Andrew Hong, MD, a pediatric oncologist at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, has cared for a number of children who develop unusual, aggressive cancers. One teenager with a deadly 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.”
Not much is known about RMC. It appears to be associated with sickle cell trait, which stems from a mutation in a single copy of the hemoglobin gene and protects people from malaria. (Full-blown sickle cell disease emerges in those who inherit two copies of the mutation.)
The teenager’s death spurred Hong to scrutinize RMC in the laboratory: What makes the tumor 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?
Undercutting tumor growth
Now, Hong and his colleagues, including scientists at Boston Children’s Hospital and the Broad Institute, report one Achilles’ heel that may be amenable to treatment.
In a recent issue of eLife, they show how loss of a key gene leaves RMC tumors exquisitely dependent on a vital cellular housekeeping apparatus, known as the ubiquitin-proteasome system. Drugs that inhibit this machinery can thwart tumor growth in laboratory models of RMC, the team reports. Moreover, these drugs are already FDA-approved for the treatment of other adult cancers.
A lot of clinical testing has already been done on proteasome inhibitors.
“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.”
RMC and SMARCB1
Initial genetic studies of RMC tumors had suggested that a key tumor suppressor gene, SMARCB1, is inactivated.
Hong and his colleagues created cellular models of RMC using patient-derived tumor cells. When they harnessed whole-genome sequencing to survey the landscape of aberrant genes, they confirmed the loss of SMARCB1 and showed that the cells depend on the gene’s loss for their survival.
A trio of complementary, large-scale approaches — RNA interference, CRISPR-Cas9 genome editing, and small molecule screening — revealed the ubiquitin-proteasome system as a critical vulnerability resulting from SMARCB1 loss. Additional experiments confirmed this finding: when RMC cells are exposed to ixazomib, a type of proteasome inhibitor, they die.
Further laboratory studies as well as clinical trials are needed before this discovery can be applied to pediatric cancer care. But 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. See the paper for a full list of authors and funders. This post is lightly adapted from the Dana-Farber blog Insight.
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