Genomic and Molecular Characterization of IGF1R as a Promising Therapeutic Target in Malignant Peripheral Nerve Sheath Tumor

By Jilong Yang, MD, PhD and Wei Zhang, PhD

Introduction

Malignant peripheral nerve sheath tumors (MPNSTs) are a type of soft tissue sarcoma of ectomesenchymal origin. They are highly malignant and account for approximately 5%–10% of soft tissue sarcomas. The World Health Organization coined the term "MPNST" in 2002 to replace previous heterogeneous and often confusing terminology, such as "malignant schwannoma," "malignant neurilemmoma," "neurogenic sarcoma," and "neurofibrosarcoma." The relative rarity of MPNST and the lack of any singular diagnostic, radiological, or pathologic signature lead to several management challenges. At present, even treated by multidisciplinary therapy such as aggressive surgery, high dose adjuvant chemotherapy, and radiotherapy, the 5 year survival rates of MPNSTs still only range from 30%-50%. Furthermore, the severe adverse side effects of aggressive surgery and high dose chemotherapy and radiotherapy, together with the poor prognosis, make it necessary to find new therapeutic methods to benefit patients with this type of aggressive sarcoma.

In a previous study, we used genome-wide, microarray-based comparative genomics hybridization (aCGH) to profile the genetic alterations of 51 MPNST tissues. Bioinformatic analysis revealed that 28.3% (15/53) of cases had amplifications of IGF1R genes. Furthermore, we found that overexpression of IGF1R occurred in 82.1% (46/56) of MPNSTs. Most importantly, the IGF1R expression had significant correlation with tumor metastasis and recurrence and was a significant molecular factor in predicting the metastasis or recurrence of MPNSTs. These are important findings with clinical relevance, because IGF1R is a target for anti-IGF1R therapeutic trials in several different types of cancers, such as MK-0640 in GISTs.

The IGF-IR is a multifunctional tyrosine kinase receptor involved in several biological processes, including cell proliferation, differentiation, DNA repair, and cell survival. It was implicated in the development and maintenance of malignant phenotypes, and interruption of IGF-1R signaling inhibited cancer cell growth and motility in in vitro and in vivo models. Therefore, IGF1R has been identified as a potential molecular target for a number of cancer types, including breast cancer, cervical cancer, NSCLC, malignant melanoma, multiple myeloma, prostate cancer, pancreatic cancer, and esophageal squamous cell carcinoma. In comparison, investigations about IGF1R-targeted therapy in sarcomas are lagging at present. In gastrointestinal stromal tumors (GISTs), two investigations showed that, in both the wild type and the c-kit mutation types of GISTs, IGF1R is a potential therapeutic target. Inhibition of IGF1R activity in vitro, with NVP-AEW541 or siRNA of IGF1R, led to cytotoxicity and apoptosis in GIST cell lines via AKT and MAPK signaling. The combination of NVP-AEW541 and imatinib in GIST cell lines induced a strong cytotoxicity response. However, there is limited data about IGF1R expression and its prognostic significance in MPNST, and the effect of IGF1R inhibition.

In the study that is partly supported by the Liddy Shriver Sarcoma Initiative, we present a comprehensive characterization of a large cohort of 51 primary tumors using aCGH technology. We applied pathway-level analyses that resulted in a unique view into the aberrant signaling networks in MPNST, which we then proceeded to validate with IHC and molecular approaches in tissue culture in two cell lines. Our studies provided evidence that IGF1R is a promising therapeutic target in MPNST patients. The results from this study are published in the journal Clinical Cancer Research.

Important Results and Conclusions

Genomic characterization of 51 MPNST tissue samples identified several frequently amplified regions harboring 2,599 genes and regions of deletion including 4,901 genes (Figure 1).

At the pathway level, we identified a significant enrichment of copy number–altering events in the insulin-like growth factor 1 receptor (IGF1R) pathway, including frequent amplifications of the IGF1Rgene itself (Figure 2A). To validate the IGF1R pathway as a potential target in MPNSTs, we first confirmed that high IGF1R protein correlated with worse tumor-free survival in an independent set of samples using immunohistochemistry (Figure 2B).

Two MPNST cell lines (ST88-14 and STS26T) were used to determine the effect of attenuating IGF1R. Inhibition of IGF1R in ST88-14 cells using small interfering RNAs or an IGF1R inhibitor, MK-0646, led to significant decreases in cell proliferation, invasion, and migration accompanied by attenuation of the PI3K/AKT and MAPK pathways (Figure 3).

Summary and Future Directions

These integrated genomic and molecular studies provide evidence that IGF1R is a promising therapeutic target in MPNST patients. This is the first time that the genetic aberrations of important signaling pathways have been investigated with the purpose of scanning possible therapeutic targets in MPNST. Extensive investigations of these pathways might give added confidence to move translational research results to clinics to benefit patients with MPNST.

By Jilong Yang, MD, PhD
Department of Pathology, Unit 85
The University of Texas MD Anderson Cancer Center in Houston, Texas
and Department of Bone and Soft Tissue Tumor
Tianjin Medical University Cancer Hospital & Institute in Tianjin, China

Wei Zhang, PhD
Professor Department of Pathology, Unit 85
Director, Cancer Genomics Core Lab
The University of Texas MD Anderson Cancer Center in Houston, Texas

References

1. Anghileri M, Miceli R, Fiore M, Mariani L, Ferrari A, Mussi C, et al. Malignant peripheral nerve sheath tumors: prognostic factors and survival in a series of patients treated at a single institution. Cancer 2006; 107:1065-74.

2. Bruchim I, Attias Z, Werner H. Targeting the IGF1 axis in cancer proliferation. Expert Opin Ther Targets 2009; 13:1179-92.

3. Cappuzzo F, Tallini G, Finocchiaro G, Wilson RS, Ligorio C, Giordano L, et al. Insulin-like growth factor receptor 1 (IGF1R) expression and survival in surgically resected non-small-cell lung cancer (NSCLC) patients. Ann Oncol; 21:562-7.

4. Chitnis MM, Yuen JS, Protheroe AS, Pollak M, Macaulay VM. The type 1 insulin-like growth factor receptor pathway. Clin Cancer Res 2008; 14:6364-70.

5. Ewing GP, Goff LW. The insulin-like growth factor signaling pathway as a target for treatment of colorectal carcinoma. Clin Colorectal Cancer; 9:219-23.

6. Grobmyer SR, Reith JD, Shahlaee A, Bush CH, Hochwald SN. Malignant Peripheral Nerve Sheath Tumor: molecular pathogenesis and current management considerations. J Surg Oncol 2008; 97:340-9.

7. Hewish M, Chau I, Cunningham D. Insulin-like growth factor 1 receptor targeted therapeutics: novel compounds and novel treatment strategies for cancer medicine. Recent Pat Anticancer Drug Discov 2009; 4:54-72.

8. Imsumran A, Adachi Y, Yamamoto H, Li R, Wang Y, Min Y, et al. Insulin-like growth factor-I receptor as a marker for prognosis and a therapeutic target in human esophageal squamous cell carcinoma. Carcinogenesis 2007; 28:947-56.

9. Janeway KA, Zhu MJ, Barretina J, Perez-Atayde A, Demetri GD, Fletcher JA. Strong expression of IGF1R in pediatric gastrointestinal stromal tumors without IGF1R genomic amplification. Int J Cancer; 127:2718-22.

10. Ji QS, Mulvihill MJ, Rosenfeld-Franklin M, Cooke A, Feng L, Mak G, et al. A novel, potent, and selective insulin-like growth factor-I receptor kinase inhibitor blocks insulin-like growth factor-I receptor signaling in vitro and inhibits insulin-like growth factor-I receptor dependent tumor growth in vivo. Mol Cancer Ther 2007; 6:2158-67.

11. Jiang Y, Wang L, Gong W, Wei D, Le X, Yao J, et al. A high expression level of insulin-like growth factor I receptor is associated with increased expression of transcription factor Sp1 and regional lymph node metastasis of human gastric cancer. Clin Exp Metastasis 2004; 21:755-64.

12. Jilong Yang, Antti Ylipää, Yan Sun, Hong Zheng, Kexin Chen, Matti Nykter, Jonathan Trent, Nancy Ratner, Dina C. Lev, Wei Zhang. Genomic and Molecular Characterization of Malignant Peripheral Nerve Sheath Tumor Identifies the IGF1R Pathway as a Primary Target for Treatment. Clin Cancer Res, 2011, 17(24):7563-7573.

13. Kaulfuss S, Burfeind P, Gaedcke J, Scharf JG. Dual silencing of insulin-like growth factor-I receptor and epidermal growth factor receptor in colorectal cancer cells is associated with decreased proliferation and enhanced apoptosis. Mol Cancer Ther 2009; 8:821-33.

14. Klinakis A, Szabolcs M, Chen G, Xuan S, Hibshoosh H, Efstratiadis A. Igf1r as a therapeutic target in a mouse model of basal-like breast cancer. Proc Natl Acad Sci U S A 2009; 106:2359-64.

15. Kwon J, Stephan S, Mukhopadhyay A, Muders MH, Dutta SK, Lau JS, et al. Insulin receptor substrate-2 mediated insulin-like growth factor-I receptor overexpression in pancreatic adenocarcinoma through protein kinase Cdelta. Cancer Res 2009; 69:1350-7.

16. Law JH, Habibi G, Hu K, Masoudi H, Wang MY, Stratford AL, 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.

17. Li R, Pourpak A, Morris SW. Inhibition of the insulin-like growth factor-1 receptor (IGF1R) tyrosine kinase as a novel cancer therapy approach. J Med Chem 2009; 52:4981-5004.

18. Liao Y, Abel U, Grobholz R, Hermani A, Trojan L, Angel P, et al. Up-regulation of insulin-like growth factor axis components in human primary prostate cancer correlates with tumor grade. Hum Pathol 2005; 36:1186-96.

19. Martins AS, Mackintosh C, Martin DH, Campos M, Hernandez T, Ordonez JL, et al. Insulin-like growth factor I receptor pathway inhibition by ADW742, alone or in combination with imatinib, doxorubicin, or vincristine, is a novel therapeutic approach in Ewing tumor. Clin Cancer Res 2006; 12:3532-40.

20. Mayeenuddin LH, Yu Y, Kang Z, Helman LJ, Cao L. Insulin-like growth factor 1 receptor antibody induces rhabdomyosarcoma cell death via a process involving AKT and Bcl-x(L). Oncogene.

21. Metalli D, Lovat F, Tripodi F, Genua M, Xu SQ, Spinelli M, et al. The insulin-like growth factor receptor I promotes motility and invasion of bladder cancer cells through Akt- and mitogen-activated protein kinase-dependent activation of paxillin. Am J Pathol; 176:2997-3006.

22. Miller SJ, Rangwala F, Williams J, Ackerman P, Kong S, Jegga AG, et al. Large-scale molecular comparison of human schwann cells to malignant peripheral nerve sheath tumor cell lines and tissues. Cancer Res 2006; 66:2584-91.

23. Moser C, Schachtschneider P, Lang SA, Gaumann A, Mori A, Zimmermann J, et al. Inhibition of insulin-like growth factor-I receptor (IGF-IR) using NVP-AEW541, a small molecule kinase inhibitor, reduces orthotopic pancreatic cancer growth and angiogenesis. Eur J Cancer 2008; 44:1577-86.

24. Nakamura K, Hongo A, Kodama J, Miyagi Y, Yoshinouchi M, Kudo T. Down-regulation of the insulin-like growth factor I receptor by antisense RNA can reverse the transformed phenotype of human cervical cancer cell lines. Cancer Res 2000; 60:760-5.

25. Pantaleo MA, Astolfi A, Di Battista M, Heinrich MC, Paterini P, Scotlandi K, et al. Insulin-like growth factor 1 receptor expression in wild-type GISTs: a potential novel therapeutic target. Int J Cancer 2009; 125:2991-4.

26. Pappano WN, Jung PM, Meulbroek JA, Wang YC, Hubbard RD, Zhang Q, et al. Reversal of oncogene transformation and suppression of tumor growth by the novel IGF1R kinase inhibitor A-928605. BMC Cancer 2009; 9:314.

27. Sabbatini P, Rowand JL, Groy A, Korenchuk S, Liu Q, Atkins C, et al. Antitumor activity of GSK1904529A, a small-molecule inhibitor of the insulin-like growth factor-I receptor tyrosine kinase. Clin Cancer Res 2009; 15:3058-67.

28. Song RX, Barnes CJ, Zhang Z, Bao Y, Kumar R, Santen RJ. The role of Shc and insulin-like growth factor 1 receptor in mediating the translocation of estrogen receptor alpha to the plasma membrane. Proc Natl Acad Sci U S A 2004; 101:2076-81.

29. Tarn C, Rink L, Merkel E, Flieder D, Pathak H, Koumbi D, et al. Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors. Proc Natl Acad Sci U S A 2008; 105:8387-92.

Genomic and Molecular Characterization of EGFR and IGF1R as Key Potential Therapeutic Targets in Malignant Peripheral Nerve Sheath Tumors

By Jilong Yang, MD, PhD and Wei Zhang, PhD

Introduction

Malignant peripheral nerve sheath tumors (MPNSTs) are a type of soft tissue sarcoma of ectomesenchymal origin. They are highly malignant and account for approximately 5%–10% of soft tissue sarcomas. They arise from major or minor peripheral nerve branches or sheaths of peripheral nerve fibers and are derived from Schwann cells or pluripotent cells originating in the neural crest. The Schwann cell is thought to be the major contributor to the formation of benign, as well as malignant neoplasm of the nerve sheath. The World Health Organization coined the term MPNST in 2002 to replace previous heterogeneous and often confusing terminology, such as "malignant schwannoma," "malignant neurilemmoma," "neurogenic sarcoma," and "neurofibrosarcoma."

MPNSTs pose significant clinical challenges because there is great variation in terms of tumor location and clinical presentation. Histologically, MPNSTs resemble fibrosarcoma in their basic organization: spindle cell tumors with long processes disposed in whorls or storiform patterns. Immunohistochemical analysis of markers, particularly S100, plays an important role in diagnosis. At the molecular level, loss of the NF1 gene and high levels of Ras activity are known hallmarks of MPNST. Despite multidisciplinary therapy, the 5-year survival rate of patients with MPNSTs still ranges from 30% to 50%. Several studies have examined the epidemiological, etiological, clinical, pathological, and molecular characteristics of MPNSTs to find new therapeutic methods. However, no significant progress has been made.

EGFR and IGFR1 as therapeutic targets for MPNSTs

Recent array comparative genomic hybridization (aCGH) studies showed that the epidermal growth factor receptor (EGFR) gene is amplified in MPNSTs. Furthermore, EGFR expression has been reported in several investigations, and the data show that EGFR expression is very important in NF-1, neurofibroma, and MPNSTs because of its significant correlation with the tumor formation and development. EGFR is a transmembrane tyrosine kinase receptor that has been implicated in a multiplicity of cancer-related signal transduction pathways, such as those regulating cellular proliferation, adhesion, and migration; neoangiogenesis; and apoptosis inhibition, which are all important features of tumorigenesis and tumor progression. EGFR induced tyrosine kinase activity plays a central role in mediating these processes and has been intensely studied to exploit it as a therapeutic target. Some small-molecule tyrosine kinase inhibitors of EGFR such as gefitinib (Iressa) and erlotinib have shown anticancer effects in patients with non-small cell lung cancer.

In our previous study, we characterized genetic alterations in MPNST tissues using genome-wide aCGH. Bioinformatic analysis revealed that a large part of the MPNST cases had amplifications ofIGF1R and EGFR. Furthermore, in our recent validation studies using immunohistochemical analysis, we found overexpression of IGF1R and EGFR in most of the MPNSTs that we analyzed. Most importantly, IGF1R and EGFR expression significantly correlated with tumor metastasis and disease recurrence.We found that the patients with IGF1R and/or EGFR expression had significantly worse disease-free survival and a significantly higher risk of tumor development than those without expression of these receptors. These are important, clinically relevant findings, as anti-EGFR– and anti-IGF1R–targeted therapies, such as gefitinib, erlotinib, and MK-0646, are being tested in clinical trials in several different types of cancer, including lung cancer and gastrointestinal stromal tumors (GISTs).

IGF1R is a multifunctional tyrosine kinase receptor involved in several biological processes, including cell proliferation and differentiation, DNA repair, and cell survival. It is also implicated in the development and maintenance of malignant phenotypes, and interruption of IGF1R signaling inhibits cancer cell growth and motility in both in vitro and in vivo models in several types of carcinoma. In comparison, there have been few investigations of IGF1R-targeted therapy in sarcomas. In GISTs, two investigations have shown that IGF1R is a potential therapeutic target, and the inhibition of IGF1R activity in vitro with NVP-AEW541 or IGF1R-specific siRNA led to cytotoxicity and apoptosis in GIST cell lines through AKT and MAPK signaling. However, there are limited data regarding IGF1R expression, its prognostic significance in MPNST, and the effect of IGF1R inhibition.

EGFR and IGF1R may cooperate to regulate tumor growth and survival. Inhibition of either EGFR or IGF1R may promote activation of the other receptor. The complicated crosstalk between the EGFR and IGF1R pathways could significantly affect the efficacy of EGFR-targeted therapy. On the basis of the crosstalk between the IGF1R and EGFR pathways, studies of combination therapies that target both pathways should be performed to determine whether this combination enhances tumor-growth inhibition. These investigations would not only provide a strategy for testing combinations of EGFR inhibitors with IGF1R-targeted therapies to achieve improved patient outcomes, but also satisfy the urgent need to explore the mechanisms of intrinsic and acquired drug resistance to enhance the antitumor efficacy of these therapies.

In this proposed translational research project, we plan to further functionally characterize IGF1R and EGFR as key targetable molecules in MPNST. First, we will use MK-0646, an IGF1R monoclonal antibody, and IGF1R-specific siRNA to treat MPNST cell lines (T265p21, ST88-14, and STS26T) to determine whether knockdown and/or inhibition of IGF1R leads to apoptosis and/or reduced cell proliferation and migration/invasion. We will examine the changes in the IGF1R pathway and its associated PI3K/AKT and MAPK pathways. For EGFR, similar approaches will be used, including experiments with siRNA interference and targeted inhibition with gefitinib. If these in vitro experiments are effective, we will test whether knockdown or inhibition of both IGF1R and EGFR can suppress the growth of MPNST xenograft tumors in nude mice. These studies will provide key evidence of whether IGF1R and EGFR activity is important for the growth of MPNSTs and whether targeting IGF1R and/or EGFR would constitute an effective targeted therapy.

Purpose of the specific investigation

On the basis of our preliminary data and reported studies in the literature, we hypothesize that IGF1R and EGFR are potential therapeutic targets for the treatment of MPNSTs. We will test this hypothesis with the following three specific aims that first examine the receptors individually and then in combination.

Specific Aim 1

We will use siRNA specific for IGF1R and the IGF1R monoclonal antibody MK-0646 (made by Merck) to treat MPNST cell lines T265p21, ST88-14, and STS26T to determine whether knockdown and/or inhibition of IGF1R leads to increased cell death and reduced cell proliferation and migration/invasion. We will also evaluate the effect on molecules in the IGF1R signaling pathway, including IRS-1, PI3K, AKT, Erk, Ras, and Bad.

Specific Aim 2

In this aim, we will use an approach similar to the one outlined in specific aim 1 to evaluate the effect of inhibiting EGFR on MPNSTs.We will use siRNA specific for EGFR and the anti-EGFR antibody gefitinib to treat MPNST cell lines to determine whether knockdown and/or inhibition of EGFR leads to apoptosis, reduced cell proliferation, and attenuated cell migration and invasion. The functional assays used for this aim will be similar to those described in specific aim 1.

Specific Aim 3

Accumulating evidence suggests that often more than one key pathway is involved in the proliferation of cancer cells. Thus, inhibition of one pathway is often ineffective. Our preliminary studies showed that EGFR and IGF1R are often co-amplified in MPNSTs. Therefore, simultaneously blocking both pathways is likely a more effective therapeutic strategy. In this aim, we will treat cells with either siRNAs specific for both genes or antibodies against both targets and evaluate the effect on MPNST cells by analyzing the same functional endpoints as described in specific aim 1.

Significance of this translational research project

MPNSTs are highly malignant tumors with a high rate of local recurrence and a significant tendency to metastasize. The survival rate of patients with MPNST remains low. The dismal outcome highlights the importance of identifying clinicopathological and molecular factors that impact MPNST prognosis and points to the urgent need to establish better therapeutic strategies for patients with MPNSTs. Our studies will provide key evidence for whether IGF1R and EGFR represent key signaling pathways for MPNSTs and whether cotargeting IGF1R and EGFR would constitute an effective therapeutic strategy. This will provide critical information for the design of a new clinical trial using anti-IGF1R and anti-EGFR therapies to treate MPNSTs.

References

1. Buck E, Eyzaguirre A, Rosenfeld-Franklin M, Thomson S, et al. Feedback mechanisms promote cooperativity for small molecule inhibitors of epidermal and insulin-like growth factor receptors. Cancer Res. 2008; 68(20):8322-32.

2. Hewish M, Chau I, Cunningham D.Insulin-like growth factor 1 receptor targeted therapeutics: novel compounds and novel treatment strategies for cancer medicine. Recent Pat Anticancer Drug Discov. 2009;4(1):54-72.

3. Hu YP, Patil SB, Panasiewicz M, Li W, Hauser J, Humphrey LE, Brattain MG. Heterogeneity of receptor function in colon carcinoma cells determined by cross-talk between type I insulin-like growth factor receptor and epidermal growth factor receptor. Cancer Res. 2008;68(19):8004-13.

4. 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(1):161-70.

5. Jiang Y, Wang L, Gong W, et al. A high expression level of insulin-like growth factor I receptor is associated with increased expression of transcription factor Sp1 and regional lymph node metastasis of human gastric cancer. Clin Exp Metastasis. 2004;21(8):755-64.

6. Keizman D, Issakov J, Meller I, Meimon N, Ish-Shalom M, Sher O, Merimsky O. Expression and significance of EGFR in malignant peripheral nerve sheath tumor. J Neurooncol. 2009;94(3):383-8.

7. Klinakis A, Szabolcs M, Chen G, Xuan S, Hibshoosh H, Efstratiadis A. Igf1r as a therapeutic target in a mouse model of basal-like breast cancer. Proc Natl Acad Sci U S A. 2009; 106(7):2359-64.

8. Kwon J, Stephan S, Mukhopadhyay A, Muders MH, Dutta SK, Lau JS, Mukhopadhyay D. Insulin receptor substrate-2 mediated insulin-like growth factor-I receptor overexpression in pancreatic adenocarcinoma through protein kinase Cdelta. Cancer Res. 2009;69(4):1350-7.

9. Liao Y, Abel U, Grobholz R, Hermani A, Trojan L, Angel P, Mayer D. Up-regulation of insulin-like growth factor axis components in human primary prostate cancer correlates with tumor grade. Hum Pathol. 2005;36(11):1186-96.

10. Lin CT, Huang TW, Nieh S, Lee SC.Treatment of a Malignant Peripheral Nerve Sheath Tumor. Onkologie. 2009;32(8-9):503-505.

11. Ling BC, Wu J, Miller SJ, Monk KR, Shamekh R, Rizvi TA, Decourten-Myers G, Vogel KS, DeClue JE, Ratner N. Role for the epidermal growth factor receptor in neurofibromatosis-related peripheral nerve tumorigenesis. Cancer Cell. 2005;7(1):65-75.

12. Ludovini V, Bellezza G, Pistola L, et al. High coexpression of both insulin-like growth factor receptor-1 (IGFR-1) and epidermal growth factor receptor (EGFR) is associated with shorter disease-free survival in resected non-small-cell lung cancer patients. Ann Oncol. 2009;20(5):842-9.

13. Pantaleo MA, Astolfi A, Di Battista M, Heinrich MC, Paterini P, Scotlandi K, Santini D, Catena F, Manara MC, Nannini M, Maleddu A, Saponara M, Lolli C, Formica S, Biasco G. Insulin-like growth factor 1 receptor expression in wild-type GISTs: A potential novel therapeutic target. Int J Cancer. 2009 Dec 15;125(12):2991-4

14. Pappano WN, Jung PM, Meulbroek JA, Wang YC, Hubbard RD, Zhang Q, Grudzien MM, Soni NB, Johnson EF, Sheppard GS, Donawho C, Buchanan FG, Davidsen SK, Bell RL, Wang J. Reversal of oncogene transformation and suppression of tumor growth by the novel IGF1R kinase inhibitor A-928605. BMC Cancer. 2009;9(1):314

15. Sachdev D, Yee D. Disrupting insulin-like growth factor signaling as a potential cancer therapy. Mol Cancer Ther 2007;6:1–12.

16. Tawbi H, Thomas D, Lucas DR, Biermann JS, Schuetze SM, Hart AL, Chugh R, Baker LH. Epidermal growth factor receptor expression and mutational analysis in synovial sarcomas and malignant peripheral nerve sheath tumors. Oncologist. 2008 Apr;13(4):459-66.

17. Williams JP, Wu J, Johansson G, Rizvi TA, Miller SC, Geiger H, Malik P, Li W, Mukouyama YS, Cancelas JA, Ratner N. Nf1 mutation expands an EGFR-dependent peripheral nerve progenitor that confers neurofibroma tumorigenic potential. Cell Stem Cell. 2008 Dec 4;3(6):658-69.

18. Zhou J, Huang W, Tao R, Ibaragi S, Lan F, Ido Y, Wu X, Alekseyev YO, Lenburg ME, Hu GF, Luo Z. Inactivation of AMPK alters gene expression and promotes growth of prostate cancer cells. Oncogene. 2009;28(18):1993-2002.

19. Zou C, Smith KD, Liu J, Lahat G, Myers S, Wang WL, Zhang W, McCutcheon IE, Slopis JM, Lazar AJ, Pollock RE, Lev D. Clinical, pathological, and molecular variables predictive of malignant peripheral nerve sheath tumor outcome. Ann Surg. 2009, 249(6):1014-22.

Grant Funding

The Liddy Shriver Sarcoma Initiative and the Reid R. Sacco Memorial Foundation co-funded this $50,000 grant in June 2010. The study was made possible, in part, by donations made in memory of Denise Grove to the Liddy Shriver Sarcoma Initiative.

An extensive report of this study's results was published in the journal Clinical Cancer Research in October 2011.

The skin lesions, coffee spots, tumor, and pathologic histology of NF1-associated MPNST (from top left) .
Recurrent gene copy alterations in the MPNST genome. Frequent gains (red) and deletions (green) are plotted with chromosome ideograms at the center. Genes of interest are indicated for the most frequently aberrant regions. (Cited from Clin Cancer Res, 2011, 17(24):7563-7573).
Alteration frequencies (deletion rate (%) on the left side of the box, and amplification rate (%) on the right) for the IGF1R pathway are shown for each gene individually. Green genes are significantly often deleted (bright green >30% of the cases; dark green >20%), and red genes are amplified (bright red >30% of the cases; dark red >20%). Copy numbers of the gray genes are infrequently altered (in less than 20% of the cases). At least one gene in this pathway was altered in 82% of cases.
Chinese MPNST patients with higher IGF1R protein expression have increasingly worse disease-free survival. Upper panel: As shown by immunohistochemical analysis (Envision+, ×400), IGF1R protein is frequently expressed. Lower panel: Survival estimators for patients with increasing levels of IGF1R protein expression are color-coded in the Kaplan-Meier plot with case number shown. The patients with higher IGF1R protein expression have increasingly worse disease-free survival. (Cited from Clin Cancer Res, 2011, 17(24):7563-7573).
IGF1R downregulated by IGF1R siRNAs significantly decreased tumor cell proliferation, invasion, and migration by blocking PI3K/AKT and MAPK pathways in ST88-14 cells. A: A pool of three IGF1R siRNAs decreased IGF1R expression, IGF1R activation, and tumor cell proliferation compared with the nonspecific control siRNA. Left panel: Inactivatation of PI3K/AKT and MAPK pathway factors with IGF1R inhibition. Right panel: the decrease of tumor cell proliferation. B: A pool of three IGF1R siRNAs significantly decreased tumor cell invasion compared with the nonspecific control siRNA. left panel, Cell invasion. Right panel, Cell count. C: A pool of three IGF1R siRNA significantly decreased tumor cell migration compared with the nonspecific control siRNA. Left panel, Cell migration. Right panel, Cell count. (Cited from Clin Cancer Res, 2011, 17(24):7563-7573).