Instead of relying on single biomarkers, researchers have started to examine overall signatures of many metabolites, which have in some cases yielded success. However, the use of multiple biomarkers could also be a drawback, Dr Raftery explained. “If you start with a signal that depends on a hundred metabolites, that’s really unwieldy to use in a clinic. [And] when you start to narrow it down to just a few biomarkers, you often lose a lot of the performance,” he said.
To Dr Weiss, the main difficulty isn’t necessarily in identifying biomarker or biomarker combinations that correlate with the disease, but finding enough patients to undertake a comprehensive study to validate them. “You need hundreds and hundreds [of patients] to get any reasonable biomarker validation,” he said.
In addition, though many metabolite changes in tissue analyses could be detectable in blood or urine, teasing them out from other metabolic changes in the body can be tricky, Dr Raftery added. “For blood or urine RCC tests, there are some roadblocks — as there are for the other cancers — that will need a technological development or two to get around the general problem of [having] a small cancer signal in a lot of noise that results from a lot of confounding factors,” he said.
Due to these limitations in developing blood- or urine-based prognostic tools, Dr Raftery sees the most promise in the development of tissue-based biomarkers as diagnostic tools, which could complement pathologists’ reports for diagnosis.
However, these are still far from being tested in the clinic, he said, adding that the development on biomarkers in RCC is probably lagging behind the discovery of biomarkers in other cancers, such breast, ovarian, or colon cancers, “because many of the samples for the rare forms of RCC are hard to come by,” he explained.
Where the field of metabolomics has already proven fruitful, however, is the identification of therapeutic targets, Dr Weiss noted. By identifying pathways that are reprogrammed in cancer and not in normal cells, researchers are developing drugs for RCC that target those pathways, he explained. Meanwhile, some metabolomics-derived drugs for other cancers have already reached the clinic, notably Tibsovo® (ivosidenib; Agios), approved by the US Food and Drug Administration in 2018, for patients with newly diagnosed or relapsed or refractory acute myeloid leukemia who have an IDH1 mutation.4 This mutation in 2009 was shown to cause the production of cancer-driving metabolites.5
Nevertheless, researchers are not discouraged from continuing the pursuit of diagnostic or prognostic disease biomarkers for cancer. “There’s an enormous need for earlier detection, therapy monitoring … [and] risk assessment for stratifying patients,” Dr Raftery said. “And I think that metabolomics still has a lot of promise in those areas.”
- Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309-314. [KZ3]
- Gupta A, Nath K, Bansal N, et al. Role of metabolomics-derived biomarkers to identify renal cell carcinoma: a comprehensive perspective of the past ten years and advancements. Expert Rev Mol Diagn. 2020;20(1):5-18.
- Trott JF, Kim J, Abu Aboud O, et al. Inhibiting tryptophan metabolism enhances interferon therapy in kidney cancer. Oncotarget. 2016;7(41):66540-66557.
- Duffy S. Tibsovo approved to treat newly diagnosed AML with IDH1 mutation. Cancer Therapy Advisor. Published May 3, 2019. Accessed February 25, 2020.
- Dang L, White DW, Gross S, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739-744.