Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kδ and CK1ε in hematological malignancies

Deng, Chao; Lipstein, Mark; Scotto, Luigi; Serrano, Xavier O. Jirau; Mangone, Michael; Liu, Shirong; Vendôme, Jérémie; Huang, Yun; Xu, Xiaoming; Deng, Shi‐Xian; Realubit, Ronald; Tatonetti, Nicholas P.; Karan, Charles; Lentzsch, Suzanne; Fruman, David A.; Honig, Barry; Landry, Donald W.; O’Connor, Owen A.

doi:10.1182/blood-2016-08-731240

Cited by 99 publications

(76 citation statements)

References 36 publications

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“…This change in chemical structure may potentially alter the toxicity profile based on the hypothesis that nitrogen-based heterocyclic backbones can cause hepatotoxicity. In addition, this different chemical structure leads to inhibition of casein kinase-1ε (CK-1ε) as well as p110δ, a property not shared by idelalisib or duvelisib [78]. This introduces some confusion regarding umbralisib’s ultimate mechanism of action.…”

Section: Pi3kα and Pi3kδ Inhibitors In Clinical Development For Thmentioning

confidence: 99%

“…Furthermore, in preclinical studies, the combination of carfilzomib plus umbralisib was synergistic at in vitro killing of primary samples from patients with multiple types of lymphoma as well as multiple lymphoma cell lines (CLL, SLL, MCL, and DLBCL). This synergy was due to the additional ability of umbralisib to inhibit CK-1ε and was not seen when idelalisib was combined with carfilzomib [78]. …”

Section: Pi3kα and Pi3kδ Inhibitors In Clinical Development For Thmentioning

confidence: 99%

“…A phase IIb trial comparing ublituximab plus umbralisib to umbralisib alone is currently enrolling patients with DLBCL. Finally, based on the preclinical data showing synergy between umbralisib and carfilzomib [78], a trial of this duo in relapsed/refractory Hodgkin and non-Hodgkin lymphoma is actively recruiting subjects (NCT02867618).…”

Section: Pi3kα and Pi3kδ Inhibitors In Clinical Development For Thmentioning

confidence: 99%

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PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma

Lampson

Brown

2017

Expert Opinion on Investigational Drugs

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Introduction Phosphatidylinositol-3-kinase (PI3K) inhibitors comprise a novel class of agents that are effective for the treatment of chronic lymphocytic leukemia (CLL) and indolent non-Hodgkin lymphoma (iNHL). The demonstrated efficacy and subsequent FDA approval of the prototypical PI3Kδ inhibitor idelalisib has led to development of multiple compounds targeting this pathway. Areas Covered We review the hypothesized therapeutic mechanisms of PI3K inhibitors, including abrogation of tonic signaling from the B cell receptor, blockade of pro-survival signals from the microenvironment, and enhancement of anti-tumor immunity. We examine toxicities of idelalisib, including bacterial infections and sepsis (possibly secondary to drug-induced neutropenia), opportunistic infections (possibly attributable to on-target inhibition of T cell function), and organ toxicities such as transaminitis and enterocolitis (possibly autoimmune, secondary to on-target inhibition of p110δ in regulatory T cells). We then summarize PI3K inhibitors that have entered clinical trials for the treatment of lymphoma, focusing on agents with significant selectivity for PI3Kα and PI3Kδ. Expert Opinion PI3K inhibitors, particularly those that target p110δ, have robust efficacy in the treatment of CLL and iNHL. However, in comparison to other novel agents, idelalisib has infectious and autoimmune toxicities that have limited its use. Outside of clinical trials, the use of PI3K inhibitors should be restricted to CLL patients who have progressed on ibrutinib or iNHL patients who have progressed on two prior therapies. Whether newer PI3K inhibitors will demonstrate differentiated toxicity profiles in comparable patient populations while retaining efficacy remains to be seen.

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Section: Pi3kα and Pi3kδ Inhibitors In Clinical Development For Thmentioning

confidence: 99%

Section: Pi3kα and Pi3kδ Inhibitors In Clinical Development For Thmentioning

confidence: 99%

Section: Pi3kα and Pi3kδ Inhibitors In Clinical Development For Thmentioning

confidence: 99%

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PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma

Lampson

Brown

2017

Expert Opinion on Investigational Drugs

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“…65 In addition, PI3Kd-inactive Tregs produced less IL-10 and expressed lower levels of CD38 1 , correlating to defective suppressive function. 68 PI3Kd-inactive Tregs were incapable of protecting against a model of induced colitis.…”

Section: Pi3k Inhibition In Immune Subsetsmentioning

confidence: 99%

“…TGR-1202 silenced c-myc translation in leukemia and lymphoma cells through inhibition of casein kinase 1 e (CK1«). 65 The effect of this inhibition on T cells is currently unknown.…”

Section: Pi3k Inhibitors and Toxicitymentioning

confidence: 99%

Emerging role of BCR signaling inhibitors in immunomodulation of chronic lymphocytic leukemia

2017

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Approved therapies that target the B-cell receptor (BCR) signaling pathway, such as ibrutinib and idelalisib, are known to show activity in chronic lymphocytic leukemia (CLL) via their direct effects on crucial survival pathways in malignant B cells. However, these therapies also have effects on T cells in CLL by mediating toxicity and possibly controlling disease. By focusing on the effects of BCR signaling inhibitors on the T-cell compartment, we may gain new insights into the comprehensive biological outcomes of systemic treatment to further understand mechanisms of drug efficacy, predict the toxicity or adverse events, and identify novel combinatorial therapies. Here, we review T-cell abnormalities in preclinical models and patient samples, finding that CLL T cells orchestrate immune dysfunction and immune-related complications. We then continue to address the effects of clinically available small molecule BCR signaling inhibitors on the immune cells, especially T cells, in the context of concomitant immune-mediated adverse events and implications for future treatment strategies. Our review suggests potentially novel mechanisms of action related to BCR inhibitors, providing a rationale to extend their use to other cancers and autoimmune disorders.

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Strategies for Targeting MYC

Longley¹,

Davies

2023

Precision Cancer Therapies, Volume 1 ‐ Targeting Oncogenic Drivers and Signaling Pathways in Lymphoid Malignancies

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Silencing c-Myc translation as a therapeutic strategy through targeting PI3Kδ and CK1ε in hematological malignancies

Abstract: Key Points A novel PI3Kδ inhibitor TGR-1202 synergizes with proteasome inhibitor carfilzomib by silencing c-Myc in preclinical models of lymphoma. The unique activity of TGR-1202 as a single agent and in combination with carfilzomib is driven by an unexpected activity targeting CK1ε.

Cited by 99 publications

References 36 publications

PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma

PI3Kδ-selective and PI3Kα/δ-combinatorial inhibitors in clinical development for B-cell non-Hodgkin lymphoma

Emerging role of BCR signaling inhibitors in immunomodulation of chronic lymphocytic leukemia

Strategies for Targeting MYC

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