2020 Discovery of the Year Awarded to Ricardo Aguiar, MD, PhD

Ricardo Aguiar, MD, PhD

Study of Lymphoma Metabolism Opens a Path to Precision Treatment

Building on their earlier findings, Ricardo Aguiar, MD, PhD, and his colleagues made a breakthrough discovery with their basic biological research on diffuse large B-cell lymphoma (DLBCL), a common and often fatal hematological malignancy.

Dr. Aguiar, professor of medicine and vice chief for research in the Division of Hematology and Medical Oncology for the Long School of Medicine at UT Health San Antonio, explained there are almost 30,000 new cases each year of DLBCL. He decided to concentrate on this specific type of lymphoma because the survival rate has not changed in 20 years.

“The outcome is still not what we wish for; approximately 40 percent of patients will die from their disease. We have been in this same 60 percent survival rate for a long time. The only way to improve the cure rate is to understand the disease better. That is our operation,” he said.

Dr. Aguiar, holder of the Bessie Bell Dean “Bebe” Bowen Cancer Research Endowment, is an MD with clinical training in hematology and oncology, and a PhD in the field of leukemia, with post-doctoral training in lymphoma biology. The research he conducted involved analyzing genetically modified human cells, mouse models of lymphoma, as well as primary tumors from patients.

Published in the May 2020 issue of Cell Chemical Biology, the paper, titled “MYC Regulation of D2HGDH and L2HGDH Influences the Epigenome and Epitranscriptome,” reveals that his team is one step closer to finding new treatments that are more effective and less toxic to patients.

“In this paper, we were able to connect three different ‘players’ – which is what I am calling the genes, pathways or systems – that are important for lymphoma development, progression, and response to therapy. The three players had not been fully connected before, especially in this disease type. That is what makes this paper important,” he said.

Dr. Aguiar identified the first player as the gene called MYC. “This is perhaps the most important gene in lymphoma development. When it becomes activated, it causes lymphoma, and in most patients with lymphoma MYC is abnormal.

“For example, if you create a mouse model with the MYC gene ‘turned on,’ the mouse develops lymphomas nearly 100 percent of the time. It is my opinion, which is shared by many other lymphoma experts, that inhibiting this gene is the holy grail in lymphoma treatment,” he said.

Dr. Aguiar said the second player in their discovery is a “system” called mitochondria metabolism. “Mitochondria are often referred to as the powerhouse of the cell because they are tasked with energy generation. We now know that it does so much more. It is a signaling organelle that produces multiple unique molecules called metabolites, which are essential for the proper functioning of the cell. And these metabolites have the capability of not only generating energy but also activating other parts of the cell including distant enzymes and proteins.

“We were the first to connect MYC to a very specific part of mitochondria metabolism. In brief, we showed that MYC increases the expression of two enzymes – D2HGDH and L2HGDH – in the mitochondria. These two enzymes remove from the cell a deleterious metabolite called 2-hydroxyglutarate and, in the process, generate an important metabolite called alpha-ketoglutarate, which is actually sold as a supplement and popular among bodybuilders and athletes.”

Notably, the researchers found that the newly identified MYC-D2HGDH/L2HGDH-alpha-ketoglutarate axis resulted in the activation of a series of additional enzymes that influence epigenetics, he said.

Epigenetics can be formally described as the study of heritable changes in gene function that do not involve changes to DNA sequence, but rather involve chemical modifications in the DNA, RNA or proteins. In a broad sense, epigenetics is the “third player” connected by the team.

“MYC connects to the mitochondria that connects to epigenetics. We showed more specifically that MYC, by inducing alpha-ketoglutarate production, activates enzymes that decrease the amount of DNA and RNA methylation. In doing so, it modulates a plethora of other genes that can contribute to cancer development,” he said.

This discovery also challenges an existing paradigm in lymphoma biology, Dr. Aguiar explained. “Because one of the genes that we found to be activated through the MYC- mitochondria metabolism interplay, it is actually better known to protect against cancer.

“The existing paradigm is contested because loss of function of that gene is commonly associated with lymphoma. In our system, we found that actually excess function of this gene may also be associated with lymphoma. Thus, we had to figure out, is it an oncogene (a gene that when ‘turned on’ causes cancer) or is it a tumor-suppression gene (a gene that when ‘turned off’ causes cancer). The analysis performed so far indicates that context is essential, and that in the subset of lymphomas in which MYC effectively activates the mitochondria, the oncogene phenotype dominates,” Dr. Aguiar said.

This context dependent presentation is at the core of the idea of precision medicine, in which every tumor is slightly different from the next and eventually the treatment needs to be tailored to a degree that nearly no patient will receive exactly the same treatment, he said. “My guess is that within the next decades, cancer treatment will slowly but surely become uniquely tailored to each person.

“Imagine this tumor that we are studying – diffuse large B-cell lymphoma. Currently, you could take 100 patients, and they all get the same treatment. This is to some extent frustrating because we already know that the tumors are very different across distinct patients. The next step is to develop drugs that are specific enough to tailor the treatment according to the tumor biology; once we have that, the cure rate will increase,” Dr. Aguiar said.

How does this work help on this front? Patients who have this kind of lymphoma have a biopsy performed and the tumor cells can be examined by Dr. Aguiar and his colleagues to demonstrate that the link between the MYC, mitochondria metabolism and epigenetics is present in the tumor. “In this instance, we can attempt to intervene with more targeted treatment approaches. This is not farfetched because there are, for example, ways to modulate mitochondria metabolism. There are drugs that are FDA-approved, although not for this tumor type, which can regulate mitochondria metabolism in cancer. In addition, there are also drugs that can act on the epigenetics side,” he added.

“By identifying the link between these genes and pathways, we expose what I call tumor vulnerabilities. We cannot at present go after MYC, which is the initiating event, because it is still not possible to effectively inhibit that gene. But we may be able to act on the second step which is the mitochondria, and hopefully we can also work on the third step, the epigenome. This is how we transfer basic biology knowledge to the clinical arena. We hope to transform this discovery into potential new treatments,” Dr. Aguiar concluded.

Dr. Aguiar in his lab on the campus of UT Health San Antonio.

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