Phosphoinositide-3 kinase (PI3K) belongs to a class of intracellular lipid kinases that phosphorylate the 3- position hydroxyl group of the inositol ring of phosphoinositide lipids (PIs) generating lipid second messengers. Activation of the PI3K pathway triggers multiple events including cell growth, cell cycle entry, cell survival and motility. While α and β isoforms are ubiquitous in their distribution, expression of δ and γ is restricted to cells of the hematopoietic system. Because these isoforms contribute to the development, maintenance, transformation, and proliferation of immune cells, targeting PI3Kδ and γ represents a promising approach in the treatment of lymphomas. PI3K δ and γ inhibition is also strongly implicated as an intervention treatment in immune cell dysfunction leading to aberrant cytokine and chemokine release. Thus, the added immune-modulating potential of selective PI3Kδ or dual δ/γ inhibitors serves to alter the tumor microenvironment while also controlling abnormal cell growth and expansion.
Lymphoma is one of the major causes of death in adult pets with approximately 1.2 million dogs seeking veterinary care. Treatment for lymphoma in dogs has largely been restricted to chemotherapeutic agents. The scientific evidence for PI3K involvement, in particular the δ and γ isoforms in various cellular processes stems from studies using small molecule inhibitors and gene-targeting approaches. In addition to regulating tumor progression, B-cell proliferation and apoptosis, PI3Kδ and γ modulate several important inflammatory events thereby modulating the tumor microenvironment. Due to genetic similarities between dogs and humans, there is a strong likelihood that the clinical responses would be the same thereby justifying the therapeutic use of the PI3Kδ or δ/γ inhibitors in canine lymphoma.
|Current Status : Phase-2 clinical in dogs|