Related Experiment Video
Updated: Jun 4, 2025
Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Anticancer Effect of C19-Position Substituted Geldanamycin Derivatives Targeting NRF2-NQO1-activated Esophageal
Hiroyuki Oshikiri1,2, Keiko Taguchi1, Wataru Hirose1,2
1Department of Biochemistry and Molecular Biology, Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan.
Abstract:
In esophageal squamous cell carcinoma, genetic activation of NRF2 increases resistance to chemotherapy and radiotherapy, which results in a significantly worse prognosis for patients. Therefore NRF2-activated cancers create an urgent clinical need to identify new therapeutic options. In this context, we previously identified the geldanamycin family of HSP90 inhibitors, which includes 17DMAG, to be synthetic lethal with NRF2 activity. As the first-generation of geldanamycin-derivative drugs were withdrawn from clinical trials due to hepatotoxicity, we designed second-generation compounds with C19-substituted structures in order to inhibit glutathione conjugation-mediated hepatotoxicity. In this study, using a variety of in vitro and in vivo cancer models, we found that C19-substituted 17DMAG compounds maintain their enhanced toxicity profile and synthetic lethal interaction with NRF2-NQO1-activated cancer cells. Importantly, using a xenograft mouse tumor model, we found that C19-substituted 17DMAG displayed significant anticancer efficacy against NRF2-NQO1-activated cancer cells without causing hepatotoxicity. These results clearly demonstrate the improved clinical potential for this new class of HSP90 inhibitor anticancer drugs, and suggest that patients with NRF2-NQO1-activated esophageal carcinoma may benefit from this novel therapeutic approach.
Insights
New HSP90 inhibitors, C19-substituted 17DMAG, show synthetic lethality with NRF2-activated cancers. These compounds offer improved efficacy and reduced hepatotoxicity for esophageal cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Genetic activation of NRF2 in esophageal squamous cell carcinoma confers resistance to chemotherapy and radiotherapy, leading to poor patient prognosis.
- NRF2-activated cancers present a critical need for novel therapeutic strategies.
- Previous identification of geldanamycin (HSP90 inhibitor) and its derivative 17DMAG showed synthetic lethality with NRF2 activity.
Purpose of the Study:
- To design and evaluate second-generation HSP90 inhibitors with C19-substituted structures to overcome the hepatotoxicity associated with first-generation compounds.
- To assess the efficacy and safety of these novel compounds in preclinical cancer models, particularly those with NRF2-NQO1 activation.
Main Methods:
- Utilized various in vitro and in vivo cancer models to test C19-substituted 17DMAG compounds.
- Assessed the synthetic lethal interaction with NRF2-NQO1-activated cancer cells.
- Evaluated anticancer efficacy and hepatotoxicity in a xenograft mouse tumor model.
Main Results:
- C19-substituted 17DMAG compounds demonstrated maintained enhanced toxicity against NRF2-NQO1-activated cancer cells.
- These novel compounds exhibited significant anticancer efficacy in a xenograft mouse model.
- Importantly, no hepatotoxicity was observed in the xenograft model.
Conclusions:
- Second-generation C19-substituted 17DMAG compounds represent a promising new class of HSP90 inhibitors with improved clinical potential.
- These novel agents show efficacy against NRF2-NQO1-activated cancers, including esophageal carcinoma, without the dose-limiting hepatotoxicity of earlier drugs.
- Patients with NRF2-NQO1-activated esophageal carcinoma may benefit from this novel therapeutic approach.
More Related Videos
09:03Establishment of Hepatocarcinoma in BALB/c-nu Mice and Investigation of the Therapeutic Effect of the Sanleng Jiashen Formula
Published on: January 26, 2024
10:42Subculture and Cryopreservation of Esophageal Adenocarcinoma Organoids: Pros and Cons for Single Cell Digestion
Published on: July 6, 2022
Related Concept Videos
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...
02:38Mitogens and the Cell Cycle
01:28Chemotherapy-Induced Nausea and Vomiting: Neurokinin-1 Receptor Antagonists
02:23Abnormal Proliferation