| Autor: |
R. Soler-Agesta, R. Moreno-Loshuertos, C. Y. Yim, M. T. Congenie, T. D. Ames, H. L. Johnson, F. Stossi, M. G. Mancini, M. A. Mancini, C. Ripollés-Yuba, J. Marco-Brualla, C. Junquera, R. Martínez-De-Mena, J. A. Enríquez, M. R. Price, J. Jimeno, A. Anel |
| Jazyk: |
angličtina |
| Rok vydání: |
2024 |
| Předmět: |
|
| Zdroj: |
Journal of Translational Medicine, Vol 22, Iss 1, Pp 1-17 (2024) |
| Druh dokumentu: |
article |
| ISSN: |
1479-5876 |
| DOI: |
10.1186/s12967-024-05739-x |
| Popis: |
Abstract PT-112 is a novel immunogenic cell death (ICD)-inducing small molecule currently under Phase 2 clinical development, including in metastatic castration-resistant prostate cancer (mCRPC), an immunologically cold and heterogeneous disease state in need of novel therapeutic approaches. PT-112 has been shown to cause ribosome biogenesis inhibition and organelle stress followed by ICD in cancer cells, culminating in anticancer immunity. In addition, clinical evidence of PT-112-driven immune effects has been observed in patient immunoprofiling. Given the unmet need for immune-based therapies in prostate cancer, along with a Phase I study (NCT#02266745) showing PT-112 activity in mCRPC patients, we investigated PT-112 effects in a panel of human prostate cancer cell lines. PT-112 demonstrated cancer cell selectivity, inhibiting cell growth and leading to cell death in prostate cancer cells without affecting the non-tumorigenic epithelial prostate cell line RWPE-1 at the concentrations tested. PT-112 also caused caspase-3 activation, as well as stress features in mitochondria including ROS generation, compromised membrane integrity, altered respiration, and morphological changes. Moreover, PT-112 induced damage-associated molecular pattern (DAMP) release, the first demonstration of ICD in human cancer cell lines, in addition to autophagy initiation across the panel. Taken together, PT-112 caused selective stress, growth inhibition and death in human prostate cancer cell lines. Our data provide additional insight into mitochondrial stress and ICD in response to PT-112. PT-112 anticancer immunogenicity could have clinical applications and is currently under investigation in a Phase 2 mCRPC study. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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