Initial Testing (Stage 1) of the IGF-1 Receptor Inhibitor BMS-754807 by the Pediatric Preclinical Testing Program

Abstract

Background

BMS-754807 is a small molecule ATP-competitive inhibitor of the type-1 insulin-like growth factor receptor currently in phase 1 clinical trials.

Procedures

BMS-754807 was tested against the Pediatric Preclinical Testing Program (PPTP) in vitro panel at concentrations ranging from 1.0 nM to 10 μM and was tested against the PPTP in vivo panels at a dose of 25 mg/kg administered orally BID for 6 days, repeated for 6 weeks.

Results

In vitro BMS-754807 showed a median EC₅₀ value of 0.62 μM against the PPTP cell lines. The median EC₅₀ for the four Ewing sarcoma cell lines was less than that for the remaining PPTP cell lines (0.19 μM vs. 0.78 μM, P = 0.0470). In vivo BMS-754807 induced significant differences in EFS distribution compared to controls in 18 of 32 evaluable solid tumor xenografts (56%) tested, but in none of the ALL xenografts studied. Criteria for intermediate activity for the time to event activity measure (EFS T/C >2) were met in 7 of 27 solid tumor xenografts evaluable for this measure. The best response was PD2 (progressive disease with growth delay), which was observed in 18 of 32 solid tumor xenografts. PD2 responses were most commonly observed in the rhabdomyosarcoma, neuroblastoma, osteosarcoma, Ewing sarcoma, and Wilms tumor panels.

Conclusions

BMS-754807 activity in vitro is consistent with a specific IGF-1R effect that has half-maximal response in the 0.1 μM range and that is observed in a minority of the PPTP cell lines. In vivo intermediate activity was most commonly observed in the neuroblastoma and rhabdomyosarcoma panels.

INTRODUCTION

For approximately two decades, the insulin like growth factor has been implicated in the pathogenesis of pediatric malignancies. Increasingly specific small molecules and antibodies directed to the insulin-like growth factor 1 receptor (IGF-1R) have renewed interest in this therapeutic strategy [1].

IGF-1R may bind both IGF-1 and IGF-2 resulting in autophosphorylation of the receptor. Phosphorylated IGF-1R initiates intracellular signaling through insulin receptor substrates 1–4 (IRS1–4) and the Src homology collagen-like adaptor protein (Shc). Phosphorylation of IRS-1 activates the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) ultimately leading to conversion of phosphatidylinositol-4,5-biphoshate (PIP₂) to phosphatidylinositol-3,4,5-biphoshate (PIP₃). PIP₃ activates phosphoinositide-dependent kinase-1 (PDK1), resulting in phosphorylation and activation of the serine/threonine kinase Akt. Akt enhances intracellular metabolism through glycogen synthase kinase-3 (GSK3); protein synthesis and cell growth through the mammalian target of rapamycin (mTOR); cell survival through BAD (a Bcl-2 family member); and cell proliferation through p28^Kip1 (reviewed in Refs. [2,3]). In parallel to the signaling activated though PI-3K, IGF-1R also activates Ras through Shc. Once activated, Ras initiates signaling through Raf, which ultimately leads to activation and phosphorylation of the mitogen-activated protein kinase-1 and -2 (MAPK) through the MAPK/ERK kinases (MEK1 and MEK2) [4]. Activation of MAPK through Ras results in enhanced proliferation, migration, and survival [4,5].

Currently in various stages of clinical development are several human or fully humanized anti-IGF-1R monoclonal antibodies, all requiring intravenous administration [1]. Clinical development of these agents is moving forward rapidly in sarcomas [6]. Small molecule inhibitors of IGF-1R have the advantage of oral bioavailability, and unlike the anti-IGF-1R antibodies, small molecule inhibitors of IGF-1R may also target the insulin receptor (IR) and the hybrid IGF-1R/IR receptor. In terms of blocking tumor growth and survival, there may be an advantage to inhibition of both IGF-1R and IR [7,8]. However, by targeting the IR, there is a possibility for symptomatic hyperglycemia in patients, thus limiting the clinical efficacy of the compounds.

BMS-754807 is an oral, reversible ATP-competitive antagonist of IGF-1R that blocks the activity of both IGF-1R and IR in in vitro kinase assays [9,10]. The agent inhibits the growth of a broad range of cancer cell lines, including mesenchymal, epithelial, and hematopoietic tumor cell lines [9]. BMS-754807 showed growth inhibitory activity against xenograft tumor models, and synergy was observed for combinations of the agent with both targeted agents and standard cytotoxic agents [9]. In the current report we have evaluated BMS-754807 against a panel of pediatric tumors, in vitro and in vivo, through the NCI-supported Pediatric Preclinical Testing Program (PPTP).

MATERIALS AND METHODS

In Vitro Testing

In vitro testing was performed using DIMSCAN, a semi-automatic fluorescence-based digital image microscopy system that quantifies viable (using fluorescein diacetate [FDA]) cell numbers in tissue culture multiwell plates [11]. Cells were incubated in the presence of BMS-754807 for 96 hr at concentrations from 1 nM to 10 μM and analyzed as previously described [12]. The activity of BMS-754807 was compared to that of a murine monoclonal antibody (mAb391) directed against the human IGF-1 receptor tested at a saturating concentration (50 μg/ml) [13].

In Vivo Tumor Growth Inhibition Studies

CB17SC-M scid^−/− female mice (Taconic Farms, Germantown, NY), were used to propagate subcutaneously implanted kidney/rhabdoid tumors, sarcomas (Ewing, osteosarcoma, rhabdomyosarcoma), neuroblastoma, and non-glioblastoma brain tumors, while BALB/c nu/nu mice were used for glioma models, as previously described [14]. Human leukemia cells were propagated by intravenous inoculation in female non-obese diabetic (NOD)/scid^−/− mice as described previously [15]. Female mice were used irrespective of the patient gender from which the original tumor was derived. All mice were maintained under barrier conditions and experiments were conducted using protocols and conditions approved by the institutional animal care and use committee of the appropriate consortium member. Ten mice (solid tumors) or eight mice (leukemias) were used in each control or treatment group. Tumor volumes (cm³) (solid tumor xenografts) or percentages of human CD45-positive (hCD45) cells (ALL xenografts) were determined as previously described [16] and responses were determined using three activity measures as previously described [16]. An in-depth description of the analysis methods is included in the Supplemental Response Definitions Section.

Statistical Methods

The exact log-rank test, as implemented using Proc StatXact for SAS^®, was used to compare event-free survival distributions between treatment and control groups. P-values were two-sided and were not adjusted for multiple comparisons given the exploratory nature of the studies. The Mann–Whitney test was used to test the difference of medians of EC₅₀ values between the groups of lines with similar tumor types to the remaining lines of the panel.

Drugs and Formulation

BMS-754807 was provided to the PPTP by Bristol Myers Squibb, through the Cancer Therapy Evaluation Program (NCI). BMS-754807 was dissolved in PEG400/water (80:20), and was administered PO twice daily (BID) for 6 days per week for 6 consecutive weeks at 25 mg/kg. mAb391 was provided to the PPTP by Bristol Myers Squibb.

RESULTS

BMS-754807 In Vitro Testing

BMS-754807 was evaluated against the 23 cell lines in the PPTP in vitro panel using 96-hr exposures to concentrations ranging from 1.0 nM to 10.0 μM. The median EC₅₀ for the in vitro panel was 0.62 μM. There was more than a 70-fold range in EC₅₀ values, with the most sensitive cell line being the rhabdomyosarcoma cell line Rh41 which had an EC₅₀ of 0.07 μM and with the least sensitive cell line (Rh18) having an EC₅₀ of 4.96 μM. The median EC₅₀ for the 4 Ewing sarcoma cell lines was less than that for the remaining 19 PPTP cell lines (0.19 μM vs. 0.78 μM, P = 0.0470) (Table I). The median EC₅₀ value for BMS-754807 for the five cell lines with the greatest response to the anti-IGF-1R monoclonal antibody mAb391 (all with inhibition >30%) was 0.12 μM, while the median EC₅₀ for the 10 cell lines with the least evidence of mAb391 treatment effect was approximately 10-fold higher at 1.0 μM (P = 0.0017). This observation is consistent with a specific IGF-1R effect for BMS-754807 that has half-maximal response in the 0.1 μM range and that is observed in a minority of the PPTP cell lines, and with a non-IGF-1R effect that occurs in all of the cell lines and that shows half-maximal response at approximately 1 μM.

TABLE I.

Activity of BMS-754807 and mAb391 Against the PPTP In Vitro Panel

Cell line		EC50 (μM)a	Median EC50 ratiob	Max inhibition (100—T/C)	mAb391 inhibition at 50 μg/ml (100—T/C)
RD	Rhabdomyosarcoma	1.12	0.56	100	17.7
Rh41	Rhabdomyosarcoma	0.07	9.20	98.4	86.4
Rh18	Rhabdomyosarcoma	4.96	0.13	100	20.8
Rh30	Rhabdomyosarcoma	0.19	3.32	98.8	39.0
BT-12	Rhabdoid (CNS)	0.78	0.79	74.7	10.9
CHLA-266	Rhabdoid (CNS)	0.89	0.70	98.0	8.2
TC-71	Ewing family tumor	0.11	5.86	98.5	69.4
CHLA-9	Ewing family tumor	0.12	5.31	96.9	28.0
CHLA-10	Ewing family tumor	0.62	1.00	98.6	0.0
CHLA-258	Ewing family tumor	0.27	2.31	99.4	50.9
GBM2	Glioblastoma	1.47	0.42	98.3	0.0
NB-1643	Neuroblastoma	0.12	5.15	93.3	47.1
NB-EBc1	Neuroblastoma	0.35	1.76	96.0	19.4
CHLA-90	Neuroblastoma	0.77	0.81	98.5	22.7
CHLA-136	Neuroblastoma	0.52	1.18	97.7	29.8
NALM-6	Pre-B cell ALL	0.49	1.26	92.7	0.0
COG-LL-317	T-cell ALL	1.38	0.45	99.6	0.0
RS4;11	Pre-B cell ALL	0.38	1.65	95.9	20.2
MOLT-4	T-cell ALL	0.53	1.18	94.9	5.4
CCRF-CEM	T-cell ALL	1.13	0.55	91.3	0.0
Kasumi-1	AML	1.20	0.52	100	14.3
Karpas-299	Anaplastic large cell lymphoma	1.64	0.38	99.7	9.8
Ramos-RA1	Burkitt’s lymphoma	1.31	0.47	100	0.0
Median		0.62	1.00	98.4	17.7

^aThe EC₅₀ is the drug concentration achieving half maximal biological effect;

^bThe median EC₅₀ ratio is the relative EC₅₀ values for the cell lines of the PPTP panel.

BMS-754807 In Vivo Testing

BMS-754807 was evaluated in 45 xenograft models. Thirty-five of 856 mice died during the study (4.1%), with 7 of 427 in the control arms (1.6%), and 28 of 429 in the BMS-754807 treatment arms (6.5%). Four solid tumor xenografts were inevaluable because of toxicity (GBM2, BT-39, and D456 from the GBM panel; CHLA-258 from the Ewing sarcoma panel) and a medulloblastoma xenograft (BT-50) was inevaluable because of inadequate growth of tumors in control animals. One of the eight ALL xenografts (ALL-4) was excluded from efficacy reporting because of excessive toxicity. A complete summary of results is provided in Supplemental Table I, including total numbers of mice, number of mice that died (or were otherwise excluded), numbers of mice with events and average times to event, tumor growth delay, as well as numbers of responses and T/C values.

Antitumor effects were evaluated using the PPTP activity measures for time to event (EFS T/C), tumor growth delay (tumor volume T/C), and objective response. BMS-754807 induced significant differences in EFS distribution compared to controls in 18 of 32 evaluable solid tumor xenografts (56%) tested as shown (Table II). Significant growth delay was observed in most of the solid tumor panels, including panels for rhabdoid tumors (3 of 3), Wilms tumor (3 of 3), rhabdomyosarcoma (2 of 6), Ewing sarcoma (2 of 4), neuroblastoma (4 of 6), and osteosarcoma (4 of 6). None of the seven evaluable ALL xenografts showed significant differences in EFS distribution between treated and control animals.

TABLE II.

Activity of BMS-754807 Against the PPTP In Vivo Tumor Panel

Xenograft line	Histology	Median time to event	P-value	EFS T/C	Median final RTV	Tumor volume T/C	P-value	T/C volume activity	EFS activity	Response activity
BT-29	Rhabdoid	21.0	0.027	1.5	>4	0.64	0.035	Low	Low	Low
KT-14	Rhabdoid	>EP	<0.001	>1.6	1.9	0.35	<0.001	Int	NE	Int
KT-12	Rhabdoid	11.4	0.008	1.5	>4	0.75	0.035	Low	Low	Low
KT-11	Wilms	17.3	0.004	1.8	>4	0.51	0.001	Low	Low	Int
KT-13	Wilms	13.4	<0.001	1.5	>4	0.39	<0.001	Int	Low	Low
KT-5	Wilms	34.3	<0.001	2.1	>4	0.60	0.003	Low	Int	Int
SK-NEP-1	Ewing	7.0	0.231	1.1	>4	0.86	0.218	Low	Low	Low
EW5	Ewing	13.4	0.042	2.1	>4	0.48	0.017	Low	Int	Int
EW8	Ewing	12.6	0.006	1.8	>4	0.73	0.035	Low	Low	Int
TC-71	Ewing	7.6	0.126	0.9	>4	1.15	0.353	Low	Low	Low
Rh10	ALV RMS	25.5	0.979	1.7	>4	0.50	0.043	Low	Low	Int
Rh28	ALV RMS	25.8	0.203	2.6	>4	0.51	0.009	Low	Low	Int
Rh30	ALV RMS	13.9	0.429	1.1	>4	0.81	0.105	Low	Low	Low
Rh30R	ALV RMS	24.8	<0.001	2.3	>4	0.34	<0.001	Int	Int	Int
Rh41	ALV RMS	20.4	0.121	1.5	>4	0.59	0.011	Low	Low	Low
Rh18	EMB RMS	26.7	<0.001	2.1	>4	0.38	<0.001	Int	Int	Int
BT-28	Medulloblastoma	8.0	0.504	0.9	>4	0.96	0.912	Low	Low	Low
BT-45	Medulloblastoma	13.4	0.174	0.9	>4	1.10	0.280	Low	Low	Low
BT-41	Ependymoma	>EP	1.000	—	2.4	0.71	0.089	Low	NE	Int
BT-44	Ependymoma	18.2	0.301	1.1	>4	0.71	0.029	Low	Low	Low
NB-SD	Neuroblastoma	10.9	0.934	0.9	>4	1.10	0.574	Low	Low	Low
NB-1771	Neuroblastoma	11.4	<0.001	2.5	>4	0.30	0.002	Int	Int	Int
NB-1691	Neuroblastoma	9.9	0.426	1.0	>4	0.88	0.481	Low	Low	Low
NB-EBc1	Neuroblastoma	13.7	<0.001	2.7	>4	0.27	<0.001	Int	Int	Int
NB-1643	Neuroblastoma	27.1	0.012	3.4	>4	0.52	0.200	Low	Int	Int
SK-N-AS	Neuroblastoma	7.7	0.004	1.6	>4	0.59	0.007	Low	Low	Int
OS-1	Osteosarcoma	>EP	<0.001	>1.3	1.3	0.75	0.035	Low	NE	Int
OS-2	Osteosarcoma	>EP	0.055	>1.2	3.0	0.76	0.079	Low	NE	Int
OS-17	Osteosarcoma	>EP	0.011	>1.4	3.1	0.77	0.074	Low	NE	Int
OS-9	Osteosarcoma	35.2	<0.001	1.6	>4	0.64	<0.001	Low	Low	Int
OS-33	Osteosarcoma	16.8	0.002	1.3	>4	0.74	0.003	Low	Low	Low
OS-31	Osteosarcoma	21.0	0.477	1.1	>4	0.94	0.353	Low	Low	Low
ALL-2	ALL B-precursor	10.9	0.612	0.7	>25	—			Low	Low
ALL-3	ALL B-precursor	4.8	0.167	0.5	>25	—			Low	Low
ALL-7	ALL B-precursor	4.2	0.932	1.0	>25	—			Low	Low
ALL-8	ALL T-cell	4.6	0.627	0.9	>25	—			Low	Low
ALL-16	ALL T-cell	4.4	0.141	0.5	>25	—			Low	Low
ALL-17	ALL B-precursor	5.5	0.100	0.6	>25	—			Low	Low
ALL-19	ALL B-precursor	4.6	0.097	0.7	>25	—			Low	Low

Criteria for intermediate activity for the time to event activity measure (EFS T/C >2) were met in 7 of 27 (26%) solid tumor xenografts evaluable for this measure. Intermediate activity was most commonly observed in the neuroblastoma panel (3 of 6) and rhabdomyosarcoma panel (2 of 6). Single xenografts in the Wilms tumor and Ewing sarcoma panels also showed intermediate activity. Five models were inevaluable for the EFS T/C activity measure due to slow tumor growth in control animals, including three xenografts from the osteosarcoma panel.

Objective responses (i.e., tumor regression) were not observed for any of the solid tumor or ALL xenografts. The best response was PD2 (progressive disease with growth delay), which was observed in 18 of 32 solid tumor xenografts. PD2 responses were most commonly observed in the rhabdomyosarcoma (4 of 6), neuroblastoma (4 of 6), osteosarcoma (4 of 6), Ewing sarcoma (2 of 4), and Wilms tumor (2 of 3) panels. Each of the ALL xenografts showed PD1 (progressive disease without growth delay) (Fig. 1).

Fig. 1.

BMS-754807 in vitro activity. Top panel: The median EC₅₀ ratio graph shows the relative EC₅₀ values for the cell lines of the PPTP panel. Each bar represents the ratio of the panel EC₅₀ to the EC₅₀ value of the indicated cell line. Bars to the right represent cell lines with higher sensitivity, while bars to the left indicate cell lines with lesser sensitivity. Bars highlighted with an asterisk (*) represent the three cell lines with greatest sensitivity to mAb391. Bottom panels: Representative dose response curves for Rh41 rhabdomyosarcoma and TC-71 Ewing sarcoma cell lines.

The in vivo testing results for the objective response measure of activity are presented in Figure 2 in a “heat-map” format as well as a “COMPARE”-like format, based on the scoring criteria described in the Supplemental Response Definitions Section. The latter analysis demonstrates relative tumor sensitivities around the midpoint score of 5 (stable disease). Typical tumor responses are shown in Figure 3 (KT14 (rhabdoid), KT5 (Wilms), Rh28 (rhabdomyosarcoma), OS1 (osteosarcoma)).

Fig. 2.

BMS-754807 in vivo objective response activity. Left: The colored heat map depicts group response scores. A high level of activity is indicated by a score of 6 or more, intermediate activity by a score of ≥2 but <6, and low activity by a score of <2. Right: Representation of tumor sensitivity based on the difference of individual tumor lines from the midpoint response (stable disease). Bars to the right of the median represent lines that are more sensitive, and to the left are tumor models that are less sensitive. Red bars indicate lines with a significant difference in EFS distribution between treatment and control groups, while blue bars indicate lines for which the EFS distributions were not significantly different.

Fig. 3.

BMS-754807 activity against individual solid tumor xenografts. Kaplan–Meier curves for EFS, median relative tumor volume graphs, and individual tumor volume graphs are shown for selected lines KT-5 (Wilms), KT-14 (rhabdoid), Rh28 (rhabdomyosarcoma), and OS-1 osteosarcoma xenografts. Controls (gray lines); Treated (black lines).

DISCUSSION

IGF-1 is a known mitogen for osteosarcoma [17–19], neuroblastoma [20,21], brain tumors (including glioblastoma [22,23], astrocytoma [24], medulloblastoma [25]), Wilms tumor [26], and hepatocellular carcinoma [27]. In alveolar rhabdomyosarcoma, the PAX3-FKHR or PAX7-FKHR chimeric transcription factors associated with t(2;13)(q35;q14) and t(1;13)(q36;q14), enhance transcription IGF-1R [28,29]. In embryonal rhabdomyosarcoma, there is loss of imprinting at the IGF-2 locus, which may be a primary genetic event for embryonal rhabdomyosarcoma [30]. In Ewing sarcoma IGF-1R is a potent mediator of autocrine growth [31,32]. Cases of Ewing sarcoma with the type-1 EWS-FLI1 chimeric transcription factor are associated with an improved prognosis and with lower IGF-1R expression compared to cases with non-type 1 translocations [33]. EWS-FLI1 silencing leads to increased levels of insulin-like growth factor binding protein 3 gene (IGFBP-3), a major regulator of IGF-1 [34]. Expression of IGF-1R, IGF-1, and IGF-2 is consistently reported in osteosarcoma cell lines and patient samples [35]. Further evidence of IGF-mediated growth in osteosarcoma can be inferred from experiments demonstrating inhibition of growth and metastases of murine osteosarcoma following hypophysectomy [36], and inhibition of tumor growth in xenografts following treatment with anti-IGF-1R antibody [37]. The role of the IGF-1 axis in acute lymphoblastic leukemia is less clearly defined [37–39].

In pediatric cancers, there are several IGF-1R targeted therapies currently in clinical trials, and an increasing body of preclinical data suggesting that IGF-1R is a high priority molecular target [6]. BMS-754807 is a small molecule inhibitor of IGF-1R with good oral bioavailability that is currently in clinical testing in adults with solid tumors. In the current report, in vitro activity of BMS-754807 was most pronounced in the Ewing sarcoma cell lines. Carboni et al. [9] also observed greater in vitro sensitivity for Ewing sarcoma cell lines compared to cell lines derived from other cancer types. Results for the murine anti-IGF-1R monoclonal antibody mAb391 show consistency with those for BMS-754807, as the EC₅₀ for BMS-754807 is 10-fold lower in the mAb391-sensitive lines compared to the mAb391-resistant lines. The BMS-754807 micromolar range activity against cell lines non-responsive to mAb391 likely reflects non-IGF-1R/non-IR inhibitory activities of BMS-754807. For example, using biochemical assays of kinase inhibition, BMS-754807 shows low nanomolar activity against Met, TrkA, TrkB, and AurA, with IC₅₀ values two- to fivefold greater than those observed for IGF-1R and IR [9].

BMS-754807 was well tolerated (6.3% mortality), so was tested at close to the maximal dose tolerated on this schedule. Toxicity was seen most frequently in the glioblastoma models that are propagated in athymic nude mice, although was no pattern of toxicity that could be associated with the mechanism of drug action. The in vivo response to previously tested anti-IGF-1R antibodies also predicts response to BMS-754807. The KT-14 rhabdoid tumor line, the EW5 Ewing tumor line, the RH10, RH28, RH30R rhabdomyosarcoma lines, the NB-1771, NB-EBc1, and NB1643 neuroblastoma lines, and the OS1, OS1, OS9, and OS17 osteosarcoma lines have consistently demonstrated intermediate to high responses to IGF-1R inhibitors [40,41]. As previously published by the PPTP, IGF-1R expression alone does not predict response to IGF-1R directed monoclonal antibodies [40]. In published studies antibodies that block ligand binding to IGF-1R induced regressions of tumors whereas BMS-754807 induced growth inhibition. The reason for this difference is not understood. However, unlike small molecule inhibitors of IGF-1R, the antibodies induce internalization and degradation of the IGF-1 receptor. The antibodies may also have superior pharmacokinetics in mice compared with the small molecule inhibitors.

A high priority for future research is to identify predictive biomarkers of response to agents targeted against IGF-1R [42]. In response to another small molecule inhibitor of IGF-1R (BMS-536924), Huang et al. recently demonstrated that IGF-1R, IGF-1, and IGF-2 are highly expressed in sensitive cell lines, while IGF binding proteins (IGFBP-3 and IGFBP-6) are highly expressed in resistant cell lines. Overexpression of EGFR and downstream components of EGFR signaling were also noted in BMS-536924 resistant tumor lines [43]. In hepatocellular carcinoma cell lines, HER3 activation by EGFR in response to IGR-1R inhibition seems to be one potential mechanism of resistance [44]. Tumor cell death is enhanced in rhabdomyosarcoma [43] and hepatocellular carcinoma cell lines [44] when both IGF-1R and EGFR signaling are inhibited. Clinical applications of IGF-1R inhibitors should focus on defining biomarkers of resistance, as well as combination strategies to inhibit alternate signaling though salvage pathways like EGFR. Cross talk between IGF-1R and EGFR make combination strategies targeting both receptors potentially more efficacious than single agent strategies.

The broad activity of BMS-754807 in pediatric sarcomas and neuroblastoma xenografts suggests that this agent may be effective in pediatric tumors. The fact that the activity of BMS-754807 is, for the most part, predicted by previously tested IGF-1R inhibitors in the PPTP panel supports the idea that a subset of pediatric tumors are susceptible to IGF-1R inhibition. Thus, it is likely that BMS-754807 may have limited single agent activity, similar to other kinase inhibitors. However, it is important to acknowledge that the efficacy of therapies targeting receptor tyrosine kinases may be maximized when used in rational combinations targeting multiple, related signaling pathways. Priority for clinical development of IGF-1R inhibitors should not be assigned based solely on results of single agent trial results. Priority should also be assigned to rational combinations in which an IGF-1R inhibitor is combined with inhibitors of targets such as mTOR [40], SRC family kinases [9], EGFR [9,43,44], or HER2 [9,45]. Further preclinical testing by the PPTP evaluating these and other rational combinations as well as combination with standard cytotoxic agents used in treatment of childhood malignancies may facilitate pediatric development of BMS-754807.