VAL-083 Shows Promise for Glioblastoma Multiforme
Phase 2 studies show in vitro effectiveness in various glioblastoma multiforme cell lines.
Options for treating the most common and most aggressive form of brain cancer, glioblastoma multiforme, are limited, but an investigational drug called dianhydrogalactitol (VAL-083; DelMar Pharmaceuticals) has demonstrated in vitro effectiveness in various glioblastoma multiforme cell lines, independent of O6-methylguanine-DNA-methyltransferase (MGMT) activity in phase 1/2 studies.
MGMT has been shown to induce resistance to temozolomide, the first-line systemic therapy for patients with glioblastoma multiforme.1
According to the American Brain Tumor Association, adults with glioblastoma who are treated with concurrent temozolomide and radiotherapy have a median survival of about 14.6 months and a 2-year survival rate of 30%. Patients who lack MGMT activity, and therefore respond better to temozolomide, have prolonged survival rates.2
Patients with progressive disease following treatment with temozolomide can receive the angiogenesis inhibitor bevacizumab, but bevacizumab therapy has not been shown to improve disease-related symptoms or survival in patients with glioblastoma. Other treatment options include carmustine alone or regimens containing lomustine, vincristine, and procarbazine.3
VAL-083, however, has been shown to overcome MGMT-induced drug resistance in vitro and has shown anticancer activity in a variety of tumors, including glioblastoma multiforme. In vitro, the drug works by inhibiting the growth of certain brain tumor initiating cells without affecting normal human neural stem cells. In contrast, temozolomide is ineffective against brain tumor initiating cells.1
RELATED: Bevacizumab at Half the Standard Dose Equivalent to Standard Dosing for Glioblastoma
Jeffrey A. Bacha, BSc, MBA, Chairman, President and CEO of DelMar Pharmaceuticals, Inc., said, “There are two things that excited us about the drug. Number one is an understanding of the historical clinical activity from the literature, so this is a compound that had activity in a number of tumor types and that's a nice place to start from with a well-defined safety profile and some evidence of efficacy, but what really peaked our interest is the differentiation of the mechanism. This is an alkylating agent, and similar to other alkylating agents, it binds to DNA and interrupts replication and leads to apoptosis. It's very clear that the cytotoxic mechanism is different from other alkylating agents used in glioblastoma multiforme, namely this is an N7 alkylator versus O6 on guanine. Therefore, the repair mechanism, such as MGMT, does not affect the cytotoxic activity of VAL-083.”
Current data from an in vivo mouse model study investigating the efficacy of VAL-083 has shown that temozolomide-sensitive tumors were sensitive to both temozolomide and VAL-083, and both interventions results in a statistically significant survival benefit compared with the control arm. Results from mice with temozolomide-resistant tumors are immature.1