Resurrecting an Alternative Treatment for NER-Deficient Bladder Cancer Patients

Discovering new cancer treatment can sometimes be a matter of connecting the dots between new pathways and old drugs. That was the case in a new paper in the TKTK issue of Clinical Cancer Research co-authored by Kent Mouw MD, PhD, co-director of Dana-Farber’s Bladder Cancer Center. Mouw and his team found a promising way to treat a subset of bladder cancers for patients who can’t tolerate the standard of care — cisplatin chemotherapy. His preclinical findings could lead to a new treatment option for those patients.

The study taps into Mouw’s previous research showing that 8-18% of bladder tumors are deficient in a pathway called nucleotide excision repair (NER), which exists to repair single-stranded DNA damage. Prior to that, in 2014 Mouw was part of the first group to realize that mutations in the NER gene ERCC2 were associated with cisplatin sensitivity in bladder cancer. 

That existing research led to Mouw’s most recent study, co-led by Boston Children’s Hospital’s Zoltan Szallasi, MD, resurrecting an abandoned chemotherapy agent, called irofulven, which was tried clinically in the 1990s with limited success across a variety of solid tumor types, from ovarian to prostate.

Knowing that irofulven damage is normally repaired by the NER pathway, and that a subset of bladder tumors are NER deficient, Mouw says, “we put those two ideas together and said, maybe irofulven is the drug that could specifically target nucleotide excision repair deficient bladder cancers.”

Kent Mouw MD, PhD.

Zeroing in

The scientists were able to identify tumors with NER deficiency through the use of next-generation sequencing technologies.

“Now we can identify patients with nucleotide excision repair deficient tumors who we believe have the highest likelihood of responding to irofulven,” says Mouw.

When the researchers administered the drug in bladder cancer mouse models and cell lines engineered to be either NER deficient or NER proficient, they found that the NER deficient models were significantly more sensitive to the drug.

“Irofulven had minimal impact on the growth of tumors that were NER proficient, but significantly shrunk or eradicated tumors that were NER deficient,” says Mouw.

Now, he and his team are pursuing clinical trials to treat NER-deficient bladder cancer patients with irofulven, with hopes of making the drug a substitute for some of the patients who can’t tolerate cisplatin. Meanwhile, the scientists continue to identify specific therapeutic vulnerabilities of bladder cancers deficient in either NER or another DNA repair pathway.

The recent paper ran in Clinical Cancer Research alongside similar preclinical findings from Memorial Sloan Kettering Cancer Center — in which irofulven was shown to successfully shrink or eliminate NER-deficient bladder tumors. Mouw’s study was conducted in close collaboration with other labs at Dana-Farber and at Fox Chase Cancer Center.