| Reference | 1. Blood. 2017 Dec 12. pii: blood-2017-08-802470. doi: 10.1182/blood-2017-08-802470. [Epub ahead of print]<br />
Activity of the PI3K-δ,γ inhibitor duvelisib in a phase I trial and preclinical models of T-cell lymphoma.<br />
Horwitz SM(1), Koch R(2), Porcu P(3), Oki Y(4), Moskowitz A(1), Perez M(1), Myskowski P(1), Officer A(5), Jaffe JD(5), Morrow SN(2), Allen K(6), Douglas M(6), Stern H(6), Sweeney J(6), Kelly P(6), Kelly V(6), Aster JC(7), Weaver D(8), Foss FM(9), Weinstock DM(10).<br />
Author information:<br />
(1)Memorial Sloan Kettering Cancer Center, New York, NY, United States. (2)Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States. (3)The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States. (4)MD Anderson Cancer Center, Houston, TX, United States. (5)Broad Institute of Harvard and MIT, Cambridge, MA, United States. (6)Infinity Pharmaceuticals, Inc., Cambridge, MA, United States. (7)Brigham and Women/'s Hospital and Harvard Medical School, Boston, MA, United States. (8)Verastem Pharmaceuticals, Needham, MA, United States. (9)Yale University Cancer Center, New Haven, CT, United States. (10)Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, United States; [email protected].<br />
Duvelisib (IPI-145) is an oral inhibitor of phosphoinositide-3-kinase (PI3K)-δ/γ isoforms currently in clinical development. PI3K-δ/γ inhibition may directly inhibit malignant T-cell growth, making Duvelisib a promising candidate for patients with peripheral (PTCL) or cutaneous (CTCL) T-cell lymphoma. Inhibition of either isoform may also contribute to clinical responses by modulating nonmalignant immune cells. We investigated these dual effects in a TCL cohort from a Phase 1, open-label study of Duvelisib in patients with relapsed or refractory PTCL [n=16] and CTCL [n=19], along with in vitro and in vivo models of TCL. The overall response rates in patients with PTCL and CTCL were 50.0% and 31.6%, respectively (p=0.32). There were 3 complete responses, all among patients with PTCL. Activity was seen across a wide spectrum of subtypes. The most frequently observed Grade 3 and 4 adverse events were transaminase increases (40% ALT, 17% AST), maculopapular rash (17%) and neutropenia (17%). Responders and non-responders had markedly different changes in serum cytokine profiles induced by Duvelisib. In vitro, Duvelisib potently killed 3 of 4 TCL lines with constitutive phospho-AKT (pAKT) versus 0 of 7 lines lacking pAKT (p=0.024) and exceeded cell killing by the PI3K-δ-specific inhibitor Idelalisib. Administration of Duvelisib to mice engrafted with a PTCL patient-derived xenograft resulted in a shift among tumor-associated macrophages from the immunosuppressive M2-like phenotype to the inflammatory M1-like phenotype. In summary, Duvelisib demonstrated promising clinical activity and an acceptable safety profile in relapsed/refractory TCL, as well as preclinical evidence of both tumor cell-autonomous and immune-mediated effects.<br />
2. Expert Opin Investig Drugs. 2017 May;26(5):625-632. doi: 10.1080/13543784.2017.1312338. Epub 2017 Apr 13.<br />
Duvelisib: a phosphoinositide-3 kinase δ/γ inhibitor for chronic lymphocytic leukemia.<br />
Vangapandu HV(1), Jain N(2), Gandhi V(1).<br />
Author information:<br />
(1)a Department of Experimental Therapeutics , The University of Texas MD Anderson Cancer Center , Houston , TX , USA. (2)b Department of Leukemia , The University of Texas MD Anderson Cancer Center , Houston , TX , USA.<br />
INTRODUCTION: Frontline chemotherapy is successful against chronic lymphocytic leukemia (CLL), but results in untoward toxicity. Further, prognostic factors, cytogenetic anomalies, and compensatory cellular signaling lead to therapy resistance or disease relapse. Therefore, for the past few years, development of targeted therapies is on the rise. PI3K is a major player in the B-cell receptor (BCR) signaling axis, which is critical for the survival and maintenance of B cells. Duvelisib, a PI3K δ/γ dual isoform specific inhibitor that induces apoptosis and reduces cytokine and chemokine levels in vitro, holds promise for CLL. Areas covered: Herein, we review PI3K isoforms and their inhibitors in general, and duvelisib in particular; examine literature on preclinical investigations, pharmacokinetics and clinical studies of duvelisib either as single agent or in combination, for patients with CLL and other lymphoid malignancies. Expert opinion: Duvelisib targets the PI3K δ isoform, which is necessary for cell proliferation and survival, and γ isoform, which is critical for cytokine signaling and pro-inflammatory responses from the microenvironment. In phase I clinical trials, duvelisib as a single agent showed promise for CLL and other lymphoid malignancies. Phase II and III trials of duvelisib alone or in combination with other agents are ongoing.<br />
3. Leukemia. 2015 Sep;29(9):1811-22. doi: 10.1038/leu.2015.105. Epub 2015 Apr 28.<br />
The phosphoinositide-3-kinase (PI3K)-delta and gamma inhibitor, IPI-145 (Duvelisib), overcomes signals from the PI3K/AKT/S6 pathway and promotes apoptosis in CLL.<br />
Balakrishnan K(1)(2), Peluso M(3), Fu M(2), Rosin NY(2), Burger JA(2), Wierda WG(2), Keating MJ(2), Faia K(3), O/'Brien S(2), Kutok JL(3), Gandhi V(1)(2).<br />
Author information:<br />
(1)Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (2)Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (3)Infinity Pharmaceuticals Inc., Cambridge, MA, USA.<br />
The functional relevance of the B-cell receptor (BCR) and the evolution of protein kinases as therapeutic targets have recently shifted the paradigm for treatment of B-cell malignancies. Inhibition of p110δ with idelalisib has shown clinical activity in chronic lymphocytic leukemia (CLL). The dynamic interplay of isoforms p110δ and p110γ in leukocytes support the hypothesis that dual blockade may provide a therapeutic benefit. IPI-145, an oral inhibitor of p110δ and p110γ isoforms, sensitizes BCR-stimulated and/or stromal co-cultured primary CLL cells to apoptosis (median 20%, n=57; P<0.0001) including samples with poor prognostic markers, unmutated IgVH (n=28) and prior treatment (n=15; P<0.0001). IPI-145 potently inhibits the CD40L/IL-2/IL-10 induced proliferation of CLL cells with an IC50 in sub-nanomolar range. A corresponding dose-responsive inhibition of pAKT(Ser473) is observed with an IC50 of 0.36 nM. IPI-145 diminishes the BCR-induced chemokines CCL3 and CCL4 secretion to 17% and 37%, respectively. Pre-treatment with 1 μM IPI-145 inhibits the chemotaxis toward CXCL12; reduces pseudoemperipolesis to median 50%, inferring its ability to interfere with homing capabilities of CLL cells. BCR-activated signaling proteins AKT(Ser473), BAD(Ser112), ERK(Thr202/Tyr204) and S6(Ser235/236) are mitigated by IPI-145. Importantly, for clinical development in hematological malignancies, IPI-145 is selective to CLL B cells, sparing normal B- and T-lymphocytes.<br />
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