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Péptidos capaces de influir en la actividad inhibidora del heterodímero MDM2/MDM4 hacia p53 y su uso en el tratamiento del cáncer

Resumen

Tipo:
Oferta Tecnológica
Referencia:
TOIT20160421001
Publicado:
18/05/2016
Caducidad:
18/05/2017
Resumen:
Un equipo de investigación italiano ha desarrollado un péptido capaz de influir en la actividad inhibidora del heterodímero MDM2/MDM4 hacia p53 restaurando la función oncosupresora del gen p53 en células cancerígenas. Para analizar el potencial terapéutico de los péptidos in vivo, los investigadores han probado los efectos antitumorales del péptido en modelos de ratón transgénicos. Los datos han demostrado que el péptido suprime el crecimiento del tumor in vivo y confirman que la interfaz de interacción de MDM4/MDM2 es un objetivo molecular potencial para el tratamiento contra el cáncer. El equipo de investigación busca socios industriales y centros de I+D con el fin de establecer acuerdos de licencia o cooperación en materia de investigación.

Details

Tittle:
Peptides able to impair the inhibiting activity of MDM2/MDM4 heterodimer towards p53 and use thereof for cancer treatment
Summary:
An Italian research team has developed a peptide able to impair the inhibiting activity of MDM2/MDM4 heterodimer towards p53 restoring the p53 onco - suppressive function in cancer cells. The team is open to various collaboration (license agreement or research cooperation agreement) with industrial partner and R-Y-D Institution.
Description:
An italian research team has developed a peptide able to reactivate the tumor suppressor p53, leading to the death of the cancerous cells. In summary, this peptide is able to cancel the collaboration between MDM4 and MDM2 inhibitors which disable p53 making it ineffective.
Using computational and mutagenesis analyses of the heterodimer binding interface, the investigators have identified a specific peptide that mimics the MDM4 C-terminus, competes with endogenous MDM4 for MDM2 binding, and activates p53 function. This peptide induces p53-dependent apoptosis in vitro and reduces tumor growth in vivo. Interestingly, interfering with the MDM2/MDM4 heterodimer specifically activates a p53-dependent oxidative stress response.
Consistently, distinct subcellular pools of MDM2/MDM4 complexes were differentially sensitive to the peptide; nuclear MDM2/MDM4 complexes were particularly highly susceptible to the peptide displacement activity. To assess the therapeutic potential of the peptides in vivo, the investigators have tested the anti-tumor effects of such peptide in mouse xenograft models.
Data have demonstrated that such peptide effectively suppresses tumor growth in vivo, and confirm that the MDM4/MDM2 interaction interface is a potential molecular target for anti-cancer therapy.
The Italian researchers are interested in finding industrial partner (SME or large company) to reach license agreement or research cooperation agreement, in order to develop the clinical phases. The Italian team is also looking for R-Y-D Institutions to investigate together on the innovative research.

Advantages and Innovations:
The therapies developed so far, with the aim to reactivate p53 in tumors, are not able to block the two inhibitors simultaneously, but selectively restrict the ability of only one of these molecules to interact with p53, leaving the other free to operate. The release of MDM2 from association with p53, for example, results in higher degradative activity of MDM2 towards MDM4 and other pro-apoptotic molecules. The growth arrest rather than the apoptotic response often occurs, while the preferred result in any cancer therapy is apoptosis. Therefore, all current methods failed to pass phase 1 of clinical trials.
The inventors have developed a method that blocks the activity of MDM2 and MDM4 simultaneously, based on recent studies indicating that formation of MDM2/MDM4 heterodimer complexes are required for efficient inactivation of p53 function.
Stage of Development:
Prototype available for demonstration
IPs:
Patents granted
CommeR Statunts Regarding IPR Status:
The patent has been just granted in Europe. The researchers still need to select the European states to convalidate the granted patent

Partner sought

Type and Role of Partner Sought:
The team is looking for industrial companies (SME or Large) to define collaboration partnerships (license agreement or research cooperation agreement) to pursue the development of the clinical phases. The team is also looking for R-Y-D Institution to investigate the peptide potential synergism in combinatorial therapies and to develop nanoparticles for the efficient delivery of the peptide in clinical applications

Client

Type and Size of Client:
R&D Institution
Already Engaged in Trans-National Cooperation:
No
Languages Spoken:
English
Italian

Keywords

Technology Keywords:
06002 Biología / biotecnología
06 CIENCIAS BIOLÓGICAS
06001003 Citología, cancerología, oncología
06002004 Ingeniería de proteínas
06001 Medicina, salud humana