PI3K Inhibitors and Their Role as Novel Agents for Targeted Therapy in Lymphoma

Sapon-Cousineau, Vladimir; Sapon-Cousineau, Sasha; Assouline, Sarit

doi:10.1007/s11864-020-00746-8

Cited by 31 publications

(26 citation statements)

References 58 publications

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“…However, so far, there has been limited success in developing approved drugs against PI3Ks. Idelalisib 75 , a specific inhibitor of PI3Kδ, which is expressed in B and T cells, has been approved for relapsed follicular B cell non-Hodgkin lymphoma (FL), relapsed chronic lymphocytic leukaemia (CLL) and relapsed small lymphocytic lymphoma (SLL), and was followed by the next-generation inhibitors copanlisib (for relapsed FL) and duvelisib (for CLL, SLL and FL) 76 . Only recently has a PI3Kα selective inhibitor, alpelisib, been approved for the treatment of hormone receptor-positive and HER2/neu-negative breast cancer harbouring mutations in the gene encoding PI3Kα 77 .…”

Section: Trends In Targeting Tyrosine Kinase Activitymentioning

confidence: 99%

Kinase drug discovery 20 years after imatinib: progress and future directions

Cohen

Cross

Jänne

2021

Nat Rev Drug Discov

690

465

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Section: Trends In Targeting Tyrosine Kinase Activitymentioning

confidence: 99%

Kinase drug discovery 20 years after imatinib: progress and future directions

Cohen

Cross

Jänne

2021

Nat Rev Drug Discov

690

465

View full text Add to dashboard Cite

show abstract

“…These inhibitors differ in their preference for PI3K isoforms which are expressed differentially in various tissues ( 336 ). Despite relevant side effects of PI3K inhibitors, they have been judged clinically manageable and thus, prompted an FDA approval for relapsed and refractory indolent B-NHL ( 335 , 337 ). Published reports on anti-angiogenic therapies in B-NHL allow the conclusion that the complex mechanisms of angiogenesis in lymphoma are incompletely understood and require further pre-clinical and translational research to develop reliable and effective anti-angiogenic treatment strategies.…”

Section: Anti-angiogenic Therapies In Combination With Chemotherapiesmentioning

confidence: 99%

Angiogenesis in Lymph Nodes Is a Critical Regulator of Immune Response and Lymphoma Growth

2020

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Tumor-induced remodeling of the microenvironment in lymph nodes (LNs) includes the formation of blood vessels, which goes beyond the regulation of metabolism, and shaping a survival niche for tumor cells. In contrast to solid tumors, which primarily rely on neo-angiogenesis, hematopoietic malignancies usually grow within pre-vascularized autochthonous niches in secondary lymphatic organs or the bone marrow. The mechanisms of vascular remodeling in expanding LNs during infection-induced responses have been studied in more detail; in contrast, insights into the conditions of lymphoma growth and lodging remain enigmatic. Based on previous murine studies and clinical trials in human, we conclude that there is not a universal LN-specific angiogenic program applicable. Instead, signaling pathways that are tightly connected to autochthonous and infiltrating cell types contribute variably to LN vascular expansion. Inflammation related angiogenesis within LNs relies on dendritic cell derived pro-inflammatory cytokines stimulating vascular endothelial growth factor-A (VEGF-A) expression in fibroblastic reticular cells, which in turn triggers vessel growth. In high-grade B cell lymphoma, angiogenesis correlates with poor prognosis. Lymphoma cells immigrate and grow in LNs and provide pro-angiogenic growth factors themselves. In contrast to infectious stimuli that impact on LN vasculature, they do not trigger the typical inflammatory and hypoxia-related stroma-remodeling cascade. Blood vessels in LNs are unique in selective recruitment of lymphocytes via high endothelial venules (HEVs). The dissemination routes of neoplastic lymphocytes are usually disease stage dependent. Early seeding via the blood stream requires the expression of the homeostatic chemokine receptor CCR7 and of L-selectin, both cooperate to facilitate transmigration of tumor and also of protective tumor-reactive lymphocytes via HEV structures. In this view, the HEV route is not only relevant for lymphoma cell homing, but also for a continuous immunosurveillance. We envision that HEV functional and structural alterations during lymphomagenesis are not only key to vascular remodeling, but also impact on tumor cell accessibility when targeted by T cell–mediated immunotherapies.

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“…Although the activation of these PKCs is inhibited by PKC inhibitors, other cellular signals (e.g., AKT) that are pro-proliferative and anti-apoptotic in cancer may be substituted for PKCs. On the other hand, certain inhibitors of PI3Ks that are upstream of PKCs and AKT show significant clinical benefits in cancer treatment [245][246][247].…”

Section: Summary and Overall Conclusionmentioning

confidence: 99%

Activators and Inhibitors of Protein Kinase C (PKC): Their Applications in Clinical Trials

et al. 2021

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Protein kinase C (PKC), a family of phospholipid-dependent serine/threonine kinase, is classed into three subfamilies based on their structural and activation characteristics: conventional or classic PKC isozymes (cPKCs; α, βI, βII, and γ), novel or non-classic PKC isozymes (nPKCs; δ, ε, η, and θ), and atypical PKC isozymes (aPKCs; ζ, ι, and λ). PKC inhibitors and activators are used to understand PKC-mediated intracellular signaling pathways and for the diagnosis and treatment of various PKC-associated diseases, such as cancers, neurological diseases, cardiovascular diseases, and infections. Many clinical trials of PKC inhibitors in cancers showed no significant clinical benefits, meaning that there is a limitation to design a cancer therapeutic strategy targeting PKC alone. This review will focus on the activators and inhibitors of PKC and their applications in clinical trials.

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PI3K Inhibitors and Their Role as Novel Agents for Targeted Therapy in Lymphoma

Cited by 31 publications

References 58 publications

Kinase drug discovery 20 years after imatinib: progress and future directions

Kinase drug discovery 20 years after imatinib: progress and future directions

Angiogenesis in Lymph Nodes Is a Critical Regulator of Immune Response and Lymphoma Growth

Activators and Inhibitors of Protein Kinase C (PKC): Their Applications in Clinical Trials

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