Ewing sarcoma is a rare cancer of the bone and soft tissue that affects children and young adults. While most newly diagnosed patients with local disease benefit from treatment with a combination of chemotherapy, radiation, and surgery, therapeutic options are bleak for those patients whose disease is metastatic or has relapsed. One of the challenges in developing better treatments for Ewing sarcoma is that very few new drug targets specific for the disease are known. Sara Buhrlage, Kim Stegmaier, and colleagues at the Dana-Farber Cancer Institute have recently identified the deubiquitinating enzyme ubiquitin specific protease 7 (USP7) as a novel therapeutic target for Ewing sarcoma. USP7 affects the ubiquitination pathway — the process by which cells clear out proteins they no longer need. The team has shown that pharmacologically blocking USP7 stabilizes the non-mutated form of tumor suppressor p53 in Ewing sarcoma cell lines and thereby suppresses cell growth. Roughly 90% of pediatric cancer patients have non-mutated p53 in their tumors, so this approach may be useful against other childhood cancers as well.
Buhrlage and her team have discovered small molecule inhibitors that covalently bind to USP7. While their lead molecule, XL177A, potently and selectively blocks the enzymatic activity of USP7 and inhibits the growth of Ewing sarcoma cells in culture, it cannot be developed as a drug because it is rapidly metabolized by the liver. The investigators plan to build on their understanding of how XL177A works to develop next generation drug candidates that are more metabolically stable. They will then test the new molecules for safety and efficacy in animal models and eventually move the most promising ones into clinical trials for Ewing sarcoma.
Schauer NJ, Liu X, Magin RS, Doherty LM, Chan WC, Ficarro SB, Hu W, Roberts RM, Iacob RE, Stolte B, Giacomelli AO, Perera S, McKay K, Boswell SA, Weisberg EL, Ray A, Chauhan D, Dhe-Paganon S, Anderson KC, Griffin JD, Li J, Hahn WC, Sorger PK, Engen JR, Stegmaier K, Marto JA, Buhrlage SJ. Selective USP7 inhibition elicits cancer cell killing through a p53-dependent mechanism. Sci Rep. 2020.
Bushman JW, Donovan KA, Schauer NJ, Liu X, Hu W, Varca AC, Buhrlage SJ, Fischer ES. Proteomics-Based Identification of DUB Substrates Using Selective Inhibitors. Cell Chem Biol. 2020.