CVM-1118 (foslinanib), a 2-phenyl-4-quinolone derivative, promotes apoptosis and inhibits vasculogenic mimicry via targeting TRAP1

Lifen Shen; Yen-Ling Chen; Chu-Chun Huang; Yu-Chiau Shyu; Richard E B Seftor; Elisabeth A Seftor; Mary J C Hendrix; Du-Shieng Chien; Yi-Wen Chu

doi:10.3389/pore.2023.1611038

CVM-1118 (foslinanib), a 2-phenyl-4-quinolone derivative, promotes apoptosis and inhibits vasculogenic mimicry via targeting TRAP1

Pathol Oncol Res. 2023 Jun 7:29:1611038. doi: 10.3389/pore.2023.1611038. eCollection 2023.

Authors

Lifen Shen¹, Yen-Ling Chen¹, Chu-Chun Huang¹, Yu-Chiau Shyu^{2

3}, Richard E B Seftor⁴, Elisabeth A Seftor⁴, Mary J C Hendrix⁴, Du-Shieng Chien¹, Yi-Wen Chu¹

Affiliations

¹ TaiRx, Inc., Taipei, Taiwan.
² Community Medicine Research Center, Chang Gung Memorial Hospital Keelung Branch, Keelung, Taiwan.
³ Department of Nursing, Chang Gung University of Science and Technology, Taoyuan, Taiwan.
⁴ Department of Biology, Shepherd University, Shepherdstown, WV, United States.

Abstract

CVM-1118 (foslinanib) is a phosphoric ester compound selected from 2-phenyl-4-quinolone derivatives. The NCI 60 cancer panel screening showed CVM-1125, the major active metabolite of CVM-1118, to exhibit growth inhibitory and cytotoxic effects at nanomolar range. CVM-1118 possesses multiple bioactivities, including inducing cellular apoptosis, cell cycle arrest at G₂/M, as well as inhibiting vasculogenic mimicry (VM) formation. The TNF receptor associated protein 1 (TRAP1) was identified as the binding target of CVM-1125 using nematic protein organization technique (NPOT) interactome analysis. Further studies demonstrated CVM-1125 reduced the protein level of TRAP1 and impeded its downstream signaling by reduction of cellular succinate levels and destabilization of HIF-1α. The pharmacogenomic biomarkers associated with CVM-1118 were also examined by Whole Genome CRISPR Knock-Out Screening. Two hits (STK11 and NF2) were confirmed with higher sensitivity to the drug in cell knock-down experiments. Biological assays indicate that the mechanism of action of CVM-1118 is via targeting TRAP1 to induce mitochondrial apoptosis, suppress tumor cell growth, and inhibit vasculogenic mimicry formation. Most importantly, the loss-of-function mutations of STK11 and NF2 are potential biomarkers of CVM-1118 which can be applied in the selection of cancer patients for CVM-1118 treatment. CVM-1118 is currently in its Phase 2a clinical development.

Keywords: CVM-1118; Hsp75; NF2; STK11; TRAP1; foslinanib; vasculogenic mimicry.

MeSH terms

Apoptosis*
Biomarkers
Cell Line, Tumor
HSP90 Heat-Shock Proteins / metabolism
Humans
Neovascularization, Pathologic* / drug therapy
Neovascularization, Pathologic* / metabolism
TNF Receptor-Associated Factor 1 / metabolism

Substances

2-phenyl-4-oxohydroquinoline
TNF Receptor-Associated Factor 1
Biomarkers
TRAP1 protein, human
HSP90 Heat-Shock Proteins

Grants and funding

The authors declare that this study received funding from TaiRx, Inc.. Five employees of this company were involved in the study design, collection, analysis, interpretation of data, and the writing of this article, in collaboration with several scientists from other institutions, but the funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to publish.