- This study explored how a novel combination, temozolomide plus a poly(ADP-ribose) glycohydrolase (PARG) inhibitor, affects IDH-mutant glioma
- The hypothesis was that PARG inhibition would result in hyperaccumulation of PAR and block it from being recycled into nicotinamide adenine dinucleotide (NAD+), prolonging and deepening the temozolomide-induced depletion of free NAD+ levels
- Both in vitro and in vivo, the combination therapy did accomplish a "two-hit" depletion of NAD+ by preventing PAR breakdown and consuming freely available NAD+
- The combination therapy also limited the escape avenues available for emergence of subclonal resistance mutations
- Making use of these non-overlapping mechanisms, metabolic cytotoxicity and DNA damage, represents a novel strategy for improving the treatment of IDH-mutant glioma
Gliomas that have mutations in the isocitrate dehydrogenase (IDH) genes are the most common primary brain cancer of younger adults. Alkylating chemotherapy can be effective, but in many patients, the cancer recurs after several years, often as malignant tumor subclones that escape DNA damage surveillance and drive the fatal progression of the disease.
Therefore, the hunt is on for therapeutic agents specific to IDH-mutant glioma that could be added to standard-of-care alkylators such as temozolomide or procarbazine. Hiroaki Nagashima, MD, PhD, research fellow in the Department of Neurosurgery at Massachusetts General Hospital, Hiroaki Wakimoto, MD, PhD, associate professor of Neurosurgery, neurosurgeon Daniel P. Cahill, MD, PhD, and neuro-oncologist Julie Miller, MD, PhD, of the Translational Neuro-Oncology Laboratory and the Mass General Cancer Center, and colleagues report success with such a combination therapy in Cancer Discovery.
Dr. Cahill and colleagues previously reported in Cancer Cell that IDH-mutant cancer cells have low levels of nicotinamide adenine dinucleotide (NAD+), a ubiquitous metabolic molecule that's vital to cell survival. Subsequently, they showed in Cancer Research that temozolomide treatment of IDH-mutant glioma can cause NAD+ to be critically depleted, resulting in a metabolically vulnerable state in these cancer cells.
The consumption of NAD+ is driven by activation of poly(ADP-ribose) polymerases (PARPs), which polymerize monomeric NAD+ into poly(ADP-ribose) (PAR), a key DNA damage signal. PARylation is regulated not just by PARPs, but also by an enzyme called poly(ADP-ribose) glycohydrolase (PARG), which causes breakdown of PAR.
The Two-Hit Hypothesis
The research team wondered whether they could enhance the therapeutic effect of temozolomide for IDH-mutant glioma by combining it with a PARG inhibitor. They theorized that this combination would cause a simultaneous "two-hit" disruption of NAD+ metabolism. Specifically, they envisioned that PARG inhibition would:
- Result in hyper-accumulation of PAR and block it from being recycled into NAD+
- Prolong and deepen the temozolomide-induced depletion of free NAD+ levels
A New Treatment Approach
Using IDH-mutant glioma cell lines and an IDH-mutant xenograft mouse model, the team became the first to show that PARG inhibition enhances the alkylating effectiveness of chemotherapy. As hypothesized, temozolomide treatment promoted PARP activation and consumption of NAD+, while PARG inactivation froze NAD+ as polymerized PAR by blocking subsequent breakdown.
PARylation recruits DNA repair machinery to the sites of chemotherapy-induced DNA damage. Thus, the combination therapy also limited the escape avenues available for the emergence of subclonal resistance mutations.
These non-overlapping mechanisms, metabolic cytotoxicity and DNA damage, represent a novel strategy for improving the treatment of IDH-mutant glioma. The strategy is also worth investigating as a way to counter resistance to PARP inhibitors across multiple cancer types.
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