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Targeting IRS-1/2 in Uveal Melanoma Inhibits In Vitro Cell Growth, Survival and Migration, and In Vivo Tumor Growth
Chandrani Chattopadhyay1, Rajat Bhattacharya2, Jason Roszik1,3
1Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Abstract:
Uveal melanoma originating in the eye and metastasizing to the liver is associated with poor prognosis and has only one approved therapeutic option. We hypothesized that liver-borne growth factors may contribute to UM growth. Therefore, we investigated the role of IGF-1/IGF-1R signaling in UM. Here, we found that IRS-1, the insulin receptor substrate, is overexpressed in both UM cells and tumors. Since we previously observed that IGF-1R antibody therapy was not clinically effective in UM, we investigated the potential of NT157, a small molecule inhibitor of IRS-1/2, in blocking this pathway in UM. NT157 treatment of multiple UM cell lines resulted in reduced cell growth and migration and increased apoptosis. This treatment also significantly inhibited UM tumor growth in vivo, in the chicken egg chorioallantoic membrane (CAM) and subcutaneous mouse models, validating the in vitro effect. Mechanistically, through reverse phase protein array (RPPA), we identified significant proteomic changes in the PI3K/AKT pathway, a downstream mediator of IGF-1 signaling, with NT157 treatment. Together, these results suggest that NT157 inhibits cell growth, survival, and migration in vitro, and tumor growth in vivo via inhibiting IGF-1 signaling in UM.
Insights
The small molecule NT157 effectively inhibits uveal melanoma (UM) growth by targeting insulin receptor substrate-1 (IRS-1). This approach shows promise for treating liver metastases, offering a new therapeutic avenue for this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Uveal melanoma (UM) with liver metastasis has a poor prognosis and limited treatment options.
- Liver-borne growth factors may drive UM progression.
- Insulin-like growth factor 1 receptor (IGF-1R) signaling is implicated in UM, but antibody therapy has shown limited efficacy.
Purpose of the Study:
- To investigate the role of insulin receptor substrate (IRS)-1/2 in UM.
- To evaluate the efficacy of NT157, a small molecule inhibitor of IRS-1/2, in blocking IGF-1 signaling in UM.
- To elucidate the mechanisms by which NT157 affects UM cell behavior and tumor growth.
Main Methods:
- Overexpression of IRS-1 in UM cells and tumors was assessed.
- NT157 treatment was applied to UM cell lines in vitro.
- UM tumor growth was evaluated in vivo using chicken embryo (CAM) and mouse models.
- Proteomic analysis using reverse phase protein array (RPPA) was performed to identify pathway alterations.
Main Results:
- NT157 treatment reduced UM cell growth, migration, and increased apoptosis in vitro.
- NT157 significantly inhibited UM tumor growth in both CAM and mouse models.
- RPPA analysis revealed significant modulation of the PI3K/AKT pathway, a downstream mediator of IGF-1 signaling, upon NT157 treatment.
Conclusions:
- NT157 effectively inhibits UM cell proliferation, survival, and migration.
- NT157 demonstrates significant anti-tumor activity in vivo, targeting IGF-1 signaling.
- NT157 represents a potential therapeutic strategy for uveal melanoma, particularly for liver metastases.
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