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New Opportunity for a IHC CDx assay predicting MEK inhibitors efficacy in high-grade ovarian cancers

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07/04/2017
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New Opportunity for a IHC CDx assay predicting MEK
inhibitors efficacy in high-grade ovarian cancers for licencing
Plateforme de criblage phénotypique Biophenics
Plateforme de criblage phénotypique Biophenics dirigée par Elaine Del Nery dans le département de Recherche translationnelle. Cette plateforme repose sur l'expertise de l'Institut Curie en biologie cellulaire. Grâce à l'automatisation de la prise d'images couplées à des algorithmes d'analyse d'images, la biologie cellulaire est mise au service de la validation de cibles et de l'identification de molécules chimiques actives plus sélectives.
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Description

  • high-grade EOC represent a high unmet medical need
  • 50% high-grade EOCs have a MEK-activated pathway
  • The MEK kinase, COT/MAP3K8, could be a valuable biomarker for predicting mek inhibitors efficacy in high-grade EOC

Opportunity

We showed that MAP3K8 controls cancer cell proliferation and migration by regulating key players in G1/S transition and adhesion dynamics. Importantly, there is a significant correlation between MAP3K8 protein level and MEK activation in human high-grade EOCs, supporting that MAP3K8 can be used as readout for MEK activation. Moreover, MAP3K8 exhibits a reliable predictive value for the efficiency of MEK inhibitors in high-grade EOCs. Indeed, using Patient-derived xenograft mouse models of high-grade EOCs, we established that MEK inhibitors significantly reduce tumour growth in tumours in which MAP3K8 accumulates (50% cases). Thus, if anti-MEK therapies have been included in clinical trials for low-grade EOC, due to the prevalence of KRAS/BRAF mutations that invariably result in constitutive MEK activation, our results demonstrate that high-grade EOC patients with COT/MAP3K8 accumulation might also greatly benefit of anti-MEK treatments combined to conventional chemotherapies.

We are seeking a co-development or licensing partner to validate this biomarker/CDx through a clinical study

Background

A wide proteomic analysis enabled us to uncover constitutive activation of MEK/ERK pathway in 50% cases of high-grade EOC. While the majority of low-grade EOC harbour KRAS/BRAF mutations that result invariably in constitutive MEK activation (BRAF being a MEK Kinase), less than 1% of high-grade EOC exhibit KRAS/BRAF mutations. Still, half high-grade EOC exhibit constitutive MEK/ERK activation, due to accumulation of COT/MAP3K8, the other MEK kinase besides BRAF.

Competitive advantages

CDx through IHC assay

Intellectual property

PCT/EP2015/071040

References

Nat Commun. 2015 Oct 12;6:8583

MAP3K8/TPL-2/COT is a potential predictive marker for MEK inhibitor treatment in high-grade serous ovarian carcinomas.

Gruosso T, Garnier C, Abelanet S, Kieffer Y, Lemesre V, Bellanger D, Bieche I, Marangoni E, Sastre-Garau X, Mieulet V, Mechta-Grigoriou F

R&D status

R&D status Poc In vivo