Exploring the Role of Metabolics in Renal Cell Carcinoma

When examining kidney cancer, clear signs of metabolic derangement at both the macroscopic and microscopic level can be seen, leading groups to perform robust metabolic profiling of kidney cancer.

A safe clinical pipeline has been established to look at metabolism in patients with kidney cancer to add to the research, according to Vitaly Margulis, MD, professor of Urology at University of Texas (UT) Southwestern Medical Center. This method shows what occurs in the metabolism of kidney cancer by infusing heavy carbon labeled molecules into patients, allowing researchers to track the progress through metabolic pathways that are potentially deranged.

At UT Southwestern, over 100 patients with kidney cancer have been infused as a way to understand what happens to the metabolic signature dynamically. This was the first time such a study has been done in humans.

Findings confirmed the oxidation of patients with kidney cancer to be significantly impaired and that this phenotype is reversed in metastatic progression and kidney cancer. With the development of technologies, the hope is to shift from static or metabolic profiling of these tumors to dynamic profiling in order to add versatility to the type of experiments that can be done.

In an interview with Targeted OncologyTM, Margulis discussed the function and findings of metabolomics in renal cell carcinoma (RCC).

Targeted Oncology: Can you provide a brief overview of the role of metabolomics in RCC?

Margulis: We've known for a long time that kidney cancer is very unique and has very specific metabolic derangements that set it apart from other tumors, and my overview is twofold. Number 1 I want to introduce a way to interrogate the metabolic milieu of cancer in a unique way, which is dynamic, and also to share some of the preliminary data that came out of those experiments.

What data do we have so far on the role that this plays in RCC?

There are several studies that look at static metabolic pictures to see what metabolites prevail, the metabolic pattern, or the pattern of metabolic derangements that happened with kidney cancer. Most of these studies looked at the snapshot of metabolic signature in time. Our unique contribution to this field is that we've introduced a way to profile what happens in metabolism of kidney cancer dynamically by infusing heavy carbon labeled molecules so we can track their progress through various metabolic pathways that are potentially deranged and kidney cancer. In this way, we can understand what happens dynamically.

Some of the interesting findings is that we've confirmed for the first time in live patients that the oxidation is significantly impaired in kidney cancer. We've confirmed a sort of so-called Warburg effect that was postulated for many years to happen in cancer. More importantly, it has shown that during the metastasis and kidney cancer, this phenotype is reversed. This is very exciting data because this was the first time that this has been done in humans. The reversal of this phenotype in metastatic progression is also a novel finding.

How has your understanding of this topic changed over the past 5-10 years?

The key here is for the development of technologies to shift from static profiling or metabolic profiling of these tumors to dynamic profiling. That adds tremendous breadth and versatility to the type of experiments that we can do and the data that we can obtain. This is the work that's ongoing. Some of this will be presented by some of the other collaborators that I've been fortunate to work with. It's a very exciting field and it's very exciting technology that we can bring to bear to understand how kidney cancer processes energy.

What is the end goal of the research? What should community oncologists be aware of about the relationship that exists here?

A lot of this work is quite preclinical, but I think we need to understand that kidney cancer is unique. It's metabolic derangements that happen in kidney cancer are unique between subtypes of kidney cancer, but also compared to other malignancies.

The goal is that once you understand the specific derangements and what brings them, it will be possible to essentially reverse the phenotype and essentially starve the tumor. It is important to understand that they are defined and phenotypic derangements that happen in kidney cancer metabolism that are unique to kidney cancer. I think there will be certain targetable interventions that can exploit that.