How do you create a drug for a target that does not exist? This question underlies research on cancers driven by the loss of a gene, like rhabdoid tumors. Eighty percent of these tumors are driven by loss of the gene SMARCB1.
These aggressive cancers are most often found in young children. The tumors can arise in the liver, kidney or parts of the central nervous system. There are 20–25 people diagnosed with malignant rhabdoid tumors in the U.S. each year.
“We used a library of existing drug compounds and CRISPR technology to look for dependencies gene by gene,” he said. “This showed us which targets rhabdoid tumors need to survive.”
Scientists found that a class of drugs called receptor tyrosine kinase inhibitors can slow the growth of rhabdoid tumors. These drugs target growth-factor receptors, including the proteins VEGFR, PDGFR, FGFR and HGFR/MET.
Different receptor tyrosine kinase inhibitors affect different subsets of rhabdoid tumor cell lines. Using immunohistochemistry, pathologists can determine which of these drugs is most likely to benefit each rhabdoid tumor.
Researchers also found that the gene PTPN11 (which encodes the protein SHP2) is needed for rhabdoid tumors to survive. This makes the gene a possible target for therapy.
“This work opened up a lot of options for studying potential therapies for rhabdoid tumors, including inhibitors of SHP2, an important signaling protein downstream of many receptor tyrosine kinases, and combinations of receptor tyrosine kinase inhibitors,” said the study’s first author Elaine Oberlick, PhD. She is a postdoctoral fellow in the Roberts lab, at Dana-Farber Cancer Institute, and the Broad Institute of MIT and Harvard.
Cell Reports published a report on this work.
Research in the Roberts lab was supported in part by the National Institutes of Health (grants R01CA172152 and R01CA113794); the Avalanna Fund; the Cure AT/RT Now Foundation; the Claudia Adams Barr Program; the Garrett B. Smith Foundation; Miles for Mary; and ALSAC, the fundraising and awareness arm of St. Jude.