Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia

Brown, Jennifer R.; Byrd, John C.; Coutre, Steven; Benson, Don M.; Flinn, Ian W.; Wagner‐Johnston, Nina D.; Spurgeon, Stephen E.; Kahl, Brad S.; Bello, Celeste M.; Webb, Heather K.; Johnson, David R.; Peterman, Sissy; Li, Daniel; Jahn, Thomas M.; Lannutti, Brian J.; Ulrich, Roger G.; Yu, Albert S.; Miller, Langdon L.; Furman, Richard R.

doi:10.1182/blood-2013-11-535047

Cited by 543 publications

(525 citation statements)

References 32 publications

(36 reference statements)

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“…Although PI3Kd is reported to play a role in some solid tumor settings, in our models inhibitors with preferential activity to PI3Kd are not active. PI3Kd signals downstream of the BCRs (28) and PI3Kd inhibitors show more profound activity in some hematologic disease (29,30), including chronic lymphocytic leukemia (31,32), and mantle cell lymphoma (33). The PI3Kb/d profile of AZD8186 may provide benefit in hematologic disease.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

Hancox

Cosulich

Hanson

et al. 2015

Molecular Cancer Therapeutics

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Loss of PTEN protein results in upregulation of the PI3K/AKT pathway, which appears dependent on the PI3Kb isoform. Inhibitors of PI3Kb have potential to reduce growth of tumors in which loss of PTEN drives tumor progression. We have developed a small-molecule inhibitor of PI3Kb and PI3Kd (AZD8186) and assessed its antitumor activity across a panel of cell lines. We have then explored the antitumor effects as single agent and in combination with docetaxel in triple-negative breast (TNBC) and prostate cancer models. In vitro, AZD8186 inhibited growth of a range of cell lines. Sensitivity was associated with inhibition of the AKT pathway. Cells sensitive to AZD8186 (GI 50 < 1 mmol/L) are enriched for, but not exclusively associated with, PTEN deficiency. In vivo, AZD8186 inhibits PI3K pathway biomarkers in prostate and TNBC tumors. Scheduling treatment with AZD8186 shows antitumor activity required only intermittent exposure, and that increased tumor control is achieved when AZD8186 is used in combination with docetaxel. AZD8186 is a potent inhibitor of PI3Kb with activity against PI3Kd signaling, and has potential to reduce growth of tumors dependent on dysregulated PTEN for growth. Moreover, AZD8186 can be combined with docetaxel, a chemotherapy commonly used to treat advanced TBNC and prostate tumors. The ability to schedule AZD8186 and maintain efficacy offers opportunity to combine AZD8186 more effectively with other drugs.

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Section: Discussionmentioning

confidence: 99%

Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

Hancox

Cosulich

Hanson

et al. 2015

Molecular Cancer Therapeutics

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“…[5][6][7][8] In these patients, the BCR signalosome inhibitors ibrutinib and idelalisib induce a rapid decrease in lymphadenopathy, accompanied by transient lymphocytosis. 6,[9][10][11] In CLL and MCL, we have previously demonstrated that ibrutinib and idelalisib target BCR-controlled -and ibrutinib also chemokinecontrolled -integrin-mediated adhesion, resulting in mobilization of the malignant cells from their protective niches in the lymphoid organs into the circulation, followed by lymphoma regression. 5,6,8 Recently, ibrutinib received FDA and EMA approval for the treatment of CLL and MCL, and idelalisib for small lymphocytic lymphoma and follicular lymphoma.…”

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confidence: 99%

Ibrutinib and idelalisib target B cell receptor- but not CXCL12/CXCR4-controlled integrin-mediated adhesion in Waldenstrom macroglobulinemia

et al. 2015

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“…3 This range is well illustrated in the 2 present studies: the model used by Chen et al is an inducible Jak2V617F…”

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confidence: 51%

“…These drugs are part of a promising new strategy for the effective targeted treatment of CLL and have been recently approved by the US Food and Drug Administration. 2,3 Among the new therapies intended for CLL, much attention is being paid to the implementation of agents with a high potential for triggering apoptosis of tumor cells. 4 The PI3K/AKT signaling pathway plays a pivotal role in regulating multiple cellular events supporting the survival of CLL B cells.…”

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confidence: 99%

Novel target to kill CLL

Robak

Smolewski

2015

Blood

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Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia

Abstract: Key Points Idelalisib was evaluated in 54 patients with heavily pretreated chronic lymphocytic leukemia, and target inhibition was documented in vivo. Oral idelalisib therapy demonstrated a favorable safety profile and rapidly induced durable disease control in the majority of patients.

Cited by 543 publications

References 32 publications

Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

Inhibition of PI3Kβ Signaling with AZD8186 Inhibits Growth of PTEN-Deficient Breast and Prostate Tumors Alone and in Combination with Docetaxel

Ibrutinib and idelalisib target B cell receptor- but not CXCL12/CXCR4-controlled integrin-mediated adhesion in Waldenstrom macroglobulinemia

Novel target to kill CLL

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