Targeting colorectal cancer via its microenvironment by inhibiting IGF-1 receptor-insulin receptor substrate and
E Sanchez-Lopez1, E Flashner-Abramson2, S Shalapour1
1Laboratory of Gene Regulation and Signal Transduction, Departments of Pharmacology and Pathology, School of Medicine, University of California, San Diego, La Jolla, CA, USA.
Abstract:
The tumor microenvironment (TME) exerts critical pro-tumorigenic effects through cytokines and growth factors that support cancer cell proliferation, survival, motility and invasion. Insulin-like growth factor-1 (IGF-1) and signal transducer and activator of transcription 3 (STAT3) stimulate colorectal cancer development and progression via cell autonomous and microenvironmental effects. Using a unique inhibitor, NT157, which targets both IGF-1 receptor (IGF-1R) and STAT3, we show that these pathways regulate many TME functions associated with sporadic colonic tumorigenesis in CPC-APC mice, in which cancer development is driven by loss of the Apc tumor suppressor gene. NT157 causes a substantial reduction in tumor burden by affecting cancer cells, cancer-associated fibroblasts (CAF) and myeloid cells. Decreased cancer cell proliferation and increased apoptosis were accompanied by inhibition of CAF activation and decreased inflammation. Furthermore, NT157 inhibited expression of pro-tumorigenic cytokines, chemokines and growth factors, including IL-6, IL-11 and IL-23 as well as CCL2, CCL5, CXCL7, CXCL5, ICAM1 and TGFβ; decreased cancer cell migratory activity and reduced their proliferation in the liver. NT157 represents a new class of anti-cancer drugs that affect both the malignant cell and its supportive microenvironment.
Insights
A novel drug, NT157, targets both Insulin-like Growth Factor-1 (IGF-1) and Signal Transducer and Activator of Transcription 3 (STAT3) pathways. This dual inhibition significantly reduces colorectal tumor burden by impacting cancer cells and the tumor microenvironment.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- The tumor microenvironment (TME) promotes cancer progression through cytokines and growth factors.
- Insulin-like Growth Factor-1 (IGF-1) and Signal Transducer and Activator of Transcription 3 (STAT3) are key drivers of colorectal cancer (CRC).
Purpose of the Study:
- To investigate the efficacy of NT157, a dual inhibitor of IGF-1 receptor (IGF-1R) and STAT3, in a mouse model of sporadic colonic tumorigenesis.
- To elucidate the impact of NT157 on cancer cells and the TME.
Main Methods:
- Utilized CPC-APC mice, which develop colon cancer due to Apc gene loss.
- Administered NT157 to assess its effects on tumor burden, cancer cell proliferation, apoptosis, and TME components.
- Analyzed the expression of key cytokines, chemokines, and growth factors.
Main Results:
- NT157 significantly reduced tumor burden in CPC-APC mice.
- The drug decreased cancer cell proliferation and increased apoptosis.
- NT157 inhibited cancer-associated fibroblasts (CAFs) activation, reduced inflammation, and suppressed pro-tumorigenic factors like IL-6, IL-11, IL-23, and TGFβ.
- Reduced cancer cell migration and liver metastasis.
Conclusions:
- NT157 effectively targets both cancer cells and the tumor microenvironment.
- This dual-targeting strategy represents a promising new class of anti-cancer drugs for colorectal cancer.
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