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A Brain Tumor/Organotypic Slice Co-culture System for Studying Tumor Microenvironment and Targeted Drug Therapies
Published on: November 7, 2015
Genomic testing, tumor microenvironment and targeted therapy of Hedgehog-related human cancers
1Department of Omics Network, National Cancer Center, 5-1-1 Tsukiji, Chuo-ward, Tokyo 104-0045, Japan mkatoh-kkr@umin.ac.jp.
Abstract:
Hedgehog signals are transduced through Patched receptors to the Smoothened (SMO)-SUFU-GLI and SMO-Gi-RhoA signaling cascades. MTOR-S6K1 and MEK-ERK signals are also transduced to GLI activators through post-translational modifications. The GLI transcription network up-regulates target genes, such as BCL2, FOXA2, FOXE1, FOXF1, FOXL1, FOXM1, GLI1, HHIP, PTCH1 and WNT2B, in a cellular context-dependent manner. Aberrant Hedgehog signaling in tumor cells leads to self-renewal, survival, proliferation and invasion. Paracrine Hedgehog signaling in the tumor microenvironment (TME), which harbors cancer-associated fibroblasts, leads to angiogenesis, fibrosis, immune evasion and neuropathic pain. Hedgehog-related genetic alterations occur frequently in basal cell carcinoma (BCC) (85%) and Sonic Hedgehog (SHH)-subgroup medulloblastoma (87%) and less frequently in breast cancer, colorectal cancer, gastric cancer, pancreatic cancer, non-small-cell lung cancer (NSCLC) and ovarian cancer. Among investigational SMO inhibitors, vismodegib and sonidegib are approved for the treatment of patients with BCC, and glasdegib is approved for the treatment of patients with acute myeloid leukemia (AML). Resistance to SMO inhibitors is caused by acquired SMO mutations, SUFU deletions, GLI2 amplification, other by-passing mechanisms of GLI activation and WNT/β-catenin signaling activation. GLI-DNA-interaction inhibitors (glabrescione B and GANT61), GLI2 destabilizers (arsenic trioxide and pirfenidone) and a GLI-deacetylation inhibitor (4SC-202) were shown to block GLI-dependent transcription and tumorigenesis in preclinical studies. By contrast, SMO inhibitors can remodel the immunosuppressive TME that is dominated by M2-like tumor-associated macrophages (M2-TAMs), myeloid-derived suppressor cells and regulatory T cells, and thus, a Phase I/II clinical trial of the immune checkpoint inhibitor pembrolizumab with or without vismodegib in BCC patients is ongoing.
Insights
Hedgehog signaling drives cancer through GLI transcription factors. Inhibitors target SMO and GLI, but resistance emerges, necessitating novel therapeutic strategies and combination therapies, including immune checkpoint inhibitors.
Area of Science:
- Molecular Biology
- Cancer Signaling Pathways
- Oncology
Background:
- The Hedgehog signaling pathway is crucial for embryonic development and is aberrantly activated in various cancers.
- This pathway involves Patched receptors, Smoothened (SMO), and GLI transcription factors, regulating target genes involved in cell growth and survival.
- Dysregulated Hedgehog signaling contributes to tumor progression, invasion, and the modulation of the tumor microenvironment (TME).
Purpose of the Study:
- To review the molecular mechanisms of Hedgehog signaling in cancer.
- To discuss current therapeutic strategies targeting the Hedgehog pathway, including SMO inhibitors and GLI-targeting agents.
- To explore mechanisms of resistance to Hedgehog pathway inhibitors and potential combination therapies.
Main Methods:
- Review of existing literature on Hedgehog signaling, cancer genetics, and therapeutic interventions.
- Analysis of preclinical and clinical data on SMO inhibitors (vismodegib, sonidegib, glasdegib) and other agents.
- Examination of resistance mechanisms and the role of the tumor microenvironment in therapeutic response.
Main Results:
- Hedgehog signaling activates GLI transcription factors, up-regulating oncogenic target genes like BCL2 and GLI1.
- Aberrant signaling promotes tumor cell self-renewal, proliferation, and invasion, while paracrine signaling impacts the TME.
- Approved SMO inhibitors show efficacy in basal cell carcinoma and acute myeloid leukemia, but resistance is a significant challenge.
Conclusions:
- Targeting Hedgehog signaling with SMO inhibitors and GLI-modulating agents offers therapeutic potential in various cancers.
- Mechanisms of resistance, including SMO mutations and GLI amplification, necessitate the development of next-generation inhibitors and combination strategies.
- SMO inhibitors may remodel the immunosuppressive TME, suggesting potential synergy with immune checkpoint inhibitors.
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