Safety, Tolerability, and Preliminary Activity of LB-100, an Inhibitor of Protein Phosphatase 2A, in Patients with Relapsed Solid Tumors: An Open-Label, Dose Escalation, First-in-Human, Phase I Trial

Chung, Vincent; Mansfield, Aaron S.; Braiteh, Fadi; Richards, Donald A.; Durivage, Henry J.; Ungerleider, Richard S.; Johnson, Francis; Kovach, John S.

doi:10.1158/1078-0432.ccr-16-2299

Cited by 90 publications

(85 citation statements)

References 34 publications

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“…LB-100, the first-in-class PP2A inhibitor studied here is currently in two clinical trials (NCI designated NCT03027388 and NCT01837667). A phase 1 safety study with 7 dose-escalations did not note relevant toxicity (Chung et al, 2017). LB-100 is a water-soluble small molecule inhibitor of PP2A (IC 50 0.9 μmol/l) and was initially designed to sensitize solid tumors to chemotherapy (Lu et al, 2009).…”

Section: Resultsmentioning

confidence: 99%

B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies

Xiao

Chan

Klemm

et al. 2018

Cell

114

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B cell activation during normal immune responses and oncogenic transformation impose increased metabolic demands on B cells and their ability to retain redox homeostasis. While the serine/threonine-protein phosphatase 2A (PP2A) was identified as a tumor suppressor in multiple types of cancer, our genetic studies revealed an essential role of PP2A in B cell tumors. Thereby, PP2A redirects glucose carbon utilization from glycolysis to the pentose phosphate pathway (PPP) to salvage oxidative stress. This unique vulnerability reflects constitutively low PPP activity in B cells and transcriptional repression of G6PD and other key PPP enzymes by the B cell transcription factors PAX5 and IKZF1. Reflecting B-cell-specific transcriptional PPP-repression, glucose carbon utilization in B cells is heavily skewed in favor of glycolysis resulting in lack of PPP-dependent antioxidant protection. These findings reveal a gatekeeper function of the PPP in a broad range of B cell malignancies that can be efficiently targeted by small molecule inhibition of PP2A and G6PD.

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Section: Resultsmentioning

confidence: 99%

B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies

Xiao

Chan

Klemm

et al. 2018

Cell

114

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“…Research on LB100 has largely focused on and highlighted its potential as a potent chemo- and radio-sensitizer. A 2016 Phase I clinical trial was completed for LB100 in combination with Docetaxol for the treatment of solid tumors [89]. The compound was found to have minimal adverse toxicities with efficacy potential that merits further clinical investigation.…”

Section: Pp2a Inhibitionmentioning

confidence: 99%

Targeting PP2A in cancer: Combination therapies

Mazhar¹,

Taylor²,

Sangodkar³

et al. 2019

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

103

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The serine/threonine phosphatase PP2A regulates a vast portion of the phosphoproteome including pathways involved in apoptosis, proliferation and DNA damage response and PP2A inactivation is a vital step in malignant transformation. Many groups have explored the therapeutic venue of combining PP2A reactivation with kinase inhibition to counteract the very changes in tumor suppressors and oncogenes that lead to cancer development. Conversely, inhibition of PP2A to complement chemotherapy and radiation-induced cancer cell death is also an area of active investigation. Here we review the studies that utilize PP2A targeted agents as combination therapy in cancer. A potential role for PP2A in tumor immunity is also highlighted.

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“…These novel insights are not only important for general understanding of rules of PP2A-mediated phosphoregulation, but also for realization that all phosphoregulation in cancer cells is not equally susceptible to modulation of PP2A activity. Rather, phosphatase-dominant targets would primarily respond to pharmacological PP2A inhibition 38,60 , whereas various PP2A reactivation therapies 14,15 , would primarily affect kinase-dominant targets.…”

Section: Unidirectionality Paradigm Of Phosphoregulation By Pp2amentioning

confidence: 99%

“…The most important notions however might be that different drug classes can be classified based on their PP2A dependency of response, and that directionality rules apply also to PP2A-dependent drug responses. These aspect may become relevant for developing combination strategies with the emerging PP2A-targeted therapies aiming either to re-activate 14,15 , or inhibit 38,60 PP2A.…”

Section: The Pp2a Dephosphorylome Both Quantitatively and Qualitativementioning

confidence: 99%

Rules for PP2A-controlled phosphosignalling and drug responses

Kauko

Imanishi

Kulesskiy

et al. 2018

Preprint

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Systemic understanding of protein phosphatase 2A (PP2A)-regulated cellular processes is still at infancy. Here, we present mass-spectrometry analysis of phospho-targets (dephosphorylome) regulated by PP2A modulation. In addition to PP2A-regulated processes and targets, the data reveal important general concepts and rules related to PP2A-mediated phosphoregulation.These include the unidirectionality paradigm of regulation of phosphorylation, and differential spatial distribution of kinase-and phosphatase-dominated phosphotargets. Data also present first systemic analysis of targets of PP2Amodulating oncoproteins, CIP2A, PME-1, and SET; including targets via which PP2A may coordinately regulate activities of cancer drivers and tumor suppressors such as MYC or TP53. To validate functional utility of this dataset, PP2A dephosphorylome activity was correlated with cancer cell responses to over 300 drugs. Notably, we find that cancer therapy responses can be broadly classified based on PP2A dephosphorylome activity, both in quantitative and qualitative manner. In summary, our data characterize rules by which PP2A coordinate cancer cell phosphosignaling and drug responses. The results also may also direct the use of emerging pharmacological approaches for PP2A activity modulation in human diseases.

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Safety, Tolerability, and Preliminary Activity of LB-100, an Inhibitor of Protein Phosphatase 2A, in Patients with Relapsed Solid Tumors: An Open-Label, Dose Escalation, First-in-Human, Phase I Trial

Cited by 90 publications

References 34 publications

B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies

B-Cell-Specific Diversion of Glucose Carbon Utilization Reveals a Unique Vulnerability in B Cell Malignancies

Targeting PP2A in cancer: Combination therapies

Rules for PP2A-controlled phosphosignalling and drug responses

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