Last Name

Principle Investigator

Collapse Overview 
Collapse description
Treatment of pediatric cancercurrently involvesthe use of high doses of toxic drugs, which result in severe side-effects. These side-effects result in 80% of long-term pediatric cancer survivors having one or more disabling or life-threatening health conditions by age 45. Secondary cancersunrelated to the originalmalignancycan also occur, and 20% of pediatric cancer patientsdo not survive long-term.Immunotherapy usingimmune checkpoint(IC)inhibitorshas shown great promise recently for certain adult cancers; however, these advances havelargely notbeen applicable to pediatric cancers. Our preliminary studies reveal a path toward changing this. Specifically, we and others have found that the Wnt/ß-catenin and PI3K/Akt pathways cooperatively promote tumorigenesis, stem cell proliferation, and resistance to anti-cancer therapies, including immunotherapy. Doxorubicin (DXR), a long-used chemotherapy drug was unexpectedlyfound to be a specificinhibitor of Akt:ß-catenin interaction at very low doses. We found that Akt-activated ß-catenin binds promoters of multiple IC genes, which are expressed specifically in therapy-resistant leukemia stem cells (LSCs). Thus, we repurposed DXR as a targeted inhibitor rather than a broadly cytotoxic chemotherapy. In contrast tothe typical clinical usage, low-dose DXR treatment inhibitsexpression of multiple ICs and stimulates immunogenic cell death (ICD)in otherwise therapy-resistant LSCs. Unlike other forms of cellular death, ICDcan induceananti-cancer immune response, effectively immunizing against cancer recurrence. Unfortunately, this effect is limited and typically not curative without additionof highly cytotoxic therapy. Here, we will test the hypothesis, supported by preliminary data,that low-dose DXRinitiatesan ICDprogram, the mechanism of whichcan be discovered using cutting-edge whole genomeCRISPR/Cas9-based chemical/genetic screens. This project will construct and validate such a screen to discover antagonists and synergists of ICD vs. therapy resistance. Ultimately, this project willreveal novel therapeutic strategies for harnessing the immune systemto enhance and potentiate the ICD response of low-dose DXR treatment, thus providingdurable, less toxic cures for pediatric cancer.
Collapse researcher role of