• Can understanding glutamine’s role in renal cancer cell metabolism lead to successful treatments for renal and other cancers? Othon Iliopoulos, MD and team have modeled precisely how cancer cells use glutamine to sustain metabolism at the molecular level in human clear cell renal carcinomas.

New Combination Therapy for Renal Cell Carcinoma

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Can understanding glutamine’s role in renal cancer cell metabolism lead to successful treatments for renal and other cancers?

Cancer cell metabolism has only recently become a major subject of study for cancer researchers hunting for cures. Hypoxia, or a shortage of oxygen, is a hallmark of human cancer cells. But because oxygen is critical to cell growth, cancer cells tend to adapt by reprogramming cell metabolism. In particular, researchers have recently learned that these cells rely on amino acid glutamine instead of glucose to metabolize carbon.

Now, for the first time, Othon Iliopoulos, MD, of Massachusetts General Hospital Cancer Center, and a team of researchers have modeled precisely how cancer cells use glutamine to sustain metabolism at the molecular level in human clear cell renal carcinomas. They then used these findings to develop a combination therapy that arrests tumor growth almost completely—not just in renal cancer but potentially in colon, breast and ovarian cancers. Their findings were published in the Journal of Clinical Investigation’s March 28, 2017, issue.

“We knew that without glutamine sometimes [cancer cells] die—or sometimes they don’t die, they just don’t grow. But we didn’t know the biochemical consequences that caused these kinds of disturbances in the cell,” said Dr. Iliopoulos, clinical director of the von Hippel-Lindau Disease/Familial Renal Cell Cancer Program at Mass General Cancer Center. “This is what we set out to understand. What specifically goes wrong if we deprive the cells of glutamine?”

Models for Treatment via HIF

Renal cell carcinomas were chosen as a target of study because although they are not typically hypoxic, they act like hypoxic cells because they carry a mutation in the von Hippel-Lindau (VHL) tumor suppressor gene. Cell metabolism reprogramming in cancer cells is typically orchestrated by a transcription factor called hypoxia inducible factor (HIF). HIF can also be activated by many cancer-associated mutations, such as a VHL mutation, which renders the cells VHL deficient. HIF is a major driver of VHL-deficient renal cancer carcinomas and contributes significantly to the growth of many cancers in addition to renal cancer.

Using a series of classic cell assays, Dr. Iliopoulos and his colleagues found that glutaminase inhibitors, or GLS1, suppress the growth of renal cancer cells that are deficient in VHL, mainly through DNA replication stress. In the absence of glutamine, the cells were unable to produce certain DNA building blocks called pyrimidines, making it impossible for the cells to duplicate their DNA. The application of GLS1 also enhanced the production of reactive oxygen species, or ROS, which independently caused DNA replication stress. When Dr. Iliopoulos and his team then filled these GLS1-inhibited cells with the pyrimidine nucleotides, the replication stress was mostly reversed.

Their next step was to see what happened if they prevented the cells from repairing the resulting DNA damage. They tested a combination treatment on the renal cancer cells using GLS1 plus olaparib, an inhibitor of the enzyme poly ADP ribose polymerase (PARP), which plays a role in DNA repair. While either of the two inhibitors in isolation slowed tumor growth, the combination treatment almost completely paralyzed growth of the renal carcinomas.

It very pleasantly surprised us that the cells were that sensitive to these manipulations.

Othon Iliopoulos, MD
Clinical Director, von Hippel-Lindau Disease/Familial Renal Cell Cancer, Massachusetts General Hospital Cancer Center; Associate Professor of Medicine, Harvard Medical Schoo

Their findings provide a model for treatment of other types of tumors that feature hypoxia or cancerassociated mutations that activate HIF—and possibly also for cancers that show defects in DNA repair pathways. So far Dr. Iliopoulos and his team have had success arresting growth in ovarian, prostate and breast cancers, both in lab cultures and in mouse models. They have already developed an umbrella clinical protocol for treatment of all four cancer types—renal, ovarian, prostate and breast—and are working on obtaining approval for clinical trials now.


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