Phase I study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3‐kinase P110d, in patients with previously treated chronic lymphocytic leukemia.

Coutré, Steven; Byrd, John C.; Furman, Richard R.; Brown, J. R.; Benson, D. M.; Wagner‐Johnston, Nina D.; Flinn, Ian W.; Kahl, Brad S.; Spurgeon, Stephen E.; Lannutti, Brian J.; Hsu, Hung-Chih; Ulrich, Roger G.; Peterman, Sissy; Holes, Leanne; Miller, L. L.; Yu, Albert S.

doi:10.1200/jco.2011.29.15_suppl.6631

Cited by 57 publications

(42 citation statements)

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“…An early-phase trial of GS-1101 in CLL reported immune-related side effects, including grade !3 pneumonia (24% of patients), neutropenia (24%), and neutropenic fever (7%; ref. 50). In contrast, early results from the phase I trials of BYL719 and GDC-0032 support the hypothesis that p110a inhibitors are less likely to exhibit immunomodulatory effects, with less than 10% of patients reporting any form of immune-related adverse event of any grade (33,51).…”

Section: P110d Inhibitors Versus Pan-pi3k and Dual Pi3k/ Mtor Inhibitcontrasting

confidence: 40%

Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors

Dienstmann¹,

Rodón²,

Serra³

et al. 2014

Molecular Cancer Therapeutics

395

331

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The frequent activation of the PI3K/AKT/mTOR pathway in cancer, and its crucial role in cell growth and survival, has made it a much desired target for pharmacologic intervention. Following the regulatory approval of the rapamycin analogs everolimus and temsirolimus, recent years have seen an explosion in the number of phosphoinositide 3-kinase (PI3K) pathway inhibitors under clinical investigation. These include: ATPcompetitive, dual inhibitors of class I PI3K and mTORC1/2; "pan-PI3K" inhibitors, which inhibit all four isoforms of class I PI3K (a, b, d, g); isoform-specific inhibitors of the various PI3K isoforms; allosteric and catalytic inhibitors of AKT; and ATP-competitive inhibitors of mTOR only (and thus mTORC1 and mTORC2). With so many agents in development, clinicians are currently faced with a wide array of clinical trials investigating a multitude of inhibitors with different mechanisms of action, being used both as single agents and in combination with other therapies. Here, we provide a review of the literature, with the aim of differentiating the genomic contexts in which these various types of inhibitors may potentially have superior activity.

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Section: P110d Inhibitors Versus Pan-pi3k and Dual Pi3k/ Mtor Inhibitcontrasting

confidence: 40%

Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors

Dienstmann¹,

Rodón²,

Serra³

et al. 2014

Molecular Cancer Therapeutics

395

331

View full text Add to dashboard Cite

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“…However, 80% of patients had a reduction in lymphadenopathy by ≥50%. 10 Interestingly, it has recently been reported that combination of GS-1101 with rituximab and/or bendamustine induces an OR higher than 78%. 32 In line with this, clinical responses to SYK 33 and BTK 34 inhibitors in CLL are also characterized by a rapid mobilization of tumoral cells from nodal masses to peripheral circulation, with a significant decrease in lymphadenopathies and splenomegaly and an increase in the number of lymphocytes in peripheral blood.…”

Section: Discussionmentioning

confidence: 99%

“…We provide here a strong rationale for undertaking clinical trials of NVP-BKM120 in chronic lymphocytic leukemia patients alone or in combination therapies. 10 However, there is some evidence to suggest possible redundancies between the different PI3K isoforms, appointing for additional therapeutic implications in B-cell malignancies. 11 In this way, NVP-BKM120, a 2,6-dimorpholino pyrimidine derivative, is a potent, orally available, pan-class I PI3K inhibitor.…”

Section: Introductionmentioning

confidence: 99%

The phosphatidylinositol-3-kinase inhibitor NVP-BKM120 overcomes resistance signals derived from microenvironment by regulating the Akt/FoxO3a/Bim axis in chronic lymphocytic leukemia cells

et al. 2013

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“…Efforts to target BCR signaling pathway with idelalisib [55][56][57][58][59][60][61] and ibrutinib 6,62-66 have shown significant clinical activity in CLL including those with high-risk genomic disease. However, despite the impressive durability of remissions obtained with ibrutinib in CLL, minimal residual disease-negative status has generally not been achieved.…”

Section: Org Frommentioning

confidence: 99%

PKC-β as a therapeutic target in CLL: PKC inhibitor AEB071 demonstrates preclinical activity in CLL

El‐Gamal¹,

Williams²,

LaFollette³

et al. 2014

Blood

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Key Points• AEB071 demonstrates preclinical in vitro and in vivo activity against CLL independent of survival signaling and stromal cell protection.• AEB071 can either inhibit or activate the WNT pathway emphasizing the importance of pharmacodynamic monitoring in its development.Targeting B-cell receptor (BCR) signaling in chronic lymphocytic leukemia (CLL) has been successful with durable remissions observed with several targeted therapeutics. Protein kinase C-b (PKC-b) is immediately downstream of BCR and has been shown to be essential to CLL cell survival and proliferation in vivo. We therefore evaluated sotrastaurin (AEB071), an orally administered potent PKC inhibitor, on CLL cell survival both in vitro and in vivo. AEB071 shows selective cytotoxicity against B-CLL cells in a dose-dependent manner. Additionally, AEB071 attenuates BCR-mediated survival pathways, inhibits CpG-induced survival and proliferation of CLL cells in vitro, and effectively blocks microenvironment-mediated survival signaling pathways in primary CLL cells. Furthermore, AEB071 alters b-catenin expression, resulting in decreased downstream transcriptional genes as c-Myc, Cyclin D1, and CD44. Lastly, our preliminary in vivo studies indicate beneficial antitumor properties of AEB071 in CLL. Taken together, our results indicate that targeting PKC-b has the potential to disrupt signaling from the microenvironment contributing to CLL cell survival and potentially drug resistance. Future efforts targeting PKC with the PKC inhibitor AEB071 as monotherapy in clinical trials of relapsed and refractory CLL patients are warranted. (Blood. 2014;124(9):1481-1491) IntroductionChronic lymphocytic leukemia (CLL) is one of the most common types of adult leukemia and is currently incurable. Decades of research into the biology of CLL and other B-cell malignancies has brought forth B-cell receptor (BCR) signaling as a common required driving force in the survival and proliferation of these tumor cells. Several survival pathways involved in BCR signaling, including the phosphatidylinositol 3-kinase (PI3K), nuclear factor-kB (NF-kB), and mitogen-activated protein kinase (MAPK)/extracellular signalregulated kinase (ERK), are constitutively active in the lymph node and bone marrow compartment of CLL where disease expansion occurs. [1][2][3] Efforts to target BCR signaling with therapeutic agents which reversibly inhibit PI3K-d 4,5 or irreversibly inhibit Bruton tyrosine kinase (BTK) 6-8 have shown significant clinical activity in CLL, including those with high-risk genomic disease, and are currently in phase 3 studies. Protein kinase C-b (PKC-b) is an immediate downstream target of BTK that has recently been shown to be overexpressed in CLL 9 and is essential to the in vivo development of CLL in Em-TCL1 mice. 10 In B cells, PKC-b is thought to be the predominant PKC isoform mediating BCRdependent NF-kB activation.11-13 Downstream of PKC-b, IkB kinase and caspase recruitment domain-containing protein 11 (CARD11 [also known as CARMA1]) are phosphorylated, le...

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Phase I study of CAL-101, an isoform-selective inhibitor of phosphatidylinositol 3‐kinase P110d, in patients with previously treated chronic lymphocytic leukemia.

Cited by 57 publications

References 0 publications

Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors

Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors

The phosphatidylinositol-3-kinase inhibitor NVP-BKM120 overcomes resistance signals derived from microenvironment by regulating the Akt/FoxO3a/Bim axis in chronic lymphocytic leukemia cells

PKC-β as a therapeutic target in CLL: PKC inhibitor AEB071 demonstrates preclinical activity in CLL

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