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research overview Dr. Perry's studies stem cells, cancer, immunology, and experimental therapeutics. While these seem like disparate fields, the lab has found surprising connections between them. Regarding stem cells, they study how normal blood-forming (hematopoietic) stem cells expand by making more of themselves, a process called self-renewal. They found that self-renewal was guided by the simultaneous activation of two genetic signaling pathways, Wnt/beta-catenin and PI3K/Akt. Pharmacological activation of these pathways drives the expansion of HSCs in culture, which are expected to be useful for therapy. In studying self-renewal, they made a mouse model that permanently activated the genetic pathways mentioned above by mutation. This resulted in the development of leukemia stem cells (LSCs), which are resistant to therapy and cause relapse. Since LSCs are particularly reliant on the interaction between Akt and beta-catenin, they did a high-throughput drug screen to discover inhibitors of this interaction. Surprisingly, a long-used chemotherapy drug, doxorubicin, would inhibit this interaction at very low doses. So, they repurposed doxorubicin as a targeted therapy against LSCs rather than a broadly toxic drug. By investigating the mechanism underlying doxorubicin's ability to target LSCs, they found that low-dose but not high-dose doxorubicin activated anti-cancer immunity. They are currently studying the details of this process and how they might 'immunize' pediatric patients against cancer relapse.

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