Abstract 4043: Design of a novel MGMT inhibitor targeted to EGFR overexpressing tumor cells: a new approach to selectively potentiate temozolomide in refractory tumors
Bibliographic record
Abstract
Abstract Temozolomide (TMZ) is an oral alkylating agent commonly used as a first-line chemotherapeutic agent for the treatment of high-grade gliomas and melanoma. Alkylation of the O6-position of guanine in DNA is mainly responsible for the antitumor effect of TMZ. The primary mechanism of chemoresistance to TMZ has been shown to be the overexpression of the DNA repair enzyme O6-methylguanine methyltransferase (MGMT) that specifically removes the methyl lesions from the O6-position of guanine. While O6-benzylguanine (O6-BG), a potent inhibitor of MGMT, was shown to sensitize tumor cells to TMZ in vitro and in vivo, the O6-BG+TMZ combination failed in clinical trial due to acute hematologic toxicity. To circumvent this problem, we wish to target O6-BG to the epidermal growth factor receptor (EGFR), a receptor that is not generally expressed in the hematological cells but overexpressed in many solid tumors. We have now successfully designed and synthesized one such molecule termed MR30 and showed that: 1) MR30 is capable of blocking EGFR and depleting MGMT levels in whole cells; 2) MR30 is a unique molecule capable of inducing stronger growth inhibition than the 2-drug combination involving clinical EGFR and MGMT inhibitors in a panel of melanoma, lung, prostate and ovarian cancer cell lines; 3) MR30 in vitro potentiated the effect of TMZ on MGMT positive cell lines; 4) its kinase inhibitory profiling over 25 different kinases demonstrated selectivity for EGFR, HER2 and EGFR mutant forms; 5) an isogenic model showed more than 70-fold selectivity towards EGFR expressing cells in growth inhibitory assay; 6) MR30 showed good cell penetration with distribution in the perinuclear region. The results in toto suggest that MR30 has the potential to be developed as a tumor selective potentiator of TMZ. Citation Format: Martin Rupp, Bertrand J. Jean-Claude. Design of a novel MGMT inhibitor targeted to EGFR overexpressing tumor cells: a new approach to selectively potentiate temozolomide in refractory tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4043. doi:10.1158/1538-7445.AM2017-4043
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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".