Related Experiment Video
Updated: May 13, 2026
Orthotopic Implantation and Peripheral Immune Cell Monitoring in the II-45 Syngeneic Rat Mesothelioma Model
Published on: October 2, 2015
Gli as a novel therapeutic target in malignant pleural mesothelioma
Hui Li1, Natalie Lui, Tiffany Cheng
1Thoracic Oncology Program, Department of Surgery, University of California San Francisco, San Francisco, CA, USA.
Abstract:
Malignant pleural mesothelioma (MPM) is a highly aggressive tumor with poor prognosis. Current treatment is rarely curative, thus novel meaningful therapies are urgently needed. Inhibition of Hedgehog (Hh) signaling at the cell membrane level in several cancers has shown anti-cancer activity in recent clinical studies. Evidence of Hh-independent Gli activation suggests Gli as a more potent therapeutic target. The current study is aimed to evaluate the potential of Gli as a therapeutic target to treat MPM. The expression profiles of Gli factors and other Hh signaling components were characterized in 46 MPM patient tissue samples by RT-PCR and immunohistochemistry. Cultured cell lines were employed to investigate the requirement of Gli activation in tumor cell growth by inhibiting Gli through siRNA or a novel small molecule Gli inhibitor (Gli-I). A xenograft model was used to evaluate Gli-I in vivo. In addition, a side by side comparison between Gli and Smoothened (Smo) inhibition was conducted in vitro using siRNA and small molecule inhibitors. Our study reported aberrant Gli1 and Gli2 activation in a large majority of tissues. Inhibition of Gli by siRNAs or Gli-I suppressed cell growth dramatically both in vitro and in vivo. Inhibition of Gli exhibited better cytotoxicity than that of Smo by siRNA and small molecule inhibitors vismodegib and cyclopamine. Combination of Gli-I and pemetrexed, as well as Gli-I and vismodegib demonstrated synergistic effects in suppression of MPM proliferation in vitro. In summary, Gli activation plays a critical role in MPM. Inhibition of Gli function holds strong potential to become a novel, clinically effective approach to treat MPM.
Insights
Targeting Gli activation offers a promising new therapy for malignant pleural mesothelioma (MPM). Inhibiting Gli significantly reduced tumor growth in vitro and in vivo, outperforming Smo inhibition.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Malignant pleural mesothelioma (MPM) is an aggressive cancer with limited treatment options.
- Hedgehog (Hh) signaling inhibition shows promise, but Gli activation is a more potent target.
- Novel therapeutic strategies are crucial for improving MPM outcomes.
Purpose of the Study:
- To investigate Gli as a therapeutic target for MPM.
- To evaluate the efficacy of Gli inhibition in MPM models.
- To compare Gli inhibition with Smo inhibition in MPM.
Main Methods:
- Characterized Gli and Hh pathway components in 46 MPM patient tissues (RT-PCR, immunohistochemistry).
- Utilized cell lines to assess Gli inhibition via siRNA and a novel small molecule inhibitor (Gli-I).
- Evaluated Gli-I efficacy in a xenograft model and compared with Smo inhibitors.
Main Results:
- Aberrant Gli1 and Gli2 activation was observed in most MPM tissues.
- Gli inhibition (siRNA, Gli-I) significantly suppressed MPM cell growth in vitro and in vivo.
- Gli inhibition demonstrated superior cytotoxicity compared to Smo inhibition (vismodegib, cyclopamine).
- Combination therapies (Gli-I with pemetrexed or vismodegib) showed synergistic anti-proliferative effects.
Conclusions:
- Gli activation is critical for MPM progression.
- Targeting Gli represents a novel and potentially effective therapeutic strategy for MPM.
- Gli inhibition offers a promising avenue for developing new MPM treatments.
