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Adding an NAMPT Inhibitor to Temozolomide Might Boost Its Effect in IDH-Mutant Glioma

Key findings

  • Human glioma cells exhibited a "window of hypervulnerability" to nicotinamide phosphoribosyltransferase (NAMPT) inhibitors for about three hours after exposure to temozolomide
  • In a mouse model of IDH-mutant fibrosarcoma, the combination of temozolomide and an NAMPT inhibitor was significantly more effective than either monotherapy at inhibiting tumor growth
  • No substantial signs of toxicity were found
  • The effect of combination treatment was genotype-specific and will not necessarily apply to all IDH-mutant cancers

Adults with glioma who have mutations in an isocitrate dehydrogenase gene (IDH1/2) gain a survival benefit from DNA-alkylating chemotherapy, recent trials have shown. Temozolomide is the drug most commonly used because it is tolerated as well as adjuvant therapy. However, most of these cancers recur after adjuvant or salvage temozolomide, so better treatment strategies are needed.

By studying the metabolic consequences of temozolomide exposure in IDH1-mutant glioma, a research team at Massachusetts General Hospital has determined that combining temozolomide with a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor is likely to improve its anticancer effect. The team is led by Daniel P. Cahill, MD, PhD, a neurosurgeon at Mass General, and includes Kensuke Tateishi, MD, PhD, researcher in the Department of Neurosurgery.

Published in Cancer Research, Dr. Cahill's team explains that mutant IDH1 produces widespread metabolic alterations in cancer cells, such as depleting the levels of glutathione and NAD+. The team speculated that drugs that inhibit NAMPT (the NAD+ biosynthetic enzyme) might help treat IDH1-mutant glioma.

The authors further explain that while most temozolomide-induced DNA lesions are rapidly corrected by the base excision repair pathway, they do produce a significant stress response. This occurs through the poly (ADP-ribose) polymerase (PARP) family of proteins, which polymerize NAD+ into poly (ADP-ribose).

In experiments with human glioma cell lines, the researchers observed a burst of NAD+ consumption associated with PARP activation in the acute time period (<3 hours) after the cells were exposed to temozolomide. In endogenous IDH1-mutant cancer cell lines, this consumption resulted in a transient but substantial reduction of the already low level of NAD+. The researchers term this period a "window of hypervulnerability" to NAMPT inhibitors.

To investigate further, they conducted experiments with mice that had IDH1-mutant fibrosarcoma cells grafted onto their flanks. The animals were divided into four groups that received distilled water; temozolomide; FK866, which is a NAMPT inhibitor; or both temozolomide and FK866. Compared with distilled water, FK866 alone significantly suppressed tumor growth. Furthermore, treatment with both temozolomide and FK866 was significantly better than either drug alone at inhibiting tumor growth. No animal had substantial signs of toxicity.

No superior effect of combination therapy was apparent when they tested IDH wild-type cancer cells or noncancerous cells.

The authors speculate that combining temozolomide with a NAMPT inhibitor would allow for optimized dosing, which would allow for lower dosages of NAMPT inhibitors that are often associated with thrombocytopenia and gastrointestinal toxicity. Another approach might be to administer one drug systemically and the other locally, to maximize the intratumoral effect. Given the time dependence of temozolomide-induced PARP activation in the laboratory, more research is needed to determine the optimal timing of combined therapy.

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