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Jun 26, 2014
 |  BC Innovations  |  Targets & Mechanisms

PI3K inhibition: solid immunotherapy

Until now, inhibition of phosphoinositide 3-kinase-d in cancer has been limited to leukemias and lymphomas because the isoform is only expressed on immune cells. A new finding that links the kinase to T cell responses in a range of solid tumor types could expand use of the inhibitors and launch a new class of immunotherapies.1

The team behind the study is planning a clinical trial of an undisclosed phosphoinositide 3-kinase-d (PI3Kd) inhibitor in solid tumors.

PI3Kd is one of four PI3K isoforms that play key roles in cell growth, differentiation and survival. The PI3Kα and PI3Kb isoforms are expressed in nearly all cell types and have been targeted in solid tumors, whereas the PI3Kg and PI3Kd isoforms are found primarily on immune cells.

Several companies are developing inhibitors of PI3Kd for hematological malignancies, autoimmune diseases and inflammatory indications in which the isoform is overactive (see "A peek at PI3K inhibitors").

In a series of studies over the last decade, the team's principal investigators, Bart Vanhaesebroeck and Klaus Okkenhaug, studied a mutant, catalytically inactive form of PI3Kd and showed the subtype to be important for the differentiation, expansion and normal function of T and B cells.2-5

Vanhaesebroeck is a professor of cell signaling at the University College London Cancer Institute, and Okkenhaug is group leader in the laboratory of lymphocyte signaling and development at the Babraham Institute.

Vanhaesebroeck told SciBX that for the new study, he and his colleagues initially thought that because mice with mutant Pi3kd have compromised immune responses, they might be more prone to developing solid cancers than wild-type mice.

However, when the researchers established tumors in mutant Pi3kd mice with cells from breast, lung and other solid tumors, they saw the opposite of what they expected. The mutant mice developed smaller primary tumors and fewer metastases and survived longer than wild-type mice given the same treatment.

In addition, PI-3065-a PI3Kd inhibitor from Roche's Genentech Inc. unit-decreased growth of breast and pancreatic tumors in...

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