Abstract 3851: Killing of Kras mutant colon cancer cells by the αGBP cytokine, a physiological PI3K inhibitor therapeutically effective <i>in vivo</i>
Bibliographic record
Abstract
Abstract Activating Kras mutations are the most frequent oncogenic mutations in human cancer. Numerous downstream pathways responsible for cell proliferation and cell survival have been shown to be deregulated by oncogenic Kras but there are no effective targeted therapies to date for Kras driven oncogenesis. Mutant-activated Kras defines a subset of patients for whom prognosis is poor and therapeutic options are limited. We demonstrate that αGBP, a cytokine produced by CD4+ and CD8+ activated T cells, which operates by inhibiting class IA and class IB PI3K, is a potent activator of apoptosis in Kras-mutant colorectal cancer cells, even when co-harboring mutant-activated PIK3CA. Mechanics initiate with inhibition of PI3K activity and Rac-independent actin reorganisation assignable to phosphoinositide changes at the plasma membrane. Cyclin E deregulation, arrest of DNA synthesis and Chk2 activation underscore events critical to the activation of intrinsic apoptosis. Clustering of CD95/Fas death receptors underscores events critical to the activation of extrinsic apoptosis. In nude mice we present the first evidence that tumor development is strongly inhibited. This first demonstration of therapeutic efficacy against Kras-mutant colon cancer suggests that Hu-r-αGBP may be therapeutically effective against other cancers harbouring activating Ras mutations. Wells, V. and Mallucci, L. (2009). Phosphoinositide 3-kinase targeting by the β-galactoside binding protein cytokine negates akt gene expression and leads aggressive breast cancer cells to apoptotic death. Breast Cancer Research 11, R2, 1-10. Wells, V., Downward, D. and Mallucci, L. (2007). Functional inhibition of PI3K by the αGBP molecule suppresses Ras-MAPK signalling to block cell proliferation. Oncogene 26, 7709-7714. Mallucci, L. and Wells, V. (2007). Alternative use of signaling by the αGBP cytokine in cell growth modulation and cancer control. From surveillance to therapy. In: Apoptosis, Cell Signaling and Human Diseases. Ed. R. Srivastava. The Humana Press Inc. Vol. I, 203-216. Patents US patent no. 7,994,113 granted August 9th 2011 PCT WO 2008/152392: Europe, Canada, Australia, Japan, published Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3851. doi:1538-7445.AM2012-3851
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 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 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".