The discovery, which combines innovative synthetic chemistry and cutting-edge mechanistic studies in molecular biology, offers a potentially powerful new approach to treating drug-resistant glioma tumors that form in the brain and spinal cord.
“A major problem in treating gliomas is that patients can rapidly develop resistance to the drug temozolomide, which has been the backbone of most glioma treatments for over 20 years,” says Ranjit Bindra, professor of therapeutic radiology at Yale School of Medicine and co-corresponding senior author of the study in the journal Science.
“Resistance arises from acquired genetic mutations that essentially make the drug invisible after about a year, leading to recurrence and death in most cases. For example, the five-year survival rate for patients with glioblastoma is 5%,” says Seth Herzon, professor of chemistry and the study’s other co-corresponding senior author. “We set out to identify new agents that can overcome acquired resistance to temozolomide.”
There are an estimated 20,000 new glioma cases diagnosed in the United States every year, more than half of which are glioblastomas, the most aggressive subtype. It is the most common type of malignant brain tumor among adults.
Many cancers, including gliomas, are characterized by defects in DNA repair. For reasons that are not well understood, a specific DNA repair protein known as MGMT is lost in more than half of gliomas.
Bindra and Herzon’s new class of molecules exploits this DNA repair defect. Their lead compound generates a specific form of DNA damage, known as an interstrand cross-link, that is highly toxic to cells.
While many agents that generate interstrand cross-links are used in the clinic for patients with cancer, most cannot discriminate between healthy tissue and tumors, leading to significant, dose-limiting toxicity. The newly developed compounds selectively generate this DNA damage in tumors but not in healthy tissue.
“In essence, we have created a tumor-selective DNA cross-linking agent,” Herzon says.
The discovery is potentially applicable to other types of tumors harboring specific DNA repair defects, a line of inquiry the researchers are pursuing. “Our discovery essentially redefines the rules on how to target cancer cells,” Bindra says.
“We are incredibly excited to test whether this can be broadly implemented as a therapeutic strategy for many subsets of cancers with DNA repair defects in the future,” Herzon says.
The researchers say they expect their lead molecule to be rapidly translated into the clinic owing to its structural similarity to temozolomide. That similarity will enable Bindra and Herzon to accelerate the scientific evaluation process, often referred to as “IND enabling studies,” which is required by the US Food and Drug Administration prior to testing in phase I clinical trials.
Clinical trials for the new compounds could begin as early as 2024, the researchers say.
The National Institutes of Health, the CureSearch Foundation, and the Yale Cancer Center funded the work. Herzon and Bindra are cofounders of the company Modifi Biosciences, which has licensed the exclusive rights to the findings from Yale University.
Source: Yale University
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