A paper “A functional screening of the kinome identifies the Polo-like kinase 4 as a potential therapeutic target for malignant rhabdoid tumors, and possibly, other embryonal tumors of the brain”, which is published in the journal Pediatric Blood & Cancer, identifies a protein kinase as a therapeutic target for rhabdoid tumors.
Malignant rhabdoid tumor is a rare, aggressive tumor that mainly affects infants and toddlers. The tumor usually arises in the kidney but can also arise in other parts of the body such as the brain. Prognosis of patients with malignant rhabdoid tumor is extremely poor that they may die within weeks of being diagnosed. Existing drugs are limited in their therapeutic effect. In this scenario, more effective treatments are in urgent need.
Protein kinases are a group of enzymes that modifies other proteins by adding phosphate groups to them. These enzymes regulate essential aspects of cell function, and mutations and dysregulation of them may cause human disease, including cancer. In this work, the researchers set out to identify kinases associated with rhabdoid tumors.
Using an advanced gene editing technique called CRISPR/Cas9, the team individually mutated 160 kinases in a rhabdoid tumor cell line and monitored these cells. By doing so, they found that the Polo-like kinase 4 (PLK4) most significantly impaired rhabdoid tumor cell growth. PLK4 CRISPR-mutated rhabdoid cells showed a great decrease in proliferation, viability, and survival. Further investigation demonstrated that PLK4 expression is upregulated in rhabdoid tumors and additional embryonal brain tumors.
Based on the findings, the researchers hypothesized that targeting PLK4 with inhibitors might be a way to inhibit rhabdoid tumor growth. They tested a potent PLK4 inhibitor called CFI-4000945 in multiple rhabdoid tumor cell lines, and found that treatment with the inhibitor resulted in significant decrease in cell proliferation, survival, migration, and invasion. On the other hand, experiments in zebrafish showed that CFI-400945 did not harm normal development, suggesting that CFI-400945 might be safe for children. (PLK4 and other molecules like can be offered by Cusabio. http://www.cusabio.com/)
The study is conducted by investigators from Ann and Robert H. Lurie Children's Hospital of Chicago, Stanley Manne Children's Research Institute, Northwestern University, Thermo Fisher Scientific, and Juntendo University.