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Defining PIK3R5-related PI3K gamma dependency as a novel therapeutic target in blood cancers including BPDCN

Dr. Luo

Qingyu Luo


Dana-Farber Cancer Institute

Project Term: July 1, 2022 - June 30, 2025

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive blood cancer without adequate treatment. In a genome-wide CRISPR interference screen, BPDCN was highly dependent on the PI3Kγ pathway and specifically the PIK3R5 adaptor subunit. A subset of leukemias may share this vulnerability. We will interrogate the mechanism of this unique dependency and integrate PIK3R5/PI3Kγ targeting with leukemia therapy. Our goal is to provide novel treatments for PIK3R5-dependent malignancies.

Lay Abstract

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is usually considered an aggressive AML subtype but it also has similarities to other blood cancers. This lack of understanding of the basic biology of BPDCN is limiting patients from getting the best treatments. Survival for BPDCN patients is only on the order of months, but it has not received the same amount of research attention as other aggressive cancers with similar lethality. Thus, it is urgent to figure out what makes BPDCN more severe than other leukemias and to explore new treatment methods. The increased growth and survival ability of cancer cells are usually driven by abnormal cell signaling pathways, which is how cells normally respond to their environment. Many successes have been made to inhibit well-explored cell signaling pathways in the treatment of human cancers. However, a pathway named PI3Kγ involving genes called PIK3R5 and PIK3CG is not as well studied. Through a cutting-edge CRISPR interference technology that can test the function of each gene in the whole human genome simultaneously, we found that BPDCN is uniquely dependent on PIK3R5 and its partner PIK3CG. This was a surprise, because only a small number of other cancers (all blood cancers) are dependent on PIK3R5. We confirmed that a PI3Kγ blocking drug can suppress BPDCN cells more effectively than in other AML cells. In this project, we will ask why PIK3R5 and PI3Kγ signaling are only important for BPDCN and a few other cancers. We will also study how blocking this pathway can combine with other drugs we already use in patients to achieve a better treatment outcome. The results of this work will provide previously unknown knowledge of how PI3Kγ makes BPDCN grow aggressively. The impact of this work might also extend to other leukemias and lymphomas that have high PIK3R5 expression and dependency. Thus, this project raises future possibility of targeting PI3Kγ signaling for the treatment of a broader but scientifically defined group of blood cancers.

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