Major progress has been made in understanding the origins and development of leukemia. In parallel, dramatic improvements in survival of patients have been achieved, most notably in childhood acute lymphoblastic leukemia (ALL).
This has been accomplished primarily through optimization of conventional chemotherapeutics, now prescribed at the cusp of tolerability. However, there remain subsets of patients, including those with acute myeloid leukemia (AML) and relapsed ALL for whom current therapy is inadequate. The mechanisms of treatment failure remain incompletely understood.
The long-term goal of the Porter Lab is to develop novel, rational combination therapies to improve the outcomes of patients with high-risk leukemias.
To do so we have optimized functional genomic screening using shRNA libraries to identify “escape pathway addictions.” As oncogene and non-oncogene addictions are context dependent (i.e. on the oncogene), we propose that escape pathway addiction becomes relevant in the context of specific therapy for a particular tumor type.
For example, to determine mechanisms of resistance, we performed a genome-wide RNA-interference screen in AML cells to identify synthetic lethality with cytarabine. One of the strongest hits from the screen was Wee1, a cell cycle checkpoint kinase activated in the context of DNA damage.
Much of the current effort in the lab is directed at understanding the role of Wee1 in leukemia cells, as it relates to leukemogenesis and resistance to chemotherapy.
This project is particularly exciting, as there is at least one Wee1 inhibitor in development and clinical trials are being planned. Other projects in the lab include the identification and validation of other escape pathway and non-oncogene addictions.
Porter Lab Members
Christopher Porter, MD
Annemie Van Linden, PhD
Dmitry Baturin, MD, PhD
James Ford, DO
Christy Gearheart, PhD