Maximizing the use of a first clinically viable MYC inhibitor

Introduction

Even though the MYC oncogene is a “most-wanted” target in cancer therapy, no MYC inhibitor has yet reached clinical approval. The applicant has developed Omomyc, the first MYC-inhibiting mini-protein to have successfully completed a Phase Ia clinical trial. The goal of this proposal is to maximize the use of this compound, as both a therapeutic and study tool, opening new lines of research in different aspects of MYC biology.

Aim 1: Delivery Methods

To start with, since Omomyc cannot efficiently cross the blood-brain barrier, excluding it from use in brain malignancies or brain metastases, we propose to validate its efficacy when delivered intracranially by different means, including:

• Osmotic pumps
• Hydrogels
• Intracarotid injection

This will be tested in glioblastoma and brain metastases.

Aim 2: Combination with PARPi

In Aim 2, we will explore the combination of Omomyc with personalized medicine, specifically PARP inhibitors (PARPi). This aim is derived from one of the pillars of MYC biology: its role in DNA damage response. Aim 2 will allow us to shed light on the role of MYC in homologous recombination and resistance to PARPi.

Aim 3: Combination with KRASi

In Aim 3, we will investigate the combination of Omomyc with KRAS inhibitors (KRASi). This aim is based on the paradigm of oncogene cooperation. Aim 3 will deliver insights into the molecular mechanisms underlying the cooperation of RAS and MYC in multiple tumor types, where their combined inhibition could represent an unprecedented therapeutic opportunity.

Aim 4: Characterization of Specific Cancers

Finally, Aim 4 will focus on the characterization of cancers such as Small Cell Lung Cancer and Gastrointestinal Stromal Tumors that have the peculiarity of being defective for MAX – MYC’s natural partner – but that recapitulate a MYC-dependent tumor phenotype. This is likely driven by other members of the MYC network, whose function could also be hindered by Omomyc treatment.

Conclusion

Notably, each of the aims explores new aspects of MYC biology, tracing new lines of research around the most deregulated oncogene in human tumors, as well as having immediate translational applicability in upcoming clinical trials of Omomyc.