MPNST poses significant clinical challenges because it is a highly malignant tumor characterized by a high rate of local recurrence and a strong tendency to metastasize (33
). The dismal prognosis highlights the importance of identifying new clinicopathologic and molecular factors that affect MPNST outcome and the urgent need to establish better therapeutic strategies for patients with MPNST. In the current study, we performed genomic and molecular studies of MPNST samples and found evidence that IGF1R protein overexpression is an important molecular marker for tumor-free survival in MPNST patients and that IGF1R is a promising therapeutic target in this disease.
A major contribution of this study is the extensive characterization of IGF1R as a potential therapeutic target for MPNST patients by genomic, IHC, and cellular biologic approaches. Several lines of evidence implicate IGF1R as a potential therapeutic target in MPNST: the IGF1R
gene is frequently amplified; the IGF1R protein expression correlates with survival; and there are significant alterations in the signaling pathway that also correlate with survival. IGF1R inhibitors have already been successfully used to treat some types of cancers (13
). IGF1R is a multifunctional tyrosine kinase receptor involved in several biologic processes, including cell proliferation, differentiation, DNA repair, and cell survival (14
). Aberrant activation of the IGF1/IGF1R axis has been associated with a worse prognosis in many tumors, including breast, gastric, and prostate cancers (36
). Furthermore, in pancreatic cancer and anaplastic thyroid carcinomas, IGF1R inhibitors were shown to also reduce vascularization and VEGF expression (38
). Therefore, IGF1R is a logical potential molecular target in several types of cancer including breast, cervical, non-small cell lung, and prostate cancers (23
). However, IGF1R-targeted therapies for sarcomas lag behind those for other cancers at present. Inhibition of IGF1R activity by its tyrosine kinase inhibitor NVP-AEW541 or its siRNA led to cytotoxicity and apoptosis in GIST cell lines by blocking the AKT and mitogen-activated protein kinase (MAPK) pathway signaling. Furthermore, the combination of NVP-AEW541 and imatinib in GIST cell lines induced a strong cytotoxic response (13
). In MPNST, however, information about IGF1R expression, its prognostic significance, and the cytotoxic potential of IGF1R inhibition is still lacking. In the current study, the aCGH profile characterized the significant genetic amplifications of IGF1R signaling pathway genes including IGF1R
itself. The deregulation of expression of IGF1R is an independent prognostic factor for this type of sarcoma. In the cell line studies, IGF1R
siRNA and monoclonal antibody MK-0646 inhibited MPNST proliferation, invasion, and migration by blocking the AKT and PI3K pathways.
The introduction of anti-IGF1R antibodies in clinical trials and the dramatic single-agent anti-IGF1R activity observed in sarcoma patients provided the initial excitement in the sarcoma community (49
). However, the benefit of this therapeutic approach does not extend to all patients, with Phase II studies demonstrating less promising responses than initially anticipated (50
). A major mechanism of resistance to highly specific inhibitors of IGF-1R, either antibodies or tyrosine kinase inhibitors may involve enhanced insulin receptor (IR)-A homodimer formation and IGF-2 production (50
). Furthermore, the sensitivity to IGF1R targeted therapy might be sarcoma-type dependent because our preclinical study shows IGF1R targeted therapy might be effective in treating MPNST patients. One possible explanation is different compensatory responses in different sarcoma types in response to IGF1R inhibition. For example, different from the results in other tumors (17
), in our study the inhibition of IGF1R did not result in the activation of EGFR pathways in MPNST and the combined inhibition of IGF1R and EGFR did not show additive antitumor effects at the cellular level, suggesting lack of cross-talk between IGF1R and EGFR pathways in MPNSTs. These indicate that targeting IGF1R in MPNST might be more efficient than in other cancer types. Thus, despite the disappointing Phase II data in some sarcoma types, this novel class of drugs may constitute an active treatment in a proportion of sarcoma patients, especially MPNSTs.
Our aCGH profile with a large MPNST cohort revealed several important genetic aberrations with clinical relevance. We found that many genetic aberration events had significant correlation with clinical parameters of MPNST patients, including AJCC staging, tumor size, local recurrence, and metastasis. Extensive investigations of these genetic events and these correlations would shed light on MPNST pathogenesis. Furthermore, the pathway analyses revealed several signaling pathway genes harboring frequent genetic aberrations such as the TFF, ERK, ARF and other signaling pathways. 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 the clinic to benefit patients with MPNST.