Abstract IA19: Targeting PI3K-δ and PI3K-γ in hematological malignancies with duvelisib (IPI-145)

PI3K-δ and PI3K-γ isoforms are preferentially expressed in leukocytes where they have distinct and mostly non-overlapping roles in immune cell function and important roles in the biology of B-cell neoplasms. Duvelisib (IPI-145), a potent, orally available, small molecule inhibitor of PI3K-δ and PI3K-γ, was designed to investigate the hypothesis that simultaneous inhibition of these two specific isoforms would demonstrate broad adaptive and innate immune cell inhibitory activity and enhanced efficacy in hematologic malignancies as well as inflammatory and autoimmune diseases. Biochemical, target occupancy, cellular, and whole blood assays indicate that the inhibition of both the PI3K-δ and PI3K-γ isoforms with duvelisib can be accomplished effectively at clinically relevant concentrations. Duvelisib displays single-agent activity across a spectrum of hematologic neoplasm cell lines and potently inhibits the in vitro proliferation of primary human CLL cells. In certain tumor cell lines, the combination of isoform selective PI3K-δ and PI3K-γ inhibitors demonstrated synergy, suggesting that combined inhibition of both PI3K-δ and PI3K-γ results in greater growth suppression than the inhibition of either isoform alone. In addition, a high throughput combination screen demonstrates synergy between duvelisib in combination with multiple classes of approved and investigational compounds in hematologic malignancies represented by a broad panel of tumor cell lines. Duvelisib is currently in late-stage development for the treatment of hematologic malignancies including iNHL and CLL. Inhibition of both the PI3K-δ and PI3K-γ isoforms targets the malignant cells as well as their microenvironment, suggesting a rationale for the favorable response rates reported in iNHL and CLL patients administered duvelisib. Citation Format: Julian Adams. Targeting PI3K-δ and PI3K-γ in hematological malignancies with duvelisib (IPI-145). [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA19.