Metabolic Imbalances Linked to Cancer Therapy Resistance

series of test tubes

Immune checkpoint inhibitors (ICIs), or blockers, have revolutionized the way some cancer patients are treated. However, effects of these treatments can vary from patient to patient. In some cases, cancer cells and/or the tumor microenvironment can adapt to resist the therapy, leading to poorer outcomes and shorter survival.

Researchers at Dana-Farber/Brigham and Women’s Cancer Center (DF/BWCC), in collaboration with the Broad Institute of MIT and Harvard, are seeking to learn how metabolic imbalances are part of adaptive resistance mechanisms found in patients treated with PD-1 checkpoint inhibitors.

In a study recently published in Nature Communications, the researchers identified a negative correlation between survival of kidney cancer and melanoma patients treated with nivolumab, one such PD1-inhibitor, and an increase in the conversion of the amino acid tryptophan to the metabolite kynurenine. The greater the change, the larger the impact on survival. Lead investigators of the study were Toni K. Choueiri, MD, and Marios Giannakis, MD, PhD, of DF/BWCC.

“Metabolism is important in immunity,” Dr. Giannakis explained. “Our study set out to assess previously underappreciated connections between metabolism and immunotherapy, an exciting area for investigation. We found that, kynurenine, which is known to be immunosuppressive, was elevated in the majority of the patients treated with nivolumab.”

A New Way to Identify Biomarkers

A number of genetic “signatures,” including mutations found in a tumor’s DNA, are associated with response to checkpoint blockers. The metabolic alteration “signatures” that Dr. Choueiri, Dr. Giannakis and their colleagues evaluated can be measured by taking blood samples—a significant advantage over more-invasive tissue-based tests.

In the study, the researchers analyzed blood samples from three independent immunotherapy trials (two Phase I trials and a large, randomized Phase III trial) and measured changes in metabolites before treatment started and at several points during treatment. The metabolites studied are involved in the metabolism of amino acids, nucleotides, nitrogen and lipids, among others.

In the melanoma patients, 78 percent had increases in the tryptophan-to-kynurenine conversion and 26.5 percent had increases of greater than 50 percent at week four of treatment. In the kidney cancer patients, nivolumab treatment was also associated with increases in kynurenine.

“The analysis showed that melanoma and kidney cancer patients with higher levels of tryptophan-to-kynurenine conversion on nivolumab had worse survival,” Dr. Choueiri said.

He pointed to the study’s finding that individuals with melanoma whose blood tests showed a greater than 50 percent increase in the kynurenine-to-tryptophan ratio had a mean survival of 15.7 months, while those with decreases in this ratio had a mean survival time of more than 39 months. The respective number for patients with kidney cancer were 16.7 and 31.3 months.

Collaboration Counts

Dr. Choueiri praised the team that helped Dr. Giannakis and him publish their findings in the highly visible Nature Communications. “We had a multidisciplinary group with a wide range of expertise in the areas of translational research, clinical trials, immunology, metabolomics, genomics and biomarkers,” he said.

“We had the Broad Institute’s expertise in metabolomics, Dana-Farber Cancer Institute’s and Brigham and Women Hospital’s superior clinical care, together with next-generation technologies, analytics and the ability to link our research with large national trials,” Dr. Giannakis added. “It was sort of a perfect storm of collaboration.”

Future Research on IDO Pathway

Drs. Choueiri and Giannakis said their findings are too preliminary to begin affecting patient care now but do provide valuable insights for future research. Their next step will be to further investigate the role of the enzymes IDO (indoleamine-2,3-diosygenase) and TDO (tryptophan 2,3-dioxygenase), which have been implicated in many forms of cancer and play a major role in synthesizing kynurenine from tryptophan. They plan to study whether combining checkpoint blockers with IDO/TDO inhibitors can benefit a selected group of patients with checkpoint-inhibition-triggered kynurenine pathway activation.

“Our findings have implications for the design and interpretation of novel combination therapies involving checkpoint inhibition and immunotherapies that target metabolites,” Drs. Choueiri and Giannakis wrote in the paper.

“We believe this initial research will lead to improved design and patient selection for future immune therapy trials,” Dr. Choueiri added. “However, as with all immunotherapy, we are not expecting a one-size-fits-all solution.”

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