Therapeutic Target Identified in Pediatric Rhabdoid Tumors


Using state-of-the-art gene editing technology, researchers have discovered a promising target to treat atypical teratoid/rhabdoid tumor (AT/RT), a highly aggressive and therapy-resistant brain tumor.

Scientists in Chicago are now reporting on a new potential for a precision medicine approach to lethal brain tumors. Using state-of-the-art gene editing technology, they have discovered a promising target to treat atypical teratoid/rhabdoid tumor (AT/RT), a highly aggressive and therapy-resistant brain tumor.

AT/RT mostly occurs in infants. Now, researchers have found that these tumors’ growth and tendency to metastasize are regulated by a protein kinase called Polo-like kinase 4 (PLK4), which is increased in AT/RT. They also have demonstrated that an experimental drug, a PLK4 inhibitor, stopped tumor growth.

In an article published in Pediatric Blood & Cancer, they report that rhabdoid tumor cell proliferation is highly dependent on PLK4 suggesting that targeting PLK4 with small-molecule inhibitors may hold a novel strategy for the treatment of malignant rhabdoid tumors MRTs. In addition, they report this approach may also help combat other embryonal tumors of the brain.

“This is the first time that PLK4 has been described as a therapeutic target for brain tumors or in pediatric cancer,” said lead author Simone Sredni, MD, PhD, who is an 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 in Chicago.

The researchers were able to identify PLK4 as a potential target for treatment by using a novel gene editing technology called CRISPR/Cas9. It allowed the team to mutate individual kinase genes in order to reveal the kinase that most significantly affected tumor cell growth.

The investigators also demonstrated that the PLK4 inhibitor (CFI-400945) was safe for normal tissue, while attacking the cancer cells. Sredni said this agent was able to significantly impair tumor proliferation, survival, invasion, and migration. At the same time, it spared normal cells. This may be a paradigm shift for the treatment of AT/RT and possibly other pediatric brain tumors.

The scientists tested the safety of the drug by exposing zebrafish larvae to extremely high doses of the drug for extended periods of time. They observed that the drug did not affect the fish development, implying that it may be safe to be used in the pediatric population.  

The investigators report that this gene-based approach may pave the way for precision medicine with stratification of patients based on the level of PLK4 expressed in their tumors. The group is currently testing the drug in animal models of AT/RT and other types of brain tumors.

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