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PI3K INHIBITION PROGRAM

The phosphoinositide-3-kinase (PI3K) signaling pathway is a key regulator in cancer proliferation and metastasis. The PI3K pathway includes four Class I isoforms: alpha, beta, delta, and gamma ( α, β, δ, and γ). It is increasingly recognized that the four isoforms play unique roles in the survival of different tumor types and in the creation of supportive tumor microenvironments.

The Role of PI3K in B-Cell Malignancies

PI3K-δ and PI3K-γ are primarily expressed in leukocytes such as B cells and T cells, where they have distinct and predominantly non-overlapping roles in key cellular functions, such as cell proliferation, cell differentiation, cell migration and activation.1

PI3K signaling also plays a significant role in supporting the growth and survival of many B-cell malignancies.2-5 PI3K activation is one direct consequence of B-cell receptor (BCR) pathway activation, a critical survival signal for malignant B cells.6 Other key survival factors also transmit signals through PI3K isoforms,2,5,7 reinforcing the dependence of certain B-cell malignancies on PI3K signaling.

Isoforms

 

In conditions like iNHL and CLL, neoplastic B cells rely on the support of non-neoplastic cells within their microenvironment. These support cells—including T cells, myeloid cells, and mesenchymal stromal cells—help sustain the proliferation and survival of malignant B cells.8

The signaling mediated by PI3K-δ and PI3K-γ provides complementary support to both the tumor microenvironment (TME) and the malignant B cell. Within the TME, support cells provide both PI3K-dependent growth and survival signals for the malignant cells, as well as PI3K-dependent signals that maintain the TME itself.9 A dual inhibitor of PI3K-δ,γ such as duvelisib may offer a more integrated approach to PI3K inhibition—one that may both disrupt intracellular PI3K signaling and help dismantle the malignant B-cell TME.

 

[1] Rommel C, Camps M, Ji H. PI3Kδ and PI3Kγ: partners in crime in inflammation in rheumatoid arthritis and beyond. Nat Rev Immunol. 2007;7(3):191-201.
[2] Lannutti BJ, Meadows SA, Herman SE, et al. CAL-101, a p110δ selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability. Blood. 2011;117(2):591-594.
[3] Martinez N, Camacho FI, Algara P, et al. The molecular signature of mantle cell lymphoma reveals multiple signals favoring cell survival. Cancer Res. 2003;63(23):8226-8232.
[4] García-Martinez JM, Wullschleger S, Preston G, et al. Effect of PI3K- and mTOR-specific inhibitors on spontaneous B-cell follicular lymphomas in PTEN/LKB1-deficient mice. Br J Cancer. 2011;104(7):1116-1125.
[5] Hoellenriegel J, Burger JA. Phosphoinositide 3'-kinase delta: turning off BCR signaling in chronic lymphocytic leukemia. Oncotarget. 2011;2(10):737-738.
[6] Davis RE, Ngo VN, Lenz G, et al. Chronic active B-cell-receptor signalling in diffuse large B-cell lymphoma. Nature. 2010;463(7277):88 -92.
[7] Herman SE, Gordon AL, Wagner AJ, et al. Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood. 2010;116(12):2078-2088.
[8] Burger JA, Gribben JG. The microenvironment in chronic lymphocytic leukemia (CLL) and other B cell malignancies: Insight into disease biology and new targeted therapies. Semin Cancer Bio. 2014;24:71-81.
[9] Peluso M, Faia K, Winkler D, et al. Duvelisib (IPI-145) inhibits malignant B-cell proliferation and disrupts signaling from the tumor microenvironment through mechanisms that are dependent on PI3K-δ and PI3K-γ. Presented at: 56th ASH Annual Meeting and Exposition; December 6-9, 2014; San Francisco, CA. Abstract 328.