Yale University scientists have developed a new class of glioma and glioblastoma (GBM) drugs that exploit tumors that lack the DNA repair enzyme O6-methylguanine methyltransferase, or MGMT. The drugs lead to the generation of cytotoxic DNA that selectively kills tumor cells in different in vivo mouse models of drug-resistant GBM without significant off-target toxicity. The new approach is based on direct DNA modification to exploit specific DNA repair defects and fight drug-resistant tumors.
The results of the study were published in Science.
About half of GBMs and two-thirds of grade II and III gliomas do not have MGMT. These cancers initially respond to treatment with the drug temozolomide (TMZ), but most patients eventually develop resistance to the drug through loss of the mismatch repair (MMR) pathway.
“The problem is that there is a resistance mechanism that involves further changes in DNA repair,” said co-senior author Seth Herzon, PhD, a professor of chemistry at Yale University School of Medicine. It involves silencing the MMR pathway which in turn limits the efficacy of TMZ. Patients usually come back and don’t respond after that first round of treatment.
In a unique strategy, the Yale team takes advantage of this lack of MGMT to selectively kill GBM tumor cells. “Deficiencies in DNA repair go hand in hand with tumorigenesis,” Herzon said. “Our strategy is essentially to exploit the DNA damage response to obtain tumor-specific activity.”
In collaboration with longtime collaborator and co-senior author Ranjit Bindra, MD, PhD, the team developed TMZ analogs that create a dynamic primary DNA lesion, which can be repaired in healthy cells with intact MGMT-mediated DNA repair mechanisms. However, cancer cells without MGMT expression cannot repair the damage.
Herzon explains that the drugs transfer a small residue of two carbons with a fluorine component to O6 of guanine to form that primary lesion that can be reversed by MGMT in healthy tissue. “That is the basis of our selectivity; we don’t just deliver physically into the tumor,” he Bindra. The drugs go everywhere, but in healthy cells, MGMT is ubiquitously expressed and can process and repair that first primary lesion.” But with MGMT minus tumors, you have that reversal pathway not available,” Herzon added. Consequently, that lesion is then converted into more toxic secondary DNA lesions that result in the selective killing of MGMT-deficient tumor cells.
Their experiments lead to a lead candidate, KL50. “One of the reasons we were able to act very quickly with this research is that our connection is structurally a very small change from TMZ,” explains Herzon. “So it has CNS penetration, it’s well tolerated, it’s available orally, and in this article we demonstrated its efficacy in vivo in intracranial models of drug-resistant GBM.”
The researchers first used immortalized, TMZ-resistant cell lines implanted in the flank of mice with drug-resistant GBM. “With KL50, we observed a reduction in tumor burden without toxicity,” Bindra added. Then the team implanted the cells into the brain tissue of the mice and observed the same efficacy without toxicity. “This was a very important result for us because CNS penetration is always a concern in these neurocancers,” he added. Finally, large TMZ-resistant GBM tumors were implanted in mouse brains and again KL50 achieved a significant reduction in tumor burden.
The team hopes to generalize this approach to create new drug treatments that take advantage of a variety of DNA repair defects, not just those related to MGMT. “We’re looking at other DNA damage repair defects that we think are clinically useful for a range of different cancer types to gain selectivity and we’re making new classes of molecules,” Herzon says.
While this concept was developed at Yale, Herzon and Bindra formed a startup, Modifi Bio, which has been in stealth mode for two years until this Science paper was published to bring these types of compounds to the clinic. Their goal is to start the first clinical trial in early 2024.