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Ex Vivo Treatment Response of Primary Tumors and/or Associated Metastases for Preclinical and Clinical Development of Therapeutics
Published on: October 2, 2014
A Novel Inhibitor of HSP70 Induces Mitochondrial Toxicity and Immune Cell Recruitment in Tumors
Thibaut Barnoud1, Jessica C Leung1, Julia I-Ju Leu2
1Program in Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, Pennsylvania.
Abstract:
The protein chaperone HSP70 is overexpressed in many cancers including colorectal cancer, where overexpression is associated with poor survival. We report here the creation of a uniquely acting HSP70 inhibitor (HSP70i) that targets multiple compartments in the cancer cell, including mitochondria. This inhibitor was mitochondria toxic and cytotoxic to colorectal cancer cells, but not to normal colon epithelial cells. Inhibition of HSP70 was efficacious as a single agent in primary and metastatic models of colorectal cancer and enabled identification of novel mitochondrial client proteins for HSP70. In a syngeneic colorectal cancer model, the inhibitor increased immune cell recruitment into tumors. Cells treated with the inhibitor secreted danger-associated molecular patterns (DAMP), including ATP and HMGB1, and functioned effectively as a tumor vaccine. Interestingly, the unique properties of this HSP70i in the disruption of mitochondrial function and the inhibition of proteostasis both contributed to DAMP release. This HSP70i constitutes a promising therapeutic opportunity in colorectal cancer and may exhibit antitumor activity against other tumor types. SIGNIFICANCE: These findings describe a novel HSP70i that disrupts mitochondrial proteostasis, demonstrating single-agent efficacy that induces immunogenic cell death in treated tumors.
Insights
A novel HSP70 inhibitor (HSP70i) shows promise for colorectal cancer therapy. This inhibitor is toxic to cancer cells, enhances anti-tumor immunity, and acts as a tumor vaccine by inducing danger signals.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- Heat shock protein 70 (HSP70) is overexpressed in colorectal cancer, correlating with poor patient survival.
- Targeting HSP70 presents a potential therapeutic strategy for colorectal cancer.
Purpose of the Study:
- To develop and evaluate a novel HSP70 inhibitor (HSP70i) with multi-compartmental targeting capabilities, including mitochondria.
- To assess the efficacy of this HSP70i as a single agent in colorectal cancer models.
- To investigate the immunomodulatory effects and mechanisms of action of the HSP70i.
Main Methods:
- Creation of a novel HSP70 inhibitor targeting multiple cellular compartments, including mitochondria.
- Assessment of inhibitor's cytotoxicity in colorectal cancer cells versus normal colon epithelial cells.
- Evaluation of the HSP70i in primary and metastatic colorectal cancer models.
- Analysis of immune cell recruitment, danger-associated molecular pattern (DAMP) secretion, and tumor vaccine potential.
Main Results:
- The HSP70i demonstrated mitochondrial toxicity and selective cytotoxicity towards colorectal cancer cells.
- Single-agent administration of HSP70i was efficacious in preclinical colorectal cancer models.
- The inhibitor promoted immune cell infiltration into tumors and induced secretion of DAMPs (ATP, HMGB1), leading to tumor vaccine effects.
- Disruption of mitochondrial function and proteostasis by HSP70i contributed to DAMP release.
Conclusions:
- This novel HSP70i effectively disrupts mitochondrial proteostasis and exhibits single-agent efficacy in colorectal cancer.
- The inhibitor induces immunogenic cell death, suggesting a promising therapeutic strategy for colorectal cancer.
- The HSP70i may hold potential for treating other cancer types due to its unique mechanism of action.
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