New study exposes key vulnerability of rare pediatric kidney tumor, reveals potential treatment

Andrew Hong, MD, knows the toll of rare childhood cancers all too well. As a pediatric oncologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, he’s cared for a number of children who develop unusual, aggressive cancer. One teenager with a deadly type of kidney cancer called renal medullary carcinoma (RMC) left a particularly deep impression on him and his colleagues.

“Seeing how quickly this patient succumbed to the disease really impacted me,” says Hong. “It’s a rare cancer and we don’t have a deep understanding of it. We used everything we had — chemotherapy, radiation, and surgery — but unfortunately, it wasn’t enough.”

The experience spurred Hong to scrutinize RMC in the laboratory: What makes the tumors tick on a biological level? Are there vulnerabilities — the molecular equivalent of Achilles’ heels — that could be exploited to engineer more effective treatments for this devastating cancer?

Now, he and his colleagues, including scientists at Boston Children’s Hospital and the Broad Institute, have published their findings in a recent issue of eLife, revealing how loss of a key gene leaves RMC tumors exquisitely dependent on a vital cellular housekeeping apparatus, known as the ubiquitin-proteasome system (UPS). Drugs that inhibit this machinery, which are already FDA-approved for the treatment of others forms of adult cancer, can thwart tumor growth in laboratory models of RMC, the team reports.

“What is really exciting is that a lot of clinical testing has already been done on proteasome inhibitors in other forms of adult cancer,” says Hong. “So, we think these will help teach us about what approaches might work best, particularly in children, as we now begin to think about a clinical trial for pediatric RMC.”

Andrew Hong, MD.
Andrew Hong, MD.

Although not much is known about RMC, it appears to be associated with sickle cell trait — a condition that protects people from malaria and stems from a mutation in a single copy of the hemoglobin gene. (Full-blown sickle cell disease emerges in those who inherit two copies of the mutant hemoglobin gene.) Initial genetic studies of RMC tumors suggested that a key tumor suppressor gene, SMARCB1, is inactivated.

Hong and his colleagues created cellular models of RMC using patient-derived tumor cells and harnessed whole-genome sequencing to survey the landscape of aberrant genes. Notably, they confirmed the loss of SMARCB1 and also demonstrated, through biochemical and functional studies, that the cells depend on the gene’s loss for their survival.

Then, using a trio of complementary, large-scale approaches — including RNA interference (RNAi), CRISPR-Cas9 genome editing, and small molecule screening — the researchers homed in on UPS as a critical vulnerability that unfolds as a result of SMARCB1 loss. Additional experiments confirmed this finding: when RMC cells are exposed to the drug ixazomib, a type of proteasome inhibitor, they die.

While further studies in the laboratory as well as clinical trials are needed before this discovery can be applied to pediatric cancer care, Hong says it is an important first step. Moreover, there are other rare pediatric cancers, including malignant rhabdoid tumors, atypical teratoid rhabdoid tumors, and epithelioid sarcomas, that harbor mutations in SMARCB1. So the team’s findings suggest that proteasome inhibitors may hold promise for thwarting those cancers, too.

Hong is the first author of the paper and William Hahn, MD, PhD, is the senior author, both of Dana-Farber. Other Dana-Farber co-authors are: Won Jun Kim; Bryan Kynnap; Gabriel Sandoval, PhD; Thomas Howard; Ji Li, PhD; Michelle Tillgren; Abigail Ward; Katherine Labella; Catherine Clinton; Brian Crompton, MD; Katherine Janeway, MD; Ole Gjoerup, PhD;  Pratiti Bandopadhayay, MBBS, PhD; Prafulla Gokhale, PhD; Susan Chi, MD; Elizabeth Mullen, MD; Cigall Kadoch, PhD; Rameen Beroukhim, MD, PhD; and Keith Ligon, MD, PhD.