Idelalisib for treatment of B-cell malignancies

Do, Bryan; Mace, Morgan; Rexwinkle, Amber

doi:10.2146/ajhp150281

Cited by 16 publications

(14 citation statements)

References 32 publications

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“…Idelalisib is a first in class, delta isoform specific, PI3-kinase inhibitor3. Idelalisib targets malignant B-cell proliferation, survival, migration and homing to lymphoid tissues through multiple mechanisms [2, 28, 29]. In the current study, we detected the effect of idelalisib on colon cancer cells.…”

Section: Discussionmentioning

confidence: 71%

Idelalisib induces PUMA-dependent apoptosis in colon cancer cells

et al. 2016

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Idelalisib, a PI3K inhibitor, specifically targeting p110δ, has been approved for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma. However, the mechanisms of action of idelalisib in colon cancer cells are not well understood. We investigated how idelalisib suppresses colon cancer cells growth and potentiates effects of other chemotherapeutic drugs. In this study, we found that idelalisib treatment induces PUMA in colon cancer cells irrespective of p53 status through the p65 pathway following AKT inhibition and glycogen synthase kinase 3β (GSK3β) activation. PUMA is necessary for idelalisib-induced apoptosis in colon cancer cells. Idelalisib also synergized with 5-FU or regorafenib to induce marked apoptosis via PUMA in colon cancer cells. Furthermore, PUMA deficiency suppressed apoptosis and antitumor effect of idelalisib in xenograft model. These results demonstrate a critical role of PUMA in mediating the anticancer effects of idelalisib in colon cancer cells and suggest that PUMA induction can be used as an indicator of idelalisib sensitivity, and also have important implications for it clinical applications.

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Section: Discussionmentioning

confidence: 71%

Idelalisib induces PUMA-dependent apoptosis in colon cancer cells

et al. 2016

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“…One advantage of using BTK as a drug target for lymphoma treatment, is due to its relatively limited expression in different cell types (Mohamed et al, 2009) and therefore has exhibited limited toxicity thus far (Wang et al, 2015). Since PI3K and STAT3 are used by many different cell types (Cantley, 2002; Levy and Lee, 2002), drugs that target these signal transduction molecules may have greater side effects (Do, Mace, and Rexwinkle, 2016; Ogura et al, 2015). Therefore, our results suggest that Ibrutinib may be an asset in the treatment of EBV-associated lymphomas with minimal side effects, which has not yet been investigated.…”

Section: Discussionmentioning

confidence: 99%

Epstein-Barr Virus Latent Membrane Protein 2A (LMP2A) enhances IL-10 production through the activation of Bruton's tyrosine kinase and STAT3

et al. 2017

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Previous data demonstrate that Epstein-Barr Virus Latent Membrane Protein 2A (LMP2A) enhances IL-10 to promote the survival of LMP2A-expressing B cell lymphomas. Since STAT3 is an important regulator of IL-10 production, we hypothesized that LMP2A activates a signal transduction cascade that increases STAT3 phosphorylation to enhance IL-10. Using LMP2A-negative and –positive B cell lines, the data indicate that LMP2A requires the early signaling molecules of the Syk/RAS/PI3K pathway to increase IL-10. Additional studies indicate that the PI3K-regulated kinase, BTK, is responsible for phosphorylating STAT3, which ultimately mediates the LMP2A-dependent increase in IL-10. These data are the first to show that LMP2A signaling results in STAT3 phosphorylation in B cells through a PI3K/BTK-dependent pathway. With the use of BTK and STAT3 inhibitors to treat B cell lymphomas in clinical trials, these findings highlight the possibility of using new pharmaceutical approaches to treat EBV-associated lymphomas that express LMP2A.

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“…It is approved for refractory indolent lymphoma (134,135). Idelalisib has shown activity either as a single agent and/or in combination with mAbs in R/R CLL in FCL and HL (136)(137)(138)(139)(140)(141)(142).…”

Section: Pi3k Inhibitorsmentioning

confidence: 99%

Overview of Targeted Drugs for Mature B-Cell Non-hodgkin Lymphomas

et al. 2019

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The improved knowledge of pathogenetic mechanisms underlying lymphomagenesis and the discovery of the critical role of tumor microenvironments have enabled the design of new drugs against cell targets and pathways. The Food and Drug Administration (FDA) has approved several monoclonal antibodies (mAbs) and small molecule inhibitors (SMIs) for targeted therapy in hematology. This review focuses on the efficacy results of the currently available targeted agents and recaps the main ongoing trials in the setting of mature B-Cell non-Hodgkin lymphomas. The objective is to summarize the different classes of novel agents approved for mature B-cell lymphomas, to describe in synoptic tables the results they achieved and, finally, to draw future scenarios as we glimpse through the ongoing clinical trials. Characteristics and therapeutic efficacy are summarized for the currently approved mAbs [i.e., anti-Cluster of differentiation (CD) mAbs, immune checkpoint inhibitors, chimeric antigen receptor (CAR) T-cell therapy, and bispecific antibodies] as well as for SMIs i.e., inhibitors of B-cell receptor signaling, proteasome, mTOR BCL-2 HDAC pathways. The biological disease profiling of B-cell lymphoma subtypes may foster the discovery of innovative drug strategies for improving survival outcome in lymphoid neoplasms, as well as the trade-offs between efficacy and toxicity. The hope for clinical advantages should carefully be coupled with mindful awareness of the potential pitfalls and the occurrence of uneven, sometimes severe, toxicities.

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Idelalisib for treatment of B-cell malignancies

Abstract: Idelalisib is a well-tolerated and effective treatment for patients with relapsed or refractory CLL or indolent NHL, providing a novel targeted therapeutic option for the management of these hematologic malignancies.

Cited by 16 publications

References 32 publications

Idelalisib induces PUMA-dependent apoptosis in colon cancer cells

Idelalisib induces PUMA-dependent apoptosis in colon cancer cells

Epstein-Barr Virus Latent Membrane Protein 2A (LMP2A) enhances IL-10 production through the activation of Bruton's tyrosine kinase and STAT3

Overview of Targeted Drugs for Mature B-Cell Non-hodgkin Lymphomas

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