bono
JS
. 
From darkness to light with biomarkers in early clinical trials of cancer drugs
.
Clin Pharmacol Ther
2009
;
85
:
131
3
.
2
Gualberto
A
,
Pollak
M
. 
Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions
.
Oncogene
2009
.
Epub 2009 Jul 6
.
3
Furstenberger
G
,
Senn
HJ
. 
Insulin-like growth factors and cancer
.
Lancet Oncol
2002
;
3
:
298
302
.
4
Sell
C
,
Rubini
M
,
Rubin
R
,
Liu
JP
,
Efstratiadis
A
,
Baserga
R
. 
Simian virus 40 large tumor antigen is unable to transform mouse embryonic fibroblasts lacking type 1 insulin-like growth factor receptor
.
Proc Natl Acad Sci U S A
1993
;
90
:
11217
21
.
5
Olmos
D
,
Okuno
S
,
Schuetze
SM
, et al
. 
Safety, pharmacokinetics and preliminary activity of the anti-IGF-IR antibody CP-751,871 in patients with sarcoma
.
J Clin Oncol
2008
;
26
:
553s
.
6
Olmos
D
,
Molife
R
,
Okuno
S
, et al
. 
Safety, tolerability and preliminary efficacy of the anti-IGF-IR monoclonal antibody CP-751,871 in patients with sarcomas and adrenocortical tumors
.
San Francisco
:
Presented at the AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics Meeting
; 
2007
. .
7
Carden
CP
,
Frentzas
S
,
Langham
M
, et al
. 
Preliminary activity in adrenocortical tumor (ACC) in phase I dose escalation study of intermittent oral dosing of OSI-906, a small-molecule insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor in patients with advanced solid tumors
.
J Clin Oncol
2009
;
27
:
3544s
.
8
Karp
DD
,
Pas-Ares
LG
,
Novello
S
, et al
. 
Phase II study of the anti-insulin-like growth factor type 1 receptor antibody CP-751,871 in combination with paclitaxel and carboplatin in previously untreated, locally advanced, or metastatic non-small-cell lung cancer
.
J Clin Oncol
2009
;
27
:
2516
22
.
9
Zha
J
,
O'Brien
C
,
Savage
H
, et al
. 
Molecular predictors of response to a humanized anti-insulin-like growth factor-I receptor monoclonal antibody in breast and colorectal cancer
.
Mol Canc Ther
2009
;
8
:
2110
21
.
10
Cao
L
,
Yu
Y
,
Darko
I
, et al
. 
Addiction to elevated insulin-like growth factor I receptor and initial modulation of the AKT pathway define the responsiveness of rhabdomyosarcoma to the targeting antibody
.
Cancer Res
2008
;
68
:
8039
48
.
11
Huang
F
,
Greer
A
,
Hurlburt
W
, et al
. 
The mechanisms of differential sensitivity to an insulin-like growth factor-1 receptor inhibitor (BMS-536924) and rationale for combining with EGFR/HER2 inhibitors
.
Cancer Res
2009
;
69
:
161
70
.
12
Byron
SA
,
Horwitz
KB
,
Richer
JK
,
Lange
CA
,
Zhang
X
,
Yee
D
. 
Insulin receptor substrates mediate distinct biological responses to insulin-like growth factor receptor activation in breast cancer cells
.
Br J Cancer
2006
;
95
:
1220
8
.
13
Mukohara
T
,
Shimada
H
,
Ogasawara
N
, et al
. 
Sensitivity of breast cancer cell lines to the novel insulin-like growth factor-1 receptor (IGF-1R) inhibitor NVP-AEW541 is dependent on the level of IRS-1 expression
.
Cancer Lett
2009
;
282
:
14
24
.
14
Law
JH
,
Habibi
G
,
Hu
K
, et al
. 
Phosphorylated insulin-like growth factor-I/insulin receptor is present in all breast cancer subtypes and is related to poor survival
.
Cancer Res
2008
;
68
:
10238
46
.
15
de Bono
JS
,
Attard
G
,
Adjei
A
, et al
. 
Potential applications for circulating tumor cells expressing the insulin-like growth factor-I receptor
.
Clin Cancer Res
2007
;
13
:
3611
6
.

Supplementary data