The development of the WPD104 molecule - berubicin, as a novel drug in glioblastoma multiforme (GBM) therapy for children and adults patients

Berubicin belongs to the anthracyclines, one of the most widespread and effective group of anticancer drugs. While the clinical treatments of anthracyclines (daunorubicin, doxorubicin, epirubicin) showed strong cytotoxic properties against many types of cancer, they are ineffective against brain tumors, including GBM, as they do not cross the blood-brain barrier (BBB). Berubicin overcomes the BBB and can affect cancer cells in the brain. Berubicin binds to DNA and inhibits topoisomerase II function, leading to the formation of double strand DNA breaks and apoptosis induction.

Standard GBM chemotherapy currently includes treatment with temozolomide (TMZ), a DNA alkylating agent. However, in about 60% of GBM patients, the lack of the methylation of the MGMT gene promoter region (O6-methylguanine-DNA methyltransferase), causes an increase in MGMT level and stimulation of DNA repair processes. Thus, MGMT limits or completely abolishes cytotoxic effects of TMZ. In patients with high MGMT expression, berubicin could be an alternative therapy, replacing inefficient TMZ.

In addition, during TMZ chemotherapy, many patients develop chemoresistance due to the induction of MDR proteins expression, which actively expel cytotoxic drugs from the cells. Previous preclinical studies on in vitro model have shown, that berubicin is highly effective apoptosis inducer even in the presence of MDR proteins.

Phase I clinical trail in patients with brain tumors, including GBM, showed significant therapeutic effect in 44% of the treated patients population. One of the patients achieved an unexpected in this phase, long-term therapeutic effect - an over 5-year survival without recurrence, which is recognized in oncology as a cure from the disease. Moreover, drug resistance was not observed and adverse effects were severely limited.

Further development of berubicin may contribute to the implementation of a new therapeutic strategy towards GBM, which will be applicable in adults as well as in children.

R & D