Abstract 1936: The central role of NFAT signalling in the mechanism of action of the TRPV6 oncochannel inhibitor and clinical candidate SOR-C13
Bibliographic record
Abstract
Abstract SOR-C13, a 13-mer peptide derived from soricidin, the paralytic peptide in saliva of the Northern Short-tailed shrew, has completed an open-label, all comers Phase I Clinical Trial for the treatment of epithelially-derived cancers. SOR-C13 is a first-in-class drug candidate for the treatment of solid tumors. SOR-C13 specifically targets and inhibits the TRPV6 calcium channel - a recognized oncochannel whose over-expression in a number of epithelial cancers (e.g. breast, ovarian, prostate) is associated with poor prognosis. An increase in TRPV6 facilitates calcium influx into the cell, which activates the calcium binding protein calmodulin. This complex in turn activates calcineurin that de-phosphorylates and activates Nuclear Factor of Activated T-cells (NFAT), a gene transcription factor involved in multiple oncogenic processes. To demonstrate the role of NFAT activation in the mechanism of action (MOA) of SOR-C13, breast cancer cells (T-47D) were transfected with a NFAT dual reporter plasmid, treated with the peptide, and NFAT activation monitored. Additionally, RT-qPCR TaqMan array profiling was performed on prostate (PC-3), breast (T-47D), ovarian (OVCAR-3 and SK-OV-3), and pancreatic (BxPC-3 and SU.86.86) cancer cell lines treated with SOR-C13 compared with untreated cells. The TaqMan array panel consisted of 187 genes involved in cancer calcium signalling associated with the MOA of TRPV6 and directly, or indirectly, involved in NFAT signalling. SOR-C13 treatment significantly inhibited NFAT activation (p < 0.05) in T-47D cells transfected with a NFAT reporter plasmid. Molecular profiling of the 6 cancer cell lines showed that many genes involved in NFAT signalling were modulated by SOR-C13 treatment. Affected genes included genes involved in cell proliferation (e.g. TGF-beta, TLR9), metastasis (e.g. ADAM12, CEACAM6), resistance to apoptosis (e.g. WISP1) and angiogenesis (e.g. FLT4). Cytokines (e.g. IL-6) and chemokines (e.g. CXCL12), involved in cancer progression and associated with NFAT signalling, as well as transcription factors (e.g. GATA4, NF-kB) were down regulated upon SOR-C13 treatment. These results highlight NFAT signalling in the mechanism of action of SOR-C13. The impact of SOR-C13 on the expression of genes involved in resistance to apoptosis, proliferation, metastasis and angiogenesis as well as on the expression of immune cytokines and transcription factors in multiple cancer cells, makes SOR-C13 an attractive, novel anti-cancer drug. Citation Format: Christopher Rice, Tyler Lutes, Michelle Davey, Vett Lloyd, Tyson J. MacCormack, John M. Stewart, Dominique Dugourd. The central role of NFAT signalling in the mechanism of action of the TRPV6 oncochannel inhibitor and clinical candidate SOR-C13 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1936.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".