Targeting lactate with the epilepsy drug stiripentol may reverse chemotherapy resistance in patients with gastric cancer, according to a recent study published by Chen et al in Nature.
Background
Chemotherapy attacks cancer cells by damaging their DNA. The cancer cells then try to rapidly repair the DNA to survive and continue growing.
Lactate is the product that builds up as cancer cells convert nutrients like glucose into energy through a process called glycolysis. During glycolysis—when there is limited oxygen—glucose is converted into pyruvate and then lactate by the LDHA enzyme.
Stiripentol was designed to target lactate production by inhibiting the LDHA enzyme from functioning.
Study Methods and Results
In the recent study, researchers examined tissue samples from 24 patients with gastric cancer—15 of whom were resistant to chemotherapy and had tumors that were progressing after treatment. They analyzed the role lactate may play in repairing cancer cells’ DNA following chemotherapy and discovered that lactate was most abundant in the chemotherapy-resistant cancer tissues.
The researchers then targeted the LDHA enzyme with stiripentol in a mouse model in order to determine whether preventing a build-up of lactate could prolong the efficacy of chemotherapy. In the mice with gastric cancer, stiripentol and chemotherapy reduced the size of tumors—a response that continued to last for 4 weeks after treatment. The tumors of the mice treated with chemotherapy alone shrank for 1 week before starting to grow again.
Additionally, the mice treated with stiripentol and chemotherapy survived for longer than those treated with chemotherapy alone. Treated with chemotherapy alone, none of the mice survived for longer than 40 days following treatment; whereas those receiving the combination therapy survived for more than 70 days.
The researchers revealed that lactate may be responsible for altering the structure and efficiency of the NBS1 protein involved in DNA repair. They examined samples from 94 patients with gastric cancer prior to receipt of chemotherapy and found that higher levels of NBS1 alteration, the NBS1 protein, and the LDHA enzyme were all associated with poorer postchemotherapy prognoses.
The researchers proposed that lactate may be responsible for chemotherapy resistance in other cancer types, since levels of the LDHA enzyme are increased in pancreatic, lung, and ovarian cancers.
Conclusions
The researchers highlighted that stiripentol demonstrated its ability to resensitize tumors to chemotherapy, shrink tumors, and prolong survival in a preclinical trial.
“This extremely promising research has uncovered a likely mechanism for how cancer evades chemotherapy. The discovery that cancer cells create energy in a process that causes a build-up of lactate won the Nobel prize in 1931. What we have now found, almost 100 years later, is that lactate has a fundamental impact on cancers’ ability to survive, as it boosts the DNA repair process after it has been damaged by chemotherapy treatment,” emphasized co–study author Axel Behrens, PhD, Professor of Stem Cell Biology at The Institute of Cancer Research in London. “In our early-stage study we’ve seen that you can prevent the build-up of lactate and make a tumor that was resistant to chemotherapy become sensitive again; the treatment continues to work. The next step is to test this in a clinical trial, and it would be wonderful if we see the same results … and give [patients] with cancer precious extra time living well. As we already have a drug to target lactate in clinical use, this discovery could reach patients even sooner,” he suggested.
Clinical trials have been initiated to evaluate whether stiripentol can make chemotherapy effective again in patients with treatment-resistant gastric cancer.
“Drug resistance remains one of the biggest challenges we face in treating cancer. While chemotherapy is effective for many patients, we need to stay one step ahead to prevent cancer becoming resistant to it,” underscored Kristian Helin, MSc, PhD, Chief Executive Officer at The Institute of Cancer Research. “It’s clear now that some patients will require a combination of therapies to keep their cancer at bay, and this study indicates an interesting new drug target that could keep chemotherapy working for longer. I look forward to seeing this research taken into clinical trials to see if it could improve the outcome for [patients] with [gastric] cancer—and hopefully other cancers, too,” he concluded.
Disclosure: The research in this study was supported by funding sources in China and by The Institute of Cancer Research. For full disclosures of the study authors, visit nature.com.
