Novel Alkylating Agent Defies Mechanisms of Resistance in GBM Tumors

Ariela Katz
Published: Wednesday, Oct 11, 2017
Nicholas Butowski, MD

Nicholas Butowski, MD
VAL-083, a novel alkylating agent that has demonstrated potency against brain tumor cells and can overcome resistance associated with methylguanine methyltransferase (MGMT), is being investigated in patients with glioblastoma multiforme (GBM) or gliosarcoma (GS) who had progressive disease during or after treatment with bevacizumab (Avastin). The drug will be tested in the phase III randomized STAR-3 trial (NCT03149575).

GBM, considered a grade 4 tumor, is the most aggressive and infiltrative form of brain cancer. Median survival in patients with a new diagnosis is just 14.6 months. Additionally, the 5-year survival rate for patients with GBM is less than 5%.1 These statistics illustrate the need for effective novel therapies in the advanced setting. “There aren’t many, if any, current standard-of-care options for recurrent glioblastoma patients,” said Nicholas Butowski, MD, professor of neurological surgery and director of translational research at University of California, San Francisco. “Most trials exclude these patients after failure with bevacizumab (Avastin). At that point, GBM becomes more invasive and harder to control, based on preclinical evidence,” Butowski said.

VAL-083 could be the answer to this unmet need for GBM therapy because it is an alkylating agent with a unique mechanism of action. Most agents in this class, such as temozolomide (Temodar), methylate the purine bases of DNA (O6-guanine, N7-guanine, and N3-adenine),2 damaging tumor cell DNA and triggering cell death, although the outcome is dependent on MGMT-mediated resistance. Conversely, VAL-083, causes highly toxic DNA lesions specifically at the N7 position of guanine in growing cells and is less affected by MGMT resistance. This more targeted approach results in double-strand DNA breaks, cell cycle arrest, and—ultimately—cell death.3 Butowski, who is the principal investigator for STAR-3, said preclinical evidence suggests that VAL-083 also succeeds against other major resistance mechanisms that have defeated alkylating agents.
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