Abstract A24: Characterizing a novel “Minimalist Hybrid Protein” inhibitor designed to target Myc activity in cancer
Notice bibliographique
Résumé
Abstract When deregulated, the c-Myc oncoprotein plays a key role in the development and progression of over 50% of all human cancers. As such, innovative and effective therapeutics are urgently needed to improve the treatment and survival of cancer patients, and we believe that directly modulating the activity of Myc would fill this important gap. Recent studies using a dominant negative protein, Omomyc, have provided evidence regarding the therapeutic value of inhibiting Myc activity in cancer. Specifically, perturbing Myc activity in vivo eradicates tumors without irreversible damage to normal cells, as demonstrated in mouse models of cancer. Using a similar yet novel strategy, we have generated a minimalist hybrid protein inhibitor known as MaxE47 (ME47), which is composed of the subdomains of different b-HLH-LZ and b-HLH transcription factor families. ME47 is designed to act as a competitive inhibitor of DNA E-box binding by the Myc/Max heterodimer. We hypothesize that ME47 can be used as a tool to better understand how best to interfere with oncogenic Myc and will lead to the development of Myc-targeted therapeutics. Using our prototype inhibitor, ME47, with Omomyc as a proof-of-concept control, we have established the cell systems and assays necessary to (1) evaluate the anti-cancer efficacy of our Minimalist Hybrid Proteins in human cancer cells, and (2) to determine their mechanism of action and specificity. Here we have demonstrated that ME47 significantly reduces anchorage-independent growth in soft agar and cell viability in tumor-derived breast cancer cell line MDA-MB-231, but not the non-transformed MCF10A breast cells. ME47 also significantly decreases tumor formation in xenograft mice. To begin to characterize the specificity and mechanism of action of ME47, luciferase reporter and chromatin immunoprecipitation assays were used to evaluate whether ME47 is Myc and/or E-box specific. Using luciferase reporter constructs fused to the promoters of established Myc target genes such as Nucleolin, we have also demonstrated that MaxE47 decreases the ability of Myc to activate target gene transcription. While this work is focused on the development of a Myc/Max E-box interaction inhibitor, Dr. Linda Penn's research group is also implementing BioID mass spectrometry to identify novel Myc interacting partners (see Penn lab abstract Dingar et al.). This work could potentially reveal new targets for a similar mode of disruptive inhibition, where a Minimalist Hybrid Protein designed to inhibit the association of the novel interacting partner and Myc would disrupt Myc activity. A direct inhibitor of Myc activity in cancer would re-define the field of Myc therapeutics and could develop into a valuable tool for personalized cancer medicine in those patients with deregulated Myc. The success we have had with our ME47 inhibitor suggests that we are progressing along the path to such an inhibitor, and we look forward to continuing our work with this inhibitor and other Minimalist Hybrid Proteins. Citation Format: K. Ashley Hickman, Lindsay C. Lustig, Dharmendra Dingar, Romina Ponzielli, Christina Bros, Warren W.C Chan, Jumi Shin, Linda J.Z Penn. Characterizing a novel “Minimalist Hybrid Protein” inhibitor designed to target Myc activity in cancer. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr A24.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,001 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,001 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».