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ERC

Mycinhibinclinic Report Summary

Project ID: 617473
Funded under: FP7-IDEAS-ERC
Country: Spain

Mid-Term Report Summary - MYCINHIBINCLINIC (Pushing Myc inhibition towards the clinic)

Deregulation of the Myc oncogene promotes tumorigenesis in most if not all cancers and is often associated with poor prognosis. However, targeting Myc has long been considered impossible, due to its nuclear localization and potential role in normal tissue maintenance and regeneration. Nevertheless, we showed that Myc inhibition displays extraordinary therapeutic benefit in various transgenic mouse models of cancer, and caused only mild, well-tolerated and reversible side effects in normal tissues. For these studies we have employed a dominant negative of Myc, called Omomyc, which we designed and validated. Omomyc has so far been utilized exclusively as gene therapy and served the purpose of pre-clinically validating the therapeutic impact of systemic Myc inhibition. In this proposal we intended to push such a therapeutic approach further towards the clinic, making use of 1. Omomyc-based Cell Penetrating Peptides (CPPs), and 2. A new generation of Myc inhibitory small molecules.
The first approach turned out to be extremely efficient and proved a feasible strategy to treat Non-Small-Cell-Lung cancer in vitro and in vivo. We characterized biophysically and biochemically the Omomyc peptide (OmomycCPP), which displayed very good cell penetrating properties, provided anti-Myc specific activity and displayed excellent therapeutic impact in NSCLC cells in culture, as well as in a mouse models of KRas-driven NSCLC. In the latter, nasal instillation of OmomycCPP resulted in a significant reduction of tumor burden and grade, as a consequence of reduced tumor proliferation and increased death. Novel and improved variants of the original peptide are being generated and validated in vitro and in vivo, in other types of cancer as well, such as glioblastoma (GBM) and triple negative breast cancer (TNBC). Further development of the peptide towards its clinical application is now being carried out by a spin-off company from the laboratory, Peptomyc S.L.
The second approach, based on anti-Myc small molecules identified by Dr. Mikhail Nikiforov from the Roswell Park Cancer Center has demonstrated encouraging therapeutic impact in LSLKRasG12D transgenic mice, showing once again the validity of a Myc inhibitory strategy in this type of cancer. The initial compounds suffered relatively poor bioavailability, and further optimization by Dr. Nikiforov is underway.
Overall the project is swiftly advancing according to its predicted timeline and it is expanding its studies beyond NSCLC, to make Myc inhibition applicable to multiple types of cancer and eventually benefit a wide range of cancer patients.

Reported by

FUNDACIO PRIVADA INSTITUT D'INVESTIGACIO ONCOLOGICA DE VALL-HEBRON
Spain
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