Inhibiting Aurora Kinases Reduces Tumor Growth and Suppresses Tumor Recurrence after Chemotherapy in Patient-Derived Triple-Negative Breast Cancer Xenografts

Romanelli, Angela; Clark, Anderson; Assayag, Franck; Château-Joubert, Sophie; Poupon, Marie‐France; Servely, Jean-Luc; Fontaine, Jean‐Jacques; Liu, Xiaohong; Spooner, E. T. C.; Goodstal, Samantha; Crémoux, Patricia de; Bièche, Ivan; Decaudin, Didier; Marangoni, Elisabetta

doi:10.1158/1535-7163.mct-12-0441-t

Cited by 42 publications

(35 citation statements)

References 35 publications

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“…The negative impact on normal tissue homeostasis could limit the utility of this combination, although prophylactic administration of granulocyte colony-stimulating factor may help decrease the duration of neutropenia (18). One area for further investigation will be to evaluate the activity of AMG 900 alone and in combination with MTAs in either patientderived cancer xenografts or a genetically engineered mouse model of human MBC (37,38). These alternative preclinical models may more closely mirror human disease (e.g., tumor heterogeneity, multifactorial nature of MDR) and allow for a more fateful assessment of drug efficacy.…”

Section: Discussionmentioning

confidence: 99%

AMG 900, a Small-Molecule Inhibitor of Aurora Kinases, Potentiates the Activity of Microtubule-Targeting Agents in Human Metastatic Breast Cancer Models

Bush

Payton

Heller

et al. 2013

Molecular Cancer Therapeutics

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Breast cancer is the most prevalent malignancy affecting women and ranks second in cancer-related deaths, in which death occurs primarily from metastatic disease. Triple-negative breast cancer (TNBC) is a more aggressive and metastatic subtype of breast cancer that is initially responsive to treatment of microtubuletargeting agents (MTA) such as taxanes. Recently, we reported the characterization of AMG 900, an orally bioavailable, potent, and highly selective pan-Aurora kinase inhibitor that is active in multidrug-resistant cell lines. In this report, we investigate the activity of AMG 900 alone and in combination with two distinct classes of MTAs (taxanes and epothilones) in multidrug-resistant TNBC cell lines and xenografts. In TNBC cells, AMG 900 inhibited phosphorylation of histone H3 on Ser 10

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Section: Discussionmentioning

confidence: 99%

AMG 900, a Small-Molecule Inhibitor of Aurora Kinases, Potentiates the Activity of Microtubule-Targeting Agents in Human Metastatic Breast Cancer Models

Bush

Payton

Heller

et al. 2013

Molecular Cancer Therapeutics

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“…Determined the efficacy of aurora kinase inhibitors in a PDTX model of triple-negative breast cancers[89]…”

Section: Figurementioning

confidence: 99%

One mouse, one patient paradigm: New avatars of personalized cancer therapy

2014

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Over the last few decades, study of cancer in mouse models has gained popularity. Sophisticated genetic manipulation technologies and commercialization of these murine systems have made it possible to generate mice to study human disease. Given the large socio-economic burden of cancer, both on academic research and the health care industry, there is a need for in vivo animal cancer models that can provide a rationale that is translatable to the clinic. Such a bench-to-bedside transition will facilitate a long term robust strategy that is economically feasible and clinically effective to manage cancer. The major hurdles in considering mouse models as a translational platform are the lack of tumor heterogeneity and genetic diversity, which are a hallmark of human cancers. The present review, while critical of these pitfalls, discusses two newly emerging concepts of personalized mouse models called “Mouse Avatars” and Co-clinical Trials. Development of “Mouse Avatars” entails implantation of patient tumor samples in mice for subsequent use in drug efficacy studies. These avatars allow for each patient to have their own tumor growing in an in vivo system, thereby allowing the identification of a personalized therapeutic regimen, eliminating the cost and toxicity associated with non-targeted chemotherapeutic measures. In Co-clinical Trials, genetically engineered mouse models (GEMMs) are used to guide therapy in an ongoing human patient trial. Murine and patient trials are conducted concurrently, and information obtained from the murine system is applied towards future clinical management of the patient’s tumor. The concurrent trials allow for a real-time integration of the murine and human tumor data. In combination with several molecular profiling techniques, the “Mouse Avatar” and Co-clinical Trial concepts have the potential to revolutionize the drug development and health care process. The present review outlines the current status, challenges and the future potential of these two new in vivo approaches in the field of personalized oncology.

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“…Phospho-S6, PmTOR, P-AKT, insulin-like growth factor-I receptor (IGF-IR), and PTEN rabbit antibodies were purchased from Cell Signaling Technology (Ozyme). Tissue microarrays (TMA) were built from the in vivo efficacy studies as previously described (8). Three xenografts from each treatment group and two tissue cores per tumor were included in the TMA.…”

Section: Morphologic and Ihc Analyses Of Tumorsmentioning

confidence: 99%

Acquired Resistance to Endocrine Treatments Is Associated with Tumor-Specific Molecular Changes in Patient-Derived Luminal Breast Cancer Xenografts

Cottu¹,

Bièche

Assayag³

et al. 2014

Clinical Cancer Research

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Purpose: Patients with luminal breast cancer (LBC) often become endocrine resistant over time. We investigated the molecular changes associated with acquired hormonoresistances in patient-derived xenografts of LBC. Experimental Design: Two LBC xenografts (HBCx22 and HBCx34) were treated with different endocrine treatments (ET) to obtain xenografts with acquired resistances to tamoxifen (TamR) and ovariectomy (OvaR). PI3K pathway activation was analyzed by Western blot analysis and IHC and responses to ET combined to everolimus were investigated in vivo. Gene expression analyses were performed by RT-PCR and Affymetrix arrays. Results: HBCx22 TamR xenograft was cross-resistant to several hormonotherapies, whereas HBCx22 OvaR and HBCx34 TamR exhibited a treatment-specific resistance profile. PI3K pathway was similarly activated in parental and resistant xenografts but the addition of everolimus did not restore the response to tamoxifen in TamR xenografts. In contrast, the combination of fulvestrant and everolimus induced tumor regression in vivo in HBCx34 TamR, where we found a cross-talk between the estrogen receptor (ER) and PI3K pathways. Expression of several ER-controlled genes and ER coregulators was significantly changed in both TamR and OvaR tumors, indicating impaired ER transcriptional activity. Expression changes associated with hormonoresistance were both tumor and treatment specific and were enriched for genes involved in cell growth, cell death, and cell survival. Conclusions: PDX models of LBC with acquired resistance to endocrine therapies show a great diversity of resistance phenotype, associated with specific deregulations of ER-mediated gene transcription. These models offer a tool for developing anticancer therapies and to investigate the dynamics of resistance emerging during pharmacologic interventions. Clin Cancer Res; 20(16); 4314–25. ©2014 AACR.

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Inhibiting Aurora Kinases Reduces Tumor Growth and Suppresses Tumor Recurrence after Chemotherapy in Patient-Derived Triple-Negative Breast Cancer Xenografts

Cited by 42 publications

References 35 publications

AMG 900, a Small-Molecule Inhibitor of Aurora Kinases, Potentiates the Activity of Microtubule-Targeting Agents in Human Metastatic Breast Cancer Models

AMG 900, a Small-Molecule Inhibitor of Aurora Kinases, Potentiates the Activity of Microtubule-Targeting Agents in Human Metastatic Breast Cancer Models

One mouse, one patient paradigm: New avatars of personalized cancer therapy

Acquired Resistance to Endocrine Treatments Is Associated with Tumor-Specific Molecular Changes in Patient-Derived Luminal Breast Cancer Xenografts

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