Insulin-like Growth Factor Receptor Inhibitors Research Articles

Advances in the Treatment of Thyroid Eye Disease Associated Extraocular Muscle Myopathy and Optic Neuropathy.

To review emerging treatments for thyroid eye disease (TED) associated extraocular muscle myopathy and dysthyroid optic neuropathy (DON). Emerging targeted biologic therapies may alter the disease course in TED. Teprotumumab, a type I insulin-like growth factor receptor inhibitor, is the most recent addition to the treatments available for TED-associated extraocular muscle myopathy causing diplopia. Small studies also suggest a potential therapeutic benefit for DON. Various recent studies have also expanded our knowledge on conventional TED therapies. The therapeutic landscape of TED and its sequelae has evolved in recent years. New targeted therapies have the potential to reduce the extraocular muscle and orbital volume expansion which can lead to diplopia and vision loss from optic nerve compression. Longer term efficacy and durability data is needed to determine the role biologics, such as teprotumumab, should play in the treatment of TED patients compared to the current standard of care.

Teprotumumab (Tepezza): from the discovery and development of medicines to USFDA approval for active thyroid eye disease (TED) treatment.

Teprotumumab (TPT) is a type I insulin-like growth factor receptor inhibitor, marketed as Tepezza; recently USFDA approved it for the treatment of thyroid eye disease (thyroid-associated ophthalmopathy (TAO), Graves ophthalmopathy/orbitopathy) in the USA. It is a monoclonal antibody although it was initially developed in collaboration with Genmab and Roche for the treatment of the tumour, but later it was investigated by River Vision Development Corporation and Horizon Therapeutics for its ophthalmic use. The drug has been designated as an orphan drug, breakthrough designation and fast-track designation. This review summarizes the milestones in the research and development including ongoing, clinical trial of TPT till now, foremost to this primary approval for thyroid-associated ophthalmopathy (TAO).

Analysis and Prospect of Targeted Therapy for Head and Neck Tumors

Head and neck tumors account for 30% of malignant tumors in the body, which is a key topic in the world. The comparative data of radiotherapy, surgical therapy or chemotherapy for the treatment of these diseases are given. The treatment of epidermal growth factor receptor inhibitor, cyclin dependent kinase inhibitor and insulin-like growth factor receptor inhibitor were analyzed. It is pointed out that molecular targeted therapy is a targeted blocker to interfere with the signal transduction pathway, which is regulated by the specific molecule and is closely related to the occurrence of tumor, so as to inhibit tumor growth and metastasis.

Small-Cell Lung Cancer: New Directions for Systemic Therapy.

The outcomes for patients with lung cancer have improved considerably over the past two decades. This has been due to the development of novel treatment approaches, a better understanding of disease biology, and, more recently, the emergence of immunotherapy as an effective option. However, for patients with small-cell lung cancer (SCLC), the treatment paradigms have largely remained the same for a long time. This status quo has not been for the lack of studying novel strategies but is mainly because several new therapies, combinations, and targeted agents have failed to demonstrate a benefit for patients with SCLC. Almquist and Ganti provided an excellent review on the treatment of limitedstage SCLC. Nearly one third of patients diagnosed with SCLC have limited-stage disease, which is potentially curable with definitive combined-modality therapy. Cisplatin-based chemotherapy administered concurrently with thoracic radiotherapy, followed by prophylactic cranial radiation, remains the standard practice for patients with good performance status. Although the use of hyperfractionated thoracic radiotherapy given in two fractions per day is considered the standard approach, its adoption has been challenged by practical and logistical realities for individual patients and care providers. Therefore, radiotherapy is given in conventional once-daily fractions at a comparable biologic dose. The use of higher-dose radiotherapy was not successful over conventional-dose radiotherapy in a phase III study of patients with locally advanced non–small-cell lung cancer (RTOG 0617). Based on these data, it appears that improvement of systemic therapy has the best potential to increase survival for patients with SCLC. For extensive-stage SCLC, systemic chemotherapy results in high response rates, but the duration of benefit is modest, and effective salvage therapies are unavailable. Administration of chemotherapy concurrently with molecularly targeted agents, such as antiangiogenic agents, hedgehog pathway inhibitors, and insulinlike growth factor receptor inhibitors, has failed to improve treatment outcomes. Consequently, more recent efforts to identify novel targets have focused on understanding the genomic landscape of SCLC, which is characterized by a high incidence of p53 mutation and RB1 loss. Because these are loss-of-function mutations, they are not amenable to conventional targeted strategies. For patients with certain driver mutations, interrupting the relevant molecular pathways is being pursued as a therapeutic strategy in ongoing studies. However, the high mutation burden observed in SCLC tumors renders modulation of any specific pathway less likely to result in meaningful clinical benefits. Novel combination approaches targeting multiple pathways are a potential way forward for certain dominant oncogenic events.

New strategies in ewing sarcoma: lost in translation?

Ewing sarcoma is the second most common pediatric malignant bone tumor. Aggressive multimodality therapy has led to an improvement in outcomes, particularly in patients with localized disease. However, therapy-related toxicities are not trivial, and the prognosis for patients with relapsed and/or metastatic disease continues to be poor. In this article, we outline some of the promising therapies that have the potential to change the Ewing sarcoma therapeutic paradigm in the not-too-distant future: insulin-like growth factor receptor inhibitors, targeting of the fusion protein, epigenetic manipulation, PARP inhibitors, and immunotherapy.

Potentiating the efficacy of molecular targeted therapy for hepatocellular carcinoma by inhibiting the insulin-like growth factor pathway.

Insulin-like growth factor (IGF) signaling pathway is an important regulatory mechanism of tumorigenesis and drug resistance in many cancers. The present study explored the potential synergistic effects between IGF receptor (IGFR) inhibition and other molecular targeted agents (MTA) in HCC cells. HCC cell lines (Hep3B, PLC5, and SK-Hep1) and HUVECs were tested. The MTA tested included sorafenib, sunitinib, and the IGFR kinase inhibitor NVP-AEW541. The potential synergistic antitumor effects were tested by median dose effect analysis and apoptosis assay in vitro and by xenograft models in vivo. The activity and functional significance of pertinent signaling pathways and expression of apoptosis-related proteins were measured by RNA interference and Western blotting. We found that IGF can activate IGFR and downstream AKT signaling activities in all the HCC cells tested, but the growth-stimulating effect of IGF was most prominent in Hep3B cells. NVP-AEW541 can abrogate IGF-induced activation of IGFR and AKT signaling in HCC cells. IGF can increase the resistance of HCC cells to sunitinib. The apoptosis-inducing effects of sunitinib, but not sorafenib, were enhanced when IGFR signaling activity was inhibited by NVP-AEW541 or IGFR knockdown. Chk2 kinase activation was found contributory to the synergistic anti-tumor effects between sunitinib and IGFR inhibition. Our data indicate that the apoptosis-potentiating effects of IGFR inhibition for HCC may be drug-specific. Combination therapy of IGFR inhibitors with other MTA may improve the therapeutic efficacy in HCC.

Evaluation of the coordinated actions of estrogen receptors with epidermal growth factor receptor and insulin‐like growth factor receptor in the expression of cell surface heparan sulfate proteoglycans and cell motility in breast cancer cells

Estradiol (E2)-estrogen receptor (ER) actions are implicated in initiation, growth and progression of hormone-dependent breast cancer. Crosstalk between ERs, epidermal growth factor receptor (EGFR) and/or insulin-like growth factor receptor (IGFR) is critical for the observed resistance to endocrine therapies. Cell surface heparan sulfate proteoglycans (HSPGs) are principal mediators of cancer cell properties and the E2-ER pathway as well as those activated by EGFR and IGFR have significant roles in regulating the expression of certain cell surface HSPGs, such as syndecan-2 (SDC-2), syndecan-4 (SDC-4) and glypican-1. In this study, we therefore evaluated the role of EGFR-IGFR signaling on the constitutive expression and E2-mediated expression of ERs and HSPGs as well as the effect of E2-ERs and IGFR/EGFR-mediated cell migration in ERα+ (MCF-7) and ERβ+ (MDA-MB-231) breast cancer cells using specific intracellular inhibitors of EGFR and IGFR. We report that the expression of ERα is mainly enhanced by IGFR, whereas ERβ expression is mainly coordinated by EGFR. Moreover, constitutive SDC-2 expression in ERα+ and ERβ+ cells is mainly mediated through the IGFR, whereas in ERα+ E2-treated cells EGFR is the active one. In contrast, SDC-4 expression is regulated by IGFR in the presence and absence of E2. E2 also seems to diminish the inhibitory effect of EGFR and IGFR inhibitors in breast cancer cell migration. These data suggest that the coordinated action of ERs with EGFR and/or IGFR is of crucial importance, providing potential targets for designing and developing novel multi-potent agents for endocrine therapies.

IS1-5 - Exploring the Anti-Tumor Efficacy of Combination Therapy with Inhibitors Targeting the Insulin-Like Growth Factor (IGF) and PI3K/AKT/MTOR Signaling Pathways for Hepatocellular Carcinoma (HCC)

ABSTRACT Background The IGFR signaling pathway plays important roles in carcinogenesis and drug resistance of many cancers, including HCC, but inhibitors targeting the IGF signaling pathway showed limited therapeutic efficacy. This study explored the efficacy of combining inhibitors targeting the IGF and PI3K/AKT/mTOR signaling pathways in HCC. Methods HCC cell lines tested included Hep3B, Huh7, and PLC5. The MTT agents tested included NVP-AEW541 (IGF receptor kinase inhibitor, Novartis), MK2206 (Akt inhibitor, MSD), BEZ235 (PI3K/mTOR inhibitor, Novartis), and RAD001 (mTOR inhibitor, Novartis). The potential synergistic antitumor effects were tested by MTT assay and median dose effect analysis in vitro and by xenograft models in vivo. Apoptosis was analyzed by flow cytometry and western blotting. The activity of pertinent signaling pathways and expression of apoptosis-related proteins were measured by western blotting and by an apoptosis protein array (Proteome ProfilerTM, R&D Systems). Results Synergistic growth-inhibitory and apoptosis-inducing effects in HCC cells were found most prominently in NVP-AEW541/ MK2206 combination, followed by NVP-AEW541/BEZ235 combination. These synergistic anti-tumor effects correlated with a more sustained inhibition of Akt and 4EBP-1 phosphorylation. Potential downstream mediators identified by the apoptosis array included survivin and clapsin. The synergistic anti-tumor effects of NVP-AEW541/MK2206 and NVP-AEW541/BEZ235 combinations were confirmed in vivo by xenograft models, with acceptable toxicity profiles. Conclusions Combination therapy of IGF receptor inhibitors with inhibitors targeting the PI3K/AKT/mTOR pathway may have therapeutic efficacy in HCC (supported by grants NHRI-EX100-9911BC, DOH100-TD-B-111-001, and NSC 100-2314-B-002-058-MY3).

Abstract 1793: Imatinib treatment for gefitinib-resistant lung cancer harboring epidermal growth factor receptor mutation

Abstract Background: Epidermal growth factor receptor (EGFR) mutant-lung cancer showed significant response to EGFR-tyrosine kinase inhibitor (TKI) treatment, however, treatment failure due to acquired resistance to EGFR-TKI become important clinical problem for long-term survivors. Our purpose is to develop the new treatment for EGFR-TKI resistance. Methods: We used PC9 human lung cancer cell line harboring EGFR exon 19 deletion (E746-A750). When PC9 cells were cultured with 2 μM gefitinib solved in dimethylsulfoxide (DMSO), most of cells died and surviving cells proliferated slowly. By 90 days-culture with 2 μM gefitinib, PC9 gefitinib resistant cells (PC9GR90) were established and confirmed that EGFR-T790M resistance-related mutation was negative. In PC9GR90, an immunoblot assay revealed MET (hepatocyte growth factor receptor) amplification and alternative EGFR3 tyrosine phosphorylation, which is known as one of the major resistant mechanisms. Results: When PC9GR90 were cultured with 2 μM gefitinib and one inhibitor (histone deacetylase inhibitor, insulin-like growth factor receptor inhibitor, gamma secretase inhibitor, or imatinib known as bcr-abl, c-kit and platelet derived growth factor receptor inhibitor), 10 μM imatinib treatment with gefitinib showed significant suppression of cell growth. The ratio of cell count of 2 μM gefitinib/DMSO and 10 μM imatinib with 2 μM gefitinib/DMSO were 91.7% and 6.0%, respectively. When imatinib concentration was decreased to 1 μM known as appropriate concentration for chronic myeloid leukemia treatment, there was no effect. The imatinib effect was not shown for NCI-H1975 lung cancer cells harboring both EGFR-L858R and -T790M. By immunoblot, we found EGFR3 phosphorylation was inhibited by imatinib treatment. Conclusion: It is the first report that imatinib inhibits EGFR3 phophorylation and induce cell death in the EGFR-TKI resistant lung cancer with MET amplification and EGFR3 phophorylation. Although further studies are required to apply this strategy to a clinical setting, we demonstrate a hopeful data to conquer one important resistant mechanism. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1793. doi:1538-7445.AM2012-1793

Abstract PL08-01: Clinical achievements reached by interfering with the IGF1R-PI3K-PTEN-AKT-mTOR axis.

Abstract PL08-01: Clinical achievements reached by interfering with the IGF1R-PI3K-PTEN-AKT-mTOR axis.

Insulin-Like Growth Factor Receptor

The insulin-like growth factor (IGF) signaling axis plays an essential role in the balance between cellular proliferation and apoptosis. Higher levels of IGF receptor are seen in lung tumor cells than normal tissue. IGF-1 receptor (IGFR-1R) and its ligand IGF-2 is overexpressed in non-small cell lung cancer (NSCLC). Elevated levels of IGF-1 in plasma are associated with an increased risk of developing lung cancer, and IGF-1R has been shown to promote the proliferation of lung cancer cells in vitro. 1 IGF-1R can hybridize with other membrane receptors leading to the activation of different tyrosine kinase domains. 2 The central role that the IGFR pathway plays in various signaling pathways in tumor cells makes the IGF axis an attractive target for therapeutic intervention. Dr. Pollak presented an overview of the science of the IGFR to establish the rationale for the development of this class of drugs for the treatment of NSCLC. There are a number of possible avenues through which the effects of IGF can be inhibited. These strategies include antibodies directed against IGF ligand, IGF-1R tyrosine kinase inhibitors, and antibodies targeting the IGF-1R. The approach of blocking the IGF-1 receptor tyrosine kinase pathway and the insulin receptor (IR) via signal transduction inhibitors is also undergoing clinical evaluation. IMC-A12 IMC-A12 is a fully humanized IgG1 monoclonal antibody with a half-life of 15 to 21 days that targets the IGF-1 receptor. 3 Both weekly and q21-day schedules are being explored. There are three ongoing randomized phase II trials with differentfirst-line platinum-based regimens including a trial that is comparing gemcitabine, carbopatin with the addition of IMC-A12, cetuximab, or both, and another evaluating carboplatin, paclitaxel bevacizumab with or without IMC-A12 in nonsquamous NSCLC. There is one randomized first-line trial of etoposide, cisplatin with or without either IMC-A12 or the hedgehog inhibitor GDC-0449 in extensive disease small cell lung cancer (EDSCLC). The combination of erlotinib plus A12 was closed due to toxicity of the combination. Currently, no additional toxicity or efficacy data are available. AMG-479 Phase I studies established thrombocytopenia as the dose-limiting toxicity of AMG-479, a fully human monoclonal antibody to IGF-1R. 4 AMG-479 is being evaluated in the front-line setting in combination with etoposide and carboplatin or cisplatin in a randomized phase I/II trial in patients with EDSCLC. Patients will receive up to six cycles of the combination then single-agent AMG 479 as maintenance therapy until disease progression. Preliminary results indicate that AMG-479 can be safely combined with etoposide and cisplatin (or carboplatin) in this patient population without impact on the delivery of AMG-479 or the chemotherapy. Activity in the phase I portion was similar to reported with chemotherapy alone. 5 The phase II portion of the trial has completed accrual and results are pending. MK-0646 MK-0646 is a fully humanized monoclonal IgG1 antibody that selectively binds to the IGF-1 receptor and not to the insulin receptor. 6 The recommended phase II dose is 10 mg/kg weekly. An overview of the compound and the design of several clinical trials were presented. In the randomized phase II IMPACT study, MK-0646 is being evaluated in combination with pemetrexed (500 mg/m 2 ) and cisplatin (75 mg/m 2 ) as first-line therapy in patients with stage IIIB or IV nonsquamous NSCLC. The phase I/II design of MK-0646 plus cisplatin and etoposide in patients with treatment-naive EDSCLC was also presented. Both studies are ongoing but not actively recruiting participants.

I‐SPY 2 breast cancer clinical trial launches nationwide

I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular Analysis 2), a breast cancer clinical trial that seeks to determine the effectiveness of certain drugs in patients with high-risk, fast-growing breast cancers, was launched in March 2010 at nearly 20 major cancer research centers across the country. The trial is sponsored by the Biomarkers Consortium, which is a public-private partnership of more than 50 organizations, including the US Food and Drug Administration (FDA), the National Institutes of Health, and major pharmaceutical companies, led by the Foundation for the National Institutes of Health. The consortium is attempting to develop biomarkers to speed drug and therapy development. I-SPY 2 incorporates a new clinical trial model that uses biomarkers from patients' tumors to determine which treatments are most effective in specific patients. The trial design will also enable researchers to use early data to determine which treatments will be more effective as the trial proceeds. “This will allow us to finally design advanced, smaller, and less expensive phase 3 trials that test the right drugs in the right patients,”Anna D. Barker, PhD, deputy director of the National Cancer Institute and cochair of the Biomarkers Consortium, stated in a news release summarizing the study. ABT-888 (veliparib), a poly(ADPribose) polymerase (PARP) inhibitor; AMG 655 (conatumumab), an APO/tumor necrosis factor- related apoptosis-inducing ligand (TRAIL) inhibitor; AMG 386, an angiogenesis inhibitor; CP-75 1,871 (figitumumab), an insulin-like growth factor receptor inhibitor; and HKI-272 (neratinib) a Pan Erb B inhibitor. The 2 principal investigators for the trial are Laura Esserman, MD, director of the Carol Franc Buck Breast Care Center at the University of California in San Francisco; and Donald Berry, PhD, chair of the department of biostatistics at the University of Texas M.D. Anderson Cancer Center in Houston, Texas. “A considerable advantage for trial participants in I-SPY 2 is that drugs and drug combinations can be given to more patients in the trial as soon as they are proven to be clearly beneficial:' Dr. Berry noted in a news release. “By the same token, drugs that are ineffective in the trial can be dropped just as quickly, which increases the safety of the study:' For more information about I-SPY 2, visit the trial's web- site at http://ispy2.org.

The potential role of insulin-like growth factor receptor inhibitors in the treatment of advanced non-small cell lung cancer

Importance of the field: Lung cancer is the leading cause of cancer-related mortality worldwide. NSCLC accounts for > 80% of all lung cancers. The treatment of advanced fit NSCLC patients seems to have reached a plateau. Considerable efforts have been initiated to identify new biological agents.Areas covered in this review: Diagnosis of NSCLC histotype is becoming extremely important to address treatment. While non-squamous histology could start to benefit from the administration of several new drugs only recently, non-adenocarcinoma subtype seems to benefit from the administration of figitumumab (CP-751,871) a fully human anti-IGF 1 receptor (IGF-1R) mAb. In this paper, we reviewed the IGF-1R pathway and its inhibitors.What the reader will gain: Approaches targeting IGF-1R include small-molecule IGF-1R tyrosine kinase inhibitors (TKIs), which are in preclinical and early clinical phases of development, and the mAbs, among which figitumumab is being investigated in Phase III trials of advanced NSCLC.Take home message: Figitumumab reported interesting results in the treatment of advanced non-adenocarcinoma NSCLC patients. Overall, in order to administer the optimal treatment to patients, a more definite histological diagnosis is mandatory.

Plenary session 2: Insulin-like growth factor receptor inhibitors

plenary session 2: Insulin-like growth factor receptor inhibitors

Combined inhibition of IGFR enhances the effects of gefitinib in H1650: a lung cancer cell line with EGFR mutation and primary resistance to EGFR-TK inhibitors

H1650 non-small cell lung cancer (NSCLC) cells display primary resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) although they have a deletion mutation on exon 19 of the EGFR gene. We investigated the effect of inhibition of both insulin-like growth factor receptor (IGFR) and EGFR signaling considering that IGFR signaling pathway has been implicated in the development and progression with therapeutic resistance of various cancers including lung cancer. Three human NSCLC cell lines with an EGFR mutation of PC-9, HCC827 and H1650 were used for experiment. Cell viability and proliferative activity were assessed by MTT and three-dimensional culture assay. Combination index was obtained by CalcuSyn software. The change of EGFR- and IGFR-related signals was evaluated by western blots. H1650 cells were 1,000 times more resistant to gefitinib and erlotinib than HCC827 and PC-9 cells possessing the same EGFR mutation. Phosphatase and tensin homolog loss and sustained phosphorylation of Akt in spite of treatment with gefitinib were evident only in H1650 cells. Interestingly, IGFR phosphorylation was decreased by gefitinib in HCC827 and PC-9 cells while being maintained in H1650 cells. Combined treatment with the IGFR inhibitors alpha-IR3 and AG1024 enhanced gefitinib-induced growth inhibition and apoptosis, and down-regulated phosphorylation of Akt, EGFR and IGFR. Combined inhibition of IGFR signaling enhances the growth inhibitory and apoptosis-inducing effects of gefitinib, suggesting that this approach could be useful to overcome the primary resistance to EGFR-TKIs in lung cancer.

Emerging role of insulin-like growth factor receptor inhibitors in oncology: early clinical trial results and future directions

Preclinical evidence that targeting the insulin-like growth factor receptor (IGF-IR) is effective in cancer treatment has been accumulating for almost two decades. Efforts to develop drugs began in the late 1990s, and initial data from clinical trials were reported in 2006. The biological rationale for IGF-IR targeting has potential relevance to many tumor types, and early results have justified expanded programs to evaluate IGF-IR-targeting agents in many areas of clinical need. More than two dozen drug candidates have been developed and clinical trials are underway for at least 12 of these. Early clinical trials reveal an acceptable safety profile together with pharmacodynamic evidence that the receptor can be successfully targeted. It is premature to draw conclusions regarding efficacy, but well-documented instances of single-agent activity were noted during phase I evaluations, and recent evidence from a phase II study suggests that co-administration of an anti-IGF-IR antibody with chemotherapy for non-small-cell lung cancer improves objective response rate and progression-free survival. With more than 70 trials involving a variety of drug candidates underway, the IGF-IR is becoming one of the most intensively investigated molecular targets in oncology. Early results justify the continuation of ongoing research across a broad range of cancer indications.

The Insulin-Like Growth Factor Pathway in Lung Cancer

The insulin-like growth factor (IGF) pathway is involved in the normal control of fetal development, tissue growth, and metabolism. Two distinct ligands (insulin-like growth factor-1 [IGF-1] and IGF-2) plus insulin, and two receptors (insulin-like growth factor receptor-1 [IGF-1R] and the insulin receptor) capable of both homo- and heteropolymerization mediate the actions of this pathway. Cellular functions of IGF-regulated signaling are influenced by the expression of a variety of receptor docking proteins, including four different insulin receptor substrate proteins. Downstream signaling is primarily through the phosphatidylinositol-3 kinase-Akt pathway and the mitogen-activated protein kinase pathway, resulting in increased cell proliferation and apoptosis inhibition. Ligand-driven activation is influenced by upstream endocrine factors (particularly for IGF-1), imprinting (for IGF-2), by multiple circulating and tissue-based IGF-binding proteins/proteases, and by the expression of the IGF-2 clearance receptor (IGF-2R). Deregulation of IGF signaling has been described in several cancer types, including both small cell and non-small cell lung cancer. A number of IGF receptor inhibitors, including monoclonal antibodies and small molecule inhibitors are currently undergoing testing in clinical trials as both monotherapy, and in combination with chemotherapy, or with other targeted agents. Preliminary results from a randomized phase II trial of an anti-IGF-1R monoclonal antibody in combination with carboplatin/paclitaxel already suggest a potential efficacy benefit from targeting this pathway in the first line advanced non-small cell lung cancer setting.

Fas expression inversely correlates with metastatic potential in osteosarcoma cells

A complex series of steps must take place to allow for a single cell to metastasize. Identifying factors responsible for these steps is essential in developing targeted therapy. We developed series of osteosarcoma cell lines with differing metastatic potentials. We used them to investigate mechanisms of metastasis and possible therapeutic targets for osteosarcoma metastasis to the lung in a nude mouse model. No correlation was found between epidermal growth factor receptor (EGFR), insulin-like growth factor receptor inhibitor (IGF-I-R), gelatinase, p53, metalloproteinase 9 (MMP 9), platelet derived growth factor receptor (PDGF-R), vascular endothelial growth factor (VEGF) and c-met expression and metastatic potential as measured by Northern analysis. By contrast, Fas expression inversely correlated with metastatic potential, and manipulation of Fas expression altered the metastatic phenotype of the cell. Our data indicate that fas gene expression may offer a new therapeutic target for the treatment of metastatic osteosarcoma in the lung.