Anti-Cancer Potential of a new Derivative of Caffeic Acid Phenethyl Ester targeting the Centrosome.

in Redox biology by Catello Giordano, Jonatan Kendler, Maximilian Sexl, Sebastian Kollman, Maxim Varenicja, Boglárka Szabó, Gerald Timelthaler, Dominik Kirchhofer, Oldamur Hollóczki, Suzanne D Turner, Richard Moriggl, Lukas Kenner, Mohamed Touaibia, Olaf Merkel

TLDR

  • Researchers developed a novel drug, CM14, which targets TUBGCP2 to treat Anaplastic Large Cell Lymphoma and other lymphomas, showing potential in solid cancers.

Abstract

Anaplastic Large Cell Lymphoma (ALCL) is an aggressive T-cell lymphoma affecting children and young adults. About 30% of patients develop therapy resistance therefore new precision medicine drugs are highly warranted. Multiple rounds of structure-activity optimization of Caffeic Acid Phenethyl Ester have resulted in CM14. CM14 causes upregulation of genes involved in oxidative stress response and downregulation of DNA replication genes leading to G2/M arrest and subsequent apoptosis induction. In accordance with this, an unbiased proteomics approach, confocal microscopy and molecular modeling showed that TUBGCP2, member of the centrosomal γ-TuRC complex, is a direct interaction partner of CM14. CM14 overcomes ALK inhibitor resistance in ALCL and is also active in T-cell Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia. Interestingly, CM14 also induced cell death in docetaxel-resistant prostate cancer cells thus suggesting an unexpected role in solid cancers. Thus, we synthesized and thoroughly characterized a novel TUBGCP2 targeting drug that is active in ALCL but has also potential for other malignancies.

Overview

  • The study explores the development of a new precision medicine drug, CM14, to treat Anaplastic Large Cell Lymphoma (ALCL) and other lymphomas.
  • CM14 is a optimized form of Caffeic Acid Phenethyl Ester that targets TUBGCP2, a centrosomal γ-TuRC complex protein, to induce apoptosis and overcome therapy resistance.
  • The study also examines the potential of CM14 in solid cancers, including docetaxel-resistant prostate cancer cells.

Comparative Analysis & Findings

  • Unbiased proteomics approach, confocal microscopy, and molecular modeling confirmed TUBGCP2 as a direct interaction partner of CM14.
  • CM14 causes G2/M arrest and subsequent apoptosis induction in ALCL cells, and is active in T-cell Acute Lymphoblastic Leukemia and Acute Myeloid Leukemia.
  • CM14 also induces cell death in docetaxel-resistant prostate cancer cells, demonstrating an unexpected role in solid cancers.

Implications and Future Directions

  • The study highlights the potential of CM14 as a new therapeutic agent for ALCL and other lymphomas, particularly in patients with ALK inhibitor resistance.
  • Future studies should investigate the mechanism of CM14's activity in solid cancers and explore its potential as a combination therapy with existing treatments.
  • Further investigation of CM14's safety and efficacy in clinical trials is necessary to confirm its therapeutic potential.
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