Precision Medicine Tumor Research

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Targeting the Causes of Infant Brain Tumors

Atypical teratoid/rhabdoid tumors (AT/RTs) are very aggressive brain tumors typically affecting infants under three-years of age. Current treatment protocols include surgery, chemotherapy with multiple drugs, and, when age and individual circumstances allow, radiation therapy. Overall survival rates are poor.

Simone Treiger Sredni, M.D., Ph.D., associate professor of pediatric neurosurgery at Northwestern University Feinberg School of Medicine and cancer researcher at the Stanley Manne Children's Research Institute at Lurie Children's, and her colleagues recently set out to find more effective and less toxic treatments for AT/RT. According to their paper, published in the journal Pediatric Blood & Cancer, they “hypothesized that a systematic screening of the kinome will reveal kinases that drive rhabdoid tumors and can be targeted by specific inhibitors.”

When conventional forms of therapy such as surgery, radiation or chemotherapy are unsafe or ineffective, a relatively new option is to target the signaling pathways that are specific to cancer cells. The result can be a more selective, effective and less toxic therapy. The kinome comprises all existent kinases, which are enzymes that, among other important functions, control cancer cells’ growth and survival and therefore can be “switched-off” when targeted by appropriate drugs (inhibitors). Presumably, once we know which “switched-on” kinases are driving the disease we can switch them off by inhibiting their expression. 

In a significant feasibility study, Sredni and her team used a technique called clustered regularly interspaced short palindromic repeats, better known as CRISPR, to identify potential kinases that could function as therapeutic targets for AT/RTs. With this novel approach, the group discovered that AT/RT have elevated levels of the Polo-like kinase 4 (PLK4) that could be lowered by drugs. Therefore, the use of an inhibitor would “switch-off” this protein causing the tumor cells to stop spreading and die. An experimental inhibitor (drug) currently being tested in adults’ refractory tumors was identified. The drug is now showing to be effective to treat AT/RT in human cells and in animal models of the disease.

“We wouldn’t have found this specific kinase using high-throughput genomics studies,” said Sredni. “This biomarker never appeared in my previous research, probably because the level of expression wouldn’t have been high enough to be detected though biostatistical analysis. Using CRISPR, we were able to functionally evaluate the loss of activity of this specific kinase and detect the effect of a slight loss of expression in the affected cells.” 

After confirming the effectiveness of the PLK4 inhibitor for AT/RTs, Sredni’s team then designed a test to assess its safety in pediatric patients – would it target just the cancer cells with the elevated kinase in question and leave non-affected cells unharmed? To test its toxicity, the team exposed zebrafish larvae to high doses of the PLK4 inhibitor and after prolonged exposure at high concentrations the fish larvae suffered no developmental abnormalities, showing that it should be safe to be used in children.

For Sredni’s team, the arrayed CRISPR libraries provided by Thermo Fisher offered a way to more rapidly and easily understand highly complex biological pathways. This is important because this same easy-to-use array format for CRISPR-Cas9 can enable even less-experienced users to explore other disease areas and gain insights into their molecular pathways and gene functions. This could put more researchers on the case, leading to the development of more targeted (precise) therapies in the future. 

“The tumors I study are notoriously unresponsive to therapy, and the drug we are testing, discovered with the help of CRISPR genome editing technology, has the potential to provide a new therapeutic avenue for children with this disease,” said Sredni. “I have never felt so close to making a contribution that will improve the prognosis of these young patients.” 

The implications of Sredni’s work for precision medicine are clear: If pediatric oncologists can test for levels of PLK4 (or other biomarkers) expressed by a tumor, they may be able to more confidently direct patients to current or future FDA-approved inhibitor therapies. Moreover, the more widespread use of arrayed CRISPR libraries for gene editing, as well as the use of other high throughput tools such as next-generation sequencing (NGS), in specific disease models or individualized patients’ samples paves the way for other researchers to build on the work of Sredni’s team.

dr simone sredni

Dr. Simone Sredni in her lab at the Stanley Manne Children's Research Institute at Lurie Children's

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