PI3K inhibitors in chronic lymphocytic leukemia: where do we go from here?

Skånland, Sigrid S.; Brown, Jennifer R.

doi:10.3324/haematol.2022.281266

Cited by 22 publications

(15 citation statements)

References 92 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the drug has been approved for the closely related B-NHL CLL as third-line therapy 59 . The data we present here suggest that duvelisib could be useful as part of a combination strategy in the treatment of MCL; this approach is currently undergoing clinical trials in CLL 60 . It is also important to note, in light of the fact that aberrations of TP53 result in inferior responses to therapy 61 , that duvelisib reduced the proliferation and migration of both the Maver-1 62 and Mino 63 cell lines which have mutations in TP53.…”

Section: Discussionmentioning

confidence: 80%

Roles of PI3Kγ and PI3Kδ in mantle cell lymphoma proliferation and migration contributing to efficacy of the PI3Kγ/δ inhibitor duvelisib

Till

Abdullah

Alnassfan

et al. 2023

Sci Rep

View full text Add to dashboard Cite

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma that is incurable with existing therapies, and therefore presents a significant unmet clinical need. The ability of this disease to overcome therapy, including those that target the B cell receptor pathway which has a pathogenic role in MCL, highlights the need to develop new treatment strategies. Herein, we demonstrate that a distinguishing feature of lymph node resident MCL cells is the expression of phosphatidylinositol 3-kinase γ (PI3Kγ), a PI3K isoform that is not highly expressed in other B cells or B-cell malignancies. By exploring the role of PI3K in MCL using different PI3K isoform inhibitors, we provide evidence that duvelisib, a dual PI3Kδ/γ inhibitor, has a greater effect than PI3Kδ- and PI3Kγ-selective inhibitors in blocking the proliferation of primary MCL cells and MCL cell lines, and in inhibiting tumour growth in a mouse xenograft model. In addition, we demonstrated that PI3Kδ/γ signalling is critical for migration of primary MCL cells and cell lines. Our data indicates that aberrant expression of PI3Kγ is a critical feature of MCL pathogenesis. Thus, we suggest that the dual PI3Kδ/γ duvelisib would be effective for the treatment of mantle cell lymphoma.

show abstract

Section: Discussionmentioning

confidence: 80%

Roles of PI3Kγ and PI3Kδ in mantle cell lymphoma proliferation and migration contributing to efficacy of the PI3Kγ/δ inhibitor duvelisib

Till

Abdullah

Alnassfan

et al. 2023

Sci Rep

View full text Add to dashboard Cite

show abstract

“…This complex history of Pi3K inhibitor development highlights the encouraging efficacy of these agents but also their severe toxicity profile [ 19 ]. It is therefore of interest to improve our knowledge of the specific side effects of these drugs [ 20 ].…”

Section: Resultsmentioning

confidence: 99%

Management of Gastro-Intestinal Toxicity of the Pi3 Kinase Inhibitor: Optimizing Future Dosing Strategies

Breal

Beuvon

Witasse-Thezy

et al. 2023

Cancers

View full text Add to dashboard Cite

The phosphatidylinositol 3-kinase (PI3K) pathway plays a key role in cancer progression and in host immunity. Idelalisib was the first of this class to be approved with the second-generation Pi3 kinase inhibitors copanlisib, duvelisib and umbralisib, subsequently being approved in the United States. Real-world data are lacking, however, in relation to the incidence and toxicity of Pi3 kinase inhibitor-induced colitis. We here review, in the first instance, the general landscape of the Pi3K inhibitors in the context of hematological malignancies, with a focus on the adverse gastrointestinal side effects reported by various clinical trials. We further review the available worldwide pharmacovigilance data in relation to these drugs. Finally, we describe our own real-world experience with idelalisib-induced colitis management in our center and in a national setting.

show abstract

“…This case demonstrates that ex vivo drug testing can indicate treatment sensitivity, but not treatment tolerability. Since PI3Ki are associated with severe toxicity [31,32], ex vivo sensitivity to a PI3Ki should not be used as a stand-alone indication for treatment. Future efforts in large patient cohorts are needed to identify predictors of both efficacy and tolerability, which should then be validated in prospective clinical trials.…”

Section: Ex Vivo Drug Sensitivity Correlates With In Vivo Sensitivity...mentioning

confidence: 99%

A tumor microenvironment model of chronic lymphocytic leukemia enables drug sensitivity testing to guide precision medicine

et al. 2023

View full text Add to dashboard Cite

The microenvironment of chronic lymphocytic leukemia (CLL) cells in lymph nodes, spleen, and bone marrow provides survival, proliferation, and drug resistance signals. Therapies need to be effective in these compartments, and pre-clinical models of CLL that are used to test drug sensitivity must mimic the tumor microenvironment to reflect clinical responses. Ex vivo models have been developed that capture individual or multiple aspects of the CLL microenvironment, but they are not necessarily compatible with high-throughput drug screens. Here, we report on a model that has reasonable associated costs, can be handled in a regularly equipped cell lab, and is compatible with ex vivo functional assays including drug sensitivity screens. The CLL cells are cultured with fibroblasts that express the ligands APRIL, BAFF and CD40L for 24 h. The transient co-culture was shown to support survival of primary CLL cells for at least 13 days, and mimic in vivo drug resistance signals. Ex vivo sensitivity and resistance to the Bcl-2 antagonist venetoclax correlated with in vivo responses. The assay was used to identify treatment vulnerabilities and guide precision medicine for a patient with relapsed CLL. Taken together, the presented CLL microenvironment model enables clinical implementation of functional precision medicine in CLL.

show abstract

PI3K inhibitors in chronic lymphocytic leukemia: where do we go from here?

Cited by 22 publications

References 92 publications

Roles of PI3Kγ and PI3Kδ in mantle cell lymphoma proliferation and migration contributing to efficacy of the PI3Kγ/δ inhibitor duvelisib

Roles of PI3Kγ and PI3Kδ in mantle cell lymphoma proliferation and migration contributing to efficacy of the PI3Kγ/δ inhibitor duvelisib

Management of Gastro-Intestinal Toxicity of the Pi3 Kinase Inhibitor: Optimizing Future Dosing Strategies

A tumor microenvironment model of chronic lymphocytic leukemia enables drug sensitivity testing to guide precision medicine

Contact Info

Product

Resources

About