High-Throughput Small-Molecule Screening Reveals Novel Vulnerabilities for Pediatric Rhabdoid Tumor
OBERLICK-DISSERTATION-2018.pdf (11.23Mb)(embargoed until: 2022-05-01)
Oberlick, Elaine Marie
MetadataShow full item record
CitationOberlick, Elaine Marie. 2018. High-Throughput Small-Molecule Screening Reveals Novel Vulnerabilities for Pediatric Rhabdoid Tumor. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractPediatric rhabdoid tumor (RT) is a rare but highly aggressive cancer of early childhood. The median age of onset is 11 months, and the disease has a high mortality within one year of diagnosis. Tumors arise in various soft tissues including kidney, brain and liver.
The cell of origin for RT is unknown, and this cancer has a very low mutational burden. The sole recurrent genomic alteration is biallelic inactivation and loss of expression of either SMARCB1, a potent tumor suppressor that encodes the SNF5/BAF47/INI1 protein, or much less frequently SMARCA4 (encoding BRG1), both members of the SWI/SNF chromatin-remodeling complex, also known as BAF (BRG1-Associated Factors).
There are few effective treatments, and, due to the lack of recurrent targetable mutations, a pressing need for new therapies.
To discover new vulnerabilities in RT, we mined data from a high-throughput small-molecule screen of 481 compounds screened against 887 cancer cell lines. A library of FDA-approved compounds was tested in 16-point concentration curves in cancer cell lines derived from 25 different adult and pediatric lineages, including nine RT lines.
Using concentration-response curves for all cell lines with all drugs we calculated area-under-concentration-response curves (AUCs) to measure sensitivity. We normalized AUCs for each small-molecule across all cancer cell lines by calculating a robust z-score using the median absolute deviation. We then identified small-molecules that showed selectivity for RT lines relative to all other cancer cell lines, hypothesizing that such molecules would reveal unique vulnerabilities of RT.
This approach revealed several promising classes of therapeutics, including RTK inhibitors, with potent activity against RT models. We validated these findings in the original RT cell lines as well as six additional RT cell lines to provide a robust representation of rhabdoid tumors from all tissue types, and explored the biological and mechanistic basis of these vulnerabilities in vitro as well as in vivo. These results provide support for further testing and translation to the clinic.
Citable link to this pagehttp://nrs.harvard.edu/urn-3:HUL.InstRepos:41127179
- FAS Theses and Dissertations