Mechanism of Action Magnifier – 2016 Desk Reference

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Duvelisib (IPI-145): a Dual Inhibitor of Phosphoinositide 3-Kinase (PI3K)-Delta and -Gamma

In B-cell malignancies, such as chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma, the malignant B cells rely on a number of internal and external stimuli to survive, such as the activation of the B-cell receptor, cytokine and chemokine signaling, or direct cell-to-cell interactions. Attracted by chemo­kines, including CXCL12 and CXCL13, the malignant B cells migrate into the lymphoid tissue.1,2 Similarly, T cells are recruited by chemokines CCL3, CCL4, and CXCL12, which are derived either directly from the tumor cells or the tumor-associated support cells.1,2 CXCL12 may also be responsible for recruitment and activation of myeloid suppressor cells.1 Once in close proximity, the cells create a tumor microenvironment that helps support tumor cell viability and proliferation through multiple interactions.2

The PI3K Pathway

Many of these interactions result in intracellular signaling via PI3K.2-5 The PI3K pathway is known to play a critical role in regulating the growth and survival of certain types of hematological cancers. The PI3K family includes 4 class isoforms: α, β, γ, and δ. Alpha and beta are ubiquitously expressed. PI3K-delta and -gamma are expressed in both normal and malignant leukocytes, and there is crosstalk between these signals within the tumor microenvironment.6

PI3K-Delta and PI3K-Gamma

The immune expression class 1 PI3K-delta and PI3K-gamma isoforms are restricted to immune cells and have distinct and predominantly non-overlapping roles in key cellular functions, including7:

  • Cell proliferation
  • Cell survival
  • Cell differentiation
  • Cell migration and activation.

Although both PI3K-delta and PI3K-gamma are expressed in the tumor and the tumor-associated support cells, many of the signals in the malignant B cells are mediated via PI3K-delta,8 while signals that promote the migration of T cells to certain chemokines and the differentiation and recruitment of myeloid cells require activation of PI3K-gamma.6

Inhibition of PI3K-delta is one potential approach in helping to reduce tumor survival and proliferation.8 However, some T-cell and myeloid-cell signals may activate PI3K-independent survival pathways in the tumor cells. Therefore, to more completely target the crosstalk in the tumor microenvironment, it is important to inhibit both PI3K-delta and PI3K-gamma.9 Dual inhibition is thought to prevent the signaling inside the malignant cells and disrupt the interactions between the tumor cells and the supporting T cells and myeloid cells, which are providing additional tumor cell survival signals. As a result, malignant B-cell growth and survival could be blocked by the dual inhibition of PI3K-delta and PI3K-gamma.

Duvelisib (IPI-145)

Duvelisib is an investigational, orally bioavailable, selective, and potent small molecule inhibitor of the delta and gamma isoforms of PI3K.10 In preclinical studies, duvelisib directly impacted the survival of primary malignant B cells9 and demonstrated substantial and sustained inhibition of AKT activation, tumor cell proliferation, and downstream target activation in CLL cells in response to tumor microenvironment-derived signals.11 In addition, in experimental models, duvelisib was effective at blocking the production of some of the tumor cell–derived chemokines that contribute to the development of the supportive microenvironment.11 Migration of tumor-supportive T cells and polarization of macrophages to protumorigenic M2 phenotype was inhibited by duvelisib.10 Therefore, duvelisib is intended to target multiple facets of the pathogenesis and maintenance of hematologic malignancies. This includes targeting: 1) intrinsic or cell-autonomous survival signaling within the tumor cell, 2) survival and growth signaling within tumor cells via factors received from non-neoplastic cells within the tumor microenvironment, and 3) the establishment and maintenance of the supportive network of non-neoplastic cells within the tumor microenvironment.

References

  1. Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006;107:1761-1767.
  2. 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 Biol. 2014;24:71-81.
  3. Chang JE, Kahl BS. PI3-kinase inhibitors in chronic lymphocytic leukemia. Curr Hematol Malig Rep. 2014;9:33-43.
  4. Herman SE, Johnson AJ. Molecular pathways: targeting phosphoinositide 3-kinase p110-delta in chronic lymphocytic leukemia. Clin Cancer Res. 2012;18:4013-4018.
  5. Lafarge ST, Johnston JB, Gibson SB, et al. Adhesion of ZAP-70+ chronic lymphocytic leukemia cells to stromal cells is enhanced by cytokines and blocked by inhibitors of the PI3-kinase pathway. Leuk Res. 2014;38:109-115.
  6. Schmid MC, Avraamides CJ, Dippold HC, et al. Receptor tyrosine kinases and TLR/IL1Rs unexpectedly activate myeloid cell PI3kγ, a single convergent point promoting tumor inflammation and progression. Cancer Cell. 2011;19:715-727.
  7. Winkler DG, Faia KL, DiNitto JP, et al. PI3K-δ and PI3K-γ inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chem Biol. 2013;20:1364-1374.
  8. Hoellenriegel J, Meadows SA, Sivina M, et al. The phosphoinositide 3’-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia. Blood. 2011;118:3603-3612.
  9. Dong S, Guinn D, Dubovsky JA, et al. IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells. Blood. 2014;124:3583-3586.
  10. Peluso M, Faia KL, Winkler DG, 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. Blood (ASH Annual Meeting Abstracts). 2014. Abstract 328.
  11. Balakrishnan K, Peluso M, Fu M, et al. 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. Leukemia. 2015;29:1811-1822.
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