Efficacy and safety of biweekly i.v. administrations of the Aurora kinase inhibitor danusertib hydrochloride in independent cohorts of patients with advanced or metastatic breast, ovarian, colorectal, pancreatic, small-cell and non-small-cell lung cancer: a multi-tumour, multi-institutional phase II study

Schöffski, Patrick; Besse, Benjamin; Gauler, Thomas; Jonge, Maja J.A. de; Scambia, Giovanni; Santoro, Armando; Davite, C.; Jannuzzo, M. G.; Petroccione, Anna; Delord, Jean‐Pierre

doi:10.1093/annonc/mdu566

Cited by 50 publications

(30 citation statements)

References 20 publications

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“…Alisertib monotherapy had only modest impact in vivo, but it remains possible that an optimized dosing regimen could improve this response. Recent clinical trials in relapsed SCLC tested Alisertib monotherapy with ~20% of patients exhibiting partial responses (Melichar et al, 2015) while a pan-Aurora kinase inhibitor had no responses in a small number of relapsed patients (Schoffski et al, 2015). Current clinical trials are assessing Alisertib in combination with chemotherapy as a second-line therapy (NCT02038647).…”

Section: Discusssionmentioning

confidence: 99%

MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition

et al. 2017

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SUMMARY Loss of the tumor suppressors RB1 and TP53 and MYC amplification are frequent oncogenic events in small cell lung cancer (SCLC). We show that Myc expression cooperates with Rb1 and Trp53 loss in the mouse lung to promote aggressive, highly metastatic tumors, that are initially sensitive to chemotherapy followed by relapse, similar to human SCLC. Importantly, MYC drives a neuroendocrine-low “variant” subset of SCLC with high NEUROD1 expression corresponding to transcriptional profiles of human SCLC. Targeted drug screening reveals that SCLC with high MYC expression is vulnerable to Aurora kinase inhibition, which combined with chemotherapy strongly suppresses tumor progression and increases survival. These data identify molecular features for patient stratification and uncover a potential targeted treatment approach for MYC-driven SCLC.

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Section: Discusssionmentioning

confidence: 99%

MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition

et al. 2017

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“…In addition to alisertib, which inhibits both AURKA and AURKB (see below), both AURKA-dominant (MK5108 and MLN-8054) and AURKB-specific (barasertib) compounds showed a strong association with RB1, implying that inhibition of either Aurora kinase should be sufficient to achieve a synthetic lethality. Because myelosuppression has been encountered in clinical studies with AURKB-specific and dual AURKA/B inhibitors (27)(28)(29), but not AURKA-dominant drugs MK5108 and MLN-8054 (30, 31), we reasoned that specific inhibition of AURKA might be better tolerated than AURKB, resulting in a better therapeutic window and permitting a higher dose intensity to more effectively treat RB1-deficient cancers.…”

Section: The Cytotoxicity Of Aurkai In Rb1-mutant Cells Is Dependent mentioning

confidence: 99%

Aurora A Kinase Inhibition Is Synthetic Lethal with Loss of the RB1 Tumor Suppressor Gene

et al. 2019

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Loss-of-function mutations in the retinoblastoma gene RB1 are common in several treatment-refractory cancers such as small-cell lung cancer and triplenegative breast cancer. To identify drugs synthetic lethal with RB1 mutation (RB1 mut), we tested 36 cell-cycle inhibitors using a cancer cell panel profi ling approach optimized to discern cytotoxic from cytostatic effects. Inhibitors of the Aurora kinases AURKA and AURKB showed the strongest RB1 association in this assay. LY3295668, an AURKA inhibitor with over 1,000-fold selectivity versus AURKB, is distinguished by minimal toxicity to bone marrow cells at concentrations active against RB1 mut cancer cells and leads to durable regression of RB1 mut tumor xenografts at exposures that are well tolerated in rodents. Genetic suppression screens identifi ed enforcers of the spindle-assembly checkpoint (SAC) as essential for LY3295668 cytotoxicity in RB1-defi cient cancers and suggest a model in which a primed SAC creates a unique dependency on AURKA for mitotic exit and survival. SIGNIFICANCE: The identifi cation of a synthetic lethal interaction between RB1 and AURKA inhibition, and the discovery of a drug that can be dosed continuously to achieve uninterrupted inhibition of AURKA kinase activity without myelosuppression, suggest a new approach for the treatment of RB1-defi cient malignancies, including patients progressing on CDK4/6 inhibitors.

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“…Preliminary evidence from a phase II study indicates that alisertib (MLN8237), an oral Aurora A kinase inhibitor, has a generally manageable safety profile and results in durable disease control in multiple cancer types [37]. The Aurora A kinase inhibitor danusertib has shown an acceptable safety profile and promising clinical activity in patients with advanced hematological malignancies [43], but limited activity in phase I/II studies in advanced solid tumors [44, 45]. The most widely tested Aurora B kinase inhibitor is barasertib (AZD1152), which has been evaluated in both patients with advanced solid tumors and those with hematological cancers.…”

Section: Discussionmentioning

confidence: 99%

A phase I study of BI 811283, an Aurora B kinase inhibitor, in patients with advanced solid tumors

Mross

Richly

Frost

et al. 2016

Cancer Chemother Pharmacol

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PurposeThis phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and antitumor activity of the Aurora B kinase inhibitor BI 811283 in patients with advanced solid tumors.MethodsBI 811283 was administered via 24-h infusion on Days 1 and 15 of a 4-week cycle (schedule A) or Day 1 of a 3-week cycle (schedule B) in a modified 3 + 3 dose-escalation design. Pharmacodynamic assessments included immunohistochemistry for phosphorylated histone H3 (pHH3) on skin biopsies to determine Aurora B kinase inhibition and plasma concentrations of caspase-cleaved CK-18 (apoptosis marker).ResultsA total of 121 patients were treated. The MTDs of BI 811283 were 125 mg (schedule A) and 230 mg (schedule B). Dose-limiting toxicities were primarily hematological (febrile neutropenia and grade 4 neutropenia); the most common drug-related adverse effects included neutropenia, fatigue, leukopenia, nausea, alopecia, diarrhea, and decreased appetite. A trend toward a decrease in pHH3 was observed, with increasing BI 811283 doses, indicating target engagement; there was no consistent trend regarding caspase-cleaved CK-18 levels. No objective response was observed although 19 patients in each schedule achieved clinical benefit (stable disease).ConclusionsBI 811283 demonstrated a generally manageable safety profile and disease stabilization in some patients.Trial registrationEudraCT No: 2007-000191-17, ClinicalTrials.gov Identifier: NCT00701324.Electronic supplementary materialThe online version of this article (doi:10.1007/s00280-016-3095-6) contains supplementary material, which is available to authorized users.

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Abstract: 2006-003772-35.

Cited by 50 publications

References 20 publications

MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition

MYC Drives Progression of Small Cell Lung Cancer to a Variant Neuroendocrine Subtype with Vulnerability to Aurora Kinase Inhibition

Aurora A Kinase Inhibition Is Synthetic Lethal with Loss of the RB1 Tumor Suppressor Gene

A phase I study of BI 811283, an Aurora B kinase inhibitor, in patients with advanced solid tumors

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