Funded Research

An ESUN Announcement

June 15, 2010: The Liddy Shriver Sarcoma Initiative and the Reid R. Sacco Memorial Foundation are co-funding a research study, "Genomic and molecular characterization of IGF1R and EGFR as key targetable oncogenic events in malignant peripheral nerve sheath tumors," at the M. D. Anderson Cancer Center in Houston, Texas and the Tianjin Medical University Cancer Hospital and Institute in Tianjin, China. This grant is also made possible, in part, by donations made in memory of Denise Grove to the Liddy Shriver Sarcoma Initiative.

This study is led by co-Principal Investigators Wei Zhang, PhD, who is a Professor and the Director of the Cancer Genomics Core Laboratory at M. D. Anderson Cancer Center and Jilong Yang, MD, PhD, who is in the Department of Bone and Soft Tissue Tumors at Tianjin Medical University Cancer Hospital and Institute and is currently a Research Fellow in the Department of Pathology at M. D. Anderson Cancer Center.

The goal of this research is to determine whether the insulin-like growth factor 1 receptor (IGF1R) and epidermal growth factor receptor (EGFR) are key targetable events in malignant peripheral nerve sheath tumor (MPNST). MPNSTs, a subtype of soft tissue sarcomas, are highly malignant and account for approximately 5-10% of all soft tissue sarcomas. The following appears in the abstract of their grant application:

Despite aggressive surgery and high dose adjuvant chemotherapy and radiotherapy, the 5 year survival rates of MPNSTs are still poor. Genetic and molecular characterization of MPNST is needed for development of more effective therapies that target the driver events of MPNST. In our previous study, we carried out a genomic study using genome-wide microarray based comparative genomics hybridization (aCGH) to profile genetic alterations of 53 MPNST tissues. Bioinformatic analysis revealed that 28.3% (15/53) and 43.4% (23/53) of cases had amplification of IGF1R and EGFR genes. Furthermore, overexpression of IGF1R and EGFR proteins occurs in 85.7% (48/56) and 58.93% (33/56), respectively, in the MPNSTs we tested by immunohistochemistry. The IGF1R and EGFR expression had significant correlation with the tumor metastasis and/or recurrence. The patients with IGF1R and/or EGFR positive expression had significantly worse disease free survival and had significantly higher hazard of tumor development than the negative ones. These are important findings with clinical relevance because EGFR and IGF1R are targets for anti- EGFR and anti-IGF1R targeted therapeutic trials in several different types of cancers. Examples include gefitinib, erlotinib, and MK-0640 in the treatment of lung cancers.

The IGFIR is a multifunctional tyrosine kinase receptor involved in several biological processes including cell proliferation, differentiation, and survival. Aberrant activation of the IGF-I/IGF1R axis was associated with poor prognosis in many neoplasms including breast, gastric, and prostate cancers. However, there is very little information about the IGF1R expression and its prognostic significance in MPNST. Therefore, our finding that IGF1R is amplified in MPNST provides important motivation to study this pathway in MPNST and to provide laboratory evidence whether inhibition of IGF1R can be a viable approach for MPNST treatment. Targeted therapy for EGFR has shown success with lung cancer treatment. Only a few reports demonstrated overexpression of EGFR in MPNSTs; whether inhibition of EGFR is useful for both NF-1 related and sporadic MPNSTs is not clear at present.

In this proposed translational research project, we plan to further functionally characterize IGF1R and EGFR as key targetable events singly or in combination in MPNST. Firstly, we will use MK-0640, the IGF1R monoclonal antibody, and siRNA for IGF1R to treat MPNST cell lines (T265p21, ST88-14, STS26T) to determine whether knockdown and/or inhibition of IGF1R lead to MPNST cell apoptosis and/or slowed cell proliferation and migration/invasion. We will examine the changes in the IGF1R pathway and its associated PI3K/AKT and MAPK pathways by evaluating IRS-1, PI3K, AKT, S6k, 4-EBP-1, Ras, Raf, MAPK, Bcl-2, Bad, PARP-1, casepase 3, and casepase 9. For EGFR, similar approaches including experiments with siRNA interference and targeted inhibition with gefitinib will be used. Further, the combined inhibition of IGF1R and EGFR will be evaluated.

These in vitro experiments, if proven effective, will prompt us to test whether knockdown of IGF1R and EGFR or inhibition of IGF1R/EGFR would suppress MPNST tumors in xenograft model in the future. These studies will provide key evidence whether IGF1R and EGFR represent key events for MPNST and whether targeting IGF1R and/or EGFR would constitute effective targeted therapy.

You can read more about the approach they are taking in this study in their article, "Genomic and Molecular Characterization of EGFR and IGF1R as Key Potential Therapeutic Targets in Malignant Peripheral Nerve Sheath Tumors," which appears in the June 2010 issue of ESUN. If their study is successful, they intend to test whether knockdown of IGF1R and EGFR or inhibition of IGF1R and EGFR would suppress MPNST xenograft tumors in nude mice and transgenic mouse model, which would further provide critical support for future clinical trials.

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