2HIT Medulloblastoma

The 2HIT Medulloblastoma project is the first drug discovery program within the Oncoheroes Biosciences R&D strategy. The program is being fostered in our Barcelona facilities, in the Barcelona Science Park lab.

Medulloblastoma (MB) is a central nervous system malignant tumor that accounts for around 20% of all childhood brain cancers and around 40% of all childhood tumors in the posterior fossa. The World Health Organization classifies MB as a malignant neuroepithelial embryonal neoplasm of the cerebellum with predominantly neuronal differentiation and with a tendency to metastasize via cerebrospinal fluid pathways. All tumors are classified as grade IV because of their highly malignant phenotype. MB exhibits high molecular heterogeneity and is classified into four distinct molecular groups with different profiles that can predict patient risk and outcome: Wingless, Sonic Hedgehog, Group 3 and Group 4. 

Among the subtypes, Group 3 MB has the worst outcome, especially if it is associated with MYC amplification with only 20% of patients surviving 5 years post-diagnosis. We have focused our first project on Group 3 MB, that accounts for approximately 25-30% of all cases, and it is found in kids, but not in adults.

Our innovative solution is our therapeutic approach, the Synthetic lethality (SL). Synthetic lethality refers to the death of cells caused by concomitant perturbations of two genes (loss-of-function mutations, RNA interference, drug treatment, etc.), each of which is nonlethal alone. The approach designed by Oncoheroes includes pharmacological modulation of both targets or a combination of a mutation of one of the targets and pharmacological blockade of the other. Oncoheroes will attack medulloblastoma cells targeting two therapeutic targets simultaneously to increase therapy effectiveness and reduce toxicity and resistance.

Thus, the main goal of the 2HIT Medulloblastoma program is, based on the specific molecular characteristics of MB groups, to identify existing drugs and develop new targeted drugs as candidates that will benefit patients with unique molecular profiles. We expect that such personalized drugs may exhibit greater therapeutic effect, low risk of treatment resistance and long-term deleterious effects. 

The program is designed to select and characterize a preclinical candidate to be ready to enter into the regulatory preclinical phase in late 2024 and to identify the biomarker for further clinical treatment support later on. This candidate is a compound/combination of compounds that exhibits in vitro activity against two targets and in vivo activity in animal models, as well as a suitable pharmacokinetic profile and no concerns on preliminary toxicity.

To date, Oncoheroes’ Drug Discovery team has identified and validated a novel SL Pair composed by Gain-of- function mutation (Driver Gene) and proto-oncogene (Target gene), and is already working on identifying promising hits.