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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 G 2 /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., Competing Interests: Authors LS, Y-LC, C-CH, D-SC, and Y-WC were employed by the company TaiRx, Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The authors declare Inoviem Scientific performed the target identification using their own proprietary technology NPOT, and provided valuable discussion on the evaluation and confirmation of the identified target., (Copyright © 2023 Shen, Chen, Huang, Shyu, Seftor, Seftor, Hendrix, Chien and Chu.)

Metastasis is a coordinated process that depends on the interaction of cancer cells with the tumor microenvironment. Members of the transmembrane-4 superfamily (TM4SF) of surface proteins have been implicated in the regulation of cancer cell metastasis, and the expression of several TM4SF members on tumor cells is inversely correlated with patient prognosis. The tumor-associated antigen L6 (TAL6), a distant member of the TM4SF, is expressed on most epithelial cell carcinomas and is a target for antibody-mediated therapy. We examined whether TAL6 may play a role in cancer metastasis by using an established series of human lung carcinoma cell lines (CL1-0 to CL1-5) that exhibit increasing invasiveness in vitro and in vivo. We found that TAL6 expression correlated with the in vitro invasiveness of CL lung carcinoma cells (r(2) = 0.98) and human carcinoma cells (r(2) = 0.69). Forced expression of TAL6 on CL1-0 lung carcinoma cells significantly increased their in vitro invasiveness and decreased the survival of SCID mice in an experimental metastasis model. Specific antibody against TAL6 (monoclonal antibody L6) significantly reduced the migration and invasiveness of CL1-5 lung carcinoma cells. The effects of monoclonal antibody L6 on CL1-5 invasion required clustering of TAL6 on the cell surface. Real-time reverse transcription-PCR of lung cancer specimens showed that increased expression of TAL6 was significantly associated with early postoperative relapse (P = 0.034) and shorter survival (P = 0.025) in squamous cell lung cancer patients. Thus, TAL6 appears to be involved in cancer invasion and metastasis.