BiopestPeptidV1, Main, Exploration, bibRecord, 000B71

Role of YAP1 as a Marker of Sensitivity to Dual AKT and P70S6K Inhibition in Ovarian and Uterine Malignancies.

Identifieur interne : 000B71 ( Main/Exploration ); précédent : 000B70; suivant : 000B72

Role of YAP1 as a Marker of Sensitivity to Dual AKT and P70S6K Inhibition in Ovarian and Uterine Malignancies.

Auteurs : Rebecca A. Previs [États-Unis] ; Guillermo N. Armaiz-Pena [Porto Rico] ; Cristina Ivan [États-Unis] ; Heather J. Dalton [États-Unis] ; Rajesha Rupaimoole [États-Unis] ; Jean M. Hansen [États-Unis] ; Yasmin Lyons [États-Unis] ; Jie Huang [États-Unis] ; Monika Haemmerle [États-Unis] ; Michael J. Wagner [États-Unis] ; Kshipra M. Gharpure [États-Unis] ; Archana S. Nagaraja [États-Unis] ; Justyna Filant [États-Unis] ; Michael H. Mcguire [États-Unis] ; Kyunghee Noh [États-Unis] ; Piotr L. Dorniak [États-Unis] ; Sarah L. Linesch [États-Unis] ; Lingegowda S. Mangala [États-Unis] ; Sunila Pradeep [États-Unis] ; Sherry Y. Wu [États-Unis] ; Anil K. Sood [États-Unis]

Source :

Journal of the National Cancer Institute [ 1460-2105 ] ; 2017.

RBID : pubmed:28376174

Descripteurs français

English descriptors

KwdEn :
- Adaptor Proteins, Signal Transducing (metabolism), Angiogenesis Inhibitors (administration & dosage), Angiogenesis Inhibitors (pharmacology), Animals (MeSH), Antineoplastic Agents, Phytogenic (administration & dosage), Antineoplastic Agents, Phytogenic (pharmacology), Antineoplastic Combined Chemotherapy Protocols (pharmacology), Apoptosis (drug effects), Bevacizumab (administration & dosage), Bevacizumab (pharmacology), Biomarkers, Tumor (metabolism), Cell Line, Tumor (MeSH), Cell Proliferation (drug effects), Female (MeSH), Humans (MeSH), Inhibitory Concentration 50 (MeSH), Kaplan-Meier Estimate (MeSH), Mice, Nude (MeSH), Ovarian Neoplasms (drug therapy), Ovarian Neoplasms (metabolism), Paclitaxel (administration & dosage), Paclitaxel (pharmacology), Phosphoproteins (metabolism), Protein Kinase Inhibitors (administration & dosage), Protein Kinase Inhibitors (pharmacology), Proto-Oncogene Proteins c-akt (antagonists & inhibitors), Proto-Oncogene Proteins c-akt (metabolism), Ribosomal Protein S6 Kinases, 70-kDa (antagonists & inhibitors), Ribosomal Protein S6 Kinases, 70-kDa (metabolism), Transcription Factors (MeSH), Tumor Burden (drug effects), Uterine Neoplasms (drug therapy), Uterine Neoplasms (metabolism), Xenograft Model Antitumor Assays (MeSH).
MESH :
- chemical , administration & dosage : Angiogenesis Inhibitors, Antineoplastic Agents, Phytogenic, Bevacizumab, Paclitaxel, Protein Kinase Inhibitors.
- chemical , antagonists & inhibitors : Proto-Oncogene Proteins c-akt, Ribosomal Protein S6 Kinases, 70-kDa.
- chemical , metabolism : Adaptor Proteins, Signal Transducing, Biomarkers, Tumor, Phosphoproteins, Proto-Oncogene Proteins c-akt, Ribosomal Protein S6 Kinases, 70-kDa.
- chemical , pharmacology : Angiogenesis Inhibitors, Antineoplastic Agents, Phytogenic, Bevacizumab, Paclitaxel, Protein Kinase Inhibitors.
- drug effects : Apoptosis, Cell Proliferation, Tumor Burden.
- drug therapy : Ovarian Neoplasms, Uterine Neoplasms.
- metabolism : Ovarian Neoplasms, Uterine Neoplasms.
- pharmacology : Antineoplastic Combined Chemotherapy Protocols.
- Animals, Cell Line, Tumor, Female, Humans, Inhibitory Concentration 50, Kaplan-Meier Estimate, Mice, Nude, Transcription Factors, Xenograft Model Antitumor Assays.

Abstract

Background

The PI3K/AKT/P70S6K pathway is an attractive therapeutic target in ovarian and uterine malignancies because of its high rate of deregulation and key roles in tumor growth. Here, we examined the biological effects of MSC2363318A, which is a novel inhibitor of AKT1, AKT3, and P70S6K.

Methods

Orthotopic murine models of ovarian and uterine cancer were utilized to study the effect of MSC2363318A on survival and regression. For each cell line, 10 mice were treated in each of the experimental arms tested. Moreover, in vitro experiments in 21 cell lines (MTT, immunoblot analysis, plasmid transfection, reverse phase protein array [RPPA]) were carried out to characterize underlying mechanisms and potential biomarkers of response. All statistical tests were two-sided.

Results

MSC2363318A decreased tumor growth and metastases in multiple murine orthotopic models of ovarian (SKOV3ip1, HeyA8, and Igrov1) and uterine (Hec1a) cancer by reducing proliferation and angiogenesis and increasing cell death. Statistically significant prolonged overall survival was achieved with combination MSC2363318A and paclitaxel in the SKUT2 (endometrioid) uterine cancer mouse model ( P < .001). Mice treated with combination MSC2363318A and paclitaxel had the longest overall survival (mean = 104.2 days, 95% confidence interval [CI] = 97.0 to 111.4) compared with those treated with vehicle (mean = 61.9 days, 95% CI = 46.3 to 77.5), MSC2363318A alone (mean = 89.7 days, 95% CI = 83.0 to 96.4), and paclitaxel alone (mean = 73.6 days, 95% CI = 53.4 to 93.8). Regression and stabilization of established tumors in the Ishikawa (endometrioid) uterine cancer model was observed in mice treated with combination MSC2363318A and paclitaxel. Synergy between MSC2363318A and paclitaxel was observed in vitro in cell lines that had an IC50 of 5 µM or greater. RPPA results identified YAP1 as a candidate marker to predict cell lines that were most sensitive to MSC2363318A (R = 0.54, P = .02). After establishment of a murine ovarian cancer model of adaptive anti-angiogenic resistance (SKOV3ip1-luciferase), we demonstrate that resensitization to bevacizumab occurs with the addition of MSC2363318A, resulting in improved overall survival ( P = .01) using the Kaplan-Meier method. Mice treated with bevacizumab induction followed by MSC2363318A had the longest overall survival (mean = 66.0 days, 95% CI = 53.9 to 78.1) compared with mice treated with control (mean = 42.0 days, 95% CI = 31.4 to 52.6) and bevacizumab-sensitive mice (mean = 47.2 days; 95% CI = 37.5 to 56.9).

Conclusions

MSC2363318A has therapeutic efficacy in multiple preclinical models of ovarian and uterine cancer. These findings support clinical development of a dual AKT/P70S6K inhibitor.

DOI: 10.1093/jnci/djw296
PubMed: 28376174
PubMed Central: PMC6059189

Affiliations:

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<author><name sortKey="Huang, Jie" sort="Huang, Jie" uniqKey="Huang J" first="Jie" last="Huang">Jie Huang</name>
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<author><name sortKey="Noh, Kyunghee" sort="Noh, Kyunghee" uniqKey="Noh K" first="Kyunghee" last="Noh">Kyunghee Noh</name>
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<author><name sortKey="Dorniak, Piotr L" sort="Dorniak, Piotr L" uniqKey="Dorniak P" first="Piotr L" last="Dorniak">Piotr L. Dorniak</name>
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<author><name sortKey="Linesch, Sarah L" sort="Linesch, Sarah L" uniqKey="Linesch S" first="Sarah L" last="Linesch">Sarah L. Linesch</name>
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<country xml:lang="fr">États-Unis</country>
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<author><name sortKey="Mangala, Lingegowda S" sort="Mangala, Lingegowda S" uniqKey="Mangala L" first="Lingegowda S" last="Mangala">Lingegowda S. Mangala</name>
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<country xml:lang="fr">États-Unis</country>
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<author><name sortKey="Pradeep, Sunila" sort="Pradeep, Sunila" uniqKey="Pradeep S" first="Sunila" last="Pradeep">Sunila Pradeep</name>
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<country xml:lang="fr">États-Unis</country>
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<author><name sortKey="Wu, Sherry Y" sort="Wu, Sherry Y" uniqKey="Wu S" first="Sherry Y" last="Wu">Sherry Y. Wu</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
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<author><name sortKey="Sood, Anil K" sort="Sood, Anil K" uniqKey="Sood A" first="Anil K" last="Sood">Anil K. Sood</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:affiliation>Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:affiliation>Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
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<sourceDesc><biblStruct><analytic><title xml:lang="en">Role of YAP1 as a Marker of Sensitivity to Dual AKT and P70S6K Inhibition in Ovarian and Uterine Malignancies.</title>
<author><name sortKey="Previs, Rebecca A" sort="Previs, Rebecca A" uniqKey="Previs R" first="Rebecca A" last="Previs">Rebecca A. Previs</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Armaiz Pena, Guillermo N" sort="Armaiz Pena, Guillermo N" uniqKey="Armaiz Pena G" first="Guillermo N" last="Armaiz-Pena">Guillermo N. Armaiz-Pena</name>
<affiliation wicri:level="1"><nlm:affiliation>Department of Basic Sciences, Division of Pharmacology, Ponce Health Sciences University, Ponce, Puerto Rico.</nlm:affiliation>
<country xml:lang="fr">Porto Rico</country>
<wicri:regionArea>Department of Basic Sciences, Division of Pharmacology, Ponce Health Sciences University, Ponce</wicri:regionArea>
<wicri:noRegion>Ponce</wicri:noRegion>
</affiliation>
<affiliation wicri:level="1"><nlm:affiliation>Division of Cancer Biology, Ponce Research Institute, Ponce, Puerto Rico.</nlm:affiliation>
<country xml:lang="fr">Porto Rico</country>
<wicri:regionArea>Division of Cancer Biology, Ponce Research Institute, Ponce</wicri:regionArea>
<wicri:noRegion>Ponce</wicri:noRegion>
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<author><name sortKey="Ivan, Cristina" sort="Ivan, Cristina" uniqKey="Ivan C" first="Cristina" last="Ivan">Cristina Ivan</name>
<affiliation wicri:level="2"><nlm:affiliation>Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
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<author><name sortKey="Dalton, Heather J" sort="Dalton, Heather J" uniqKey="Dalton H" first="Heather J" last="Dalton">Heather J. Dalton</name>
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<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
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<author><name sortKey="Rupaimoole, Rajesha" sort="Rupaimoole, Rajesha" uniqKey="Rupaimoole R" first="Rajesha" last="Rupaimoole">Rajesha Rupaimoole</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
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<author><name sortKey="Hansen, Jean M" sort="Hansen, Jean M" uniqKey="Hansen J" first="Jean M" last="Hansen">Jean M. Hansen</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Lyons, Yasmin" sort="Lyons, Yasmin" uniqKey="Lyons Y" first="Yasmin" last="Lyons">Yasmin Lyons</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Huang, Jie" sort="Huang, Jie" uniqKey="Huang J" first="Jie" last="Huang">Jie Huang</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Haemmerle, Monika" sort="Haemmerle, Monika" uniqKey="Haemmerle M" first="Monika" last="Haemmerle">Monika Haemmerle</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Wagner, Michael J" sort="Wagner, Michael J" uniqKey="Wagner M" first="Michael J" last="Wagner">Michael J. Wagner</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Gharpure, Kshipra M" sort="Gharpure, Kshipra M" uniqKey="Gharpure K" first="Kshipra M" last="Gharpure">Kshipra M. Gharpure</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Nagaraja, Archana S" sort="Nagaraja, Archana S" uniqKey="Nagaraja A" first="Archana S" last="Nagaraja">Archana S. Nagaraja</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Filant, Justyna" sort="Filant, Justyna" uniqKey="Filant J" first="Justyna" last="Filant">Justyna Filant</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mcguire, Michael H" sort="Mcguire, Michael H" uniqKey="Mcguire M" first="Michael H" last="Mcguire">Michael H. Mcguire</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Noh, Kyunghee" sort="Noh, Kyunghee" uniqKey="Noh K" first="Kyunghee" last="Noh">Kyunghee Noh</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Dorniak, Piotr L" sort="Dorniak, Piotr L" uniqKey="Dorniak P" first="Piotr L" last="Dorniak">Piotr L. Dorniak</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Linesch, Sarah L" sort="Linesch, Sarah L" uniqKey="Linesch S" first="Sarah L" last="Linesch">Sarah L. Linesch</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Mangala, Lingegowda S" sort="Mangala, Lingegowda S" uniqKey="Mangala L" first="Lingegowda S" last="Mangala">Lingegowda S. Mangala</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:affiliation>Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Pradeep, Sunila" sort="Pradeep, Sunila" uniqKey="Pradeep S" first="Sunila" last="Pradeep">Sunila Pradeep</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Wu, Sherry Y" sort="Wu, Sherry Y" uniqKey="Wu S" first="Sherry Y" last="Wu">Sherry Y. Wu</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Sood, Anil K" sort="Sood, Anil K" uniqKey="Sood A" first="Anil K" last="Sood">Anil K. Sood</name>
<affiliation wicri:level="2"><nlm:affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:affiliation>Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
<affiliation wicri:level="2"><nlm:affiliation>Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</nlm:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX</wicri:regionArea>
<placeName><region type="state">Texas</region>
</placeName>
</affiliation>
</author>
</analytic>
<series><title level="j">Journal of the National Cancer Institute</title>
<idno type="eISSN">1460-2105</idno>
<imprint><date when="2017" type="published">2017</date>
</imprint>
</series>
</biblStruct>
</sourceDesc>
</fileDesc>
<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adaptor Proteins, Signal Transducing (metabolism)</term>
<term>Angiogenesis Inhibitors (administration & dosage)</term>
<term>Angiogenesis Inhibitors (pharmacology)</term>
<term>Animals (MeSH)</term>
<term>Antineoplastic Agents, Phytogenic (administration & dosage)</term>
<term>Antineoplastic Agents, Phytogenic (pharmacology)</term>
<term>Antineoplastic Combined Chemotherapy Protocols (pharmacology)</term>
<term>Apoptosis (drug effects)</term>
<term>Bevacizumab (administration & dosage)</term>
<term>Bevacizumab (pharmacology)</term>
<term>Biomarkers, Tumor (metabolism)</term>
<term>Cell Line, Tumor (MeSH)</term>
<term>Cell Proliferation (drug effects)</term>
<term>Female (MeSH)</term>
<term>Humans (MeSH)</term>
<term>Inhibitory Concentration 50 (MeSH)</term>
<term>Kaplan-Meier Estimate (MeSH)</term>
<term>Mice, Nude (MeSH)</term>
<term>Ovarian Neoplasms (drug therapy)</term>
<term>Ovarian Neoplasms (metabolism)</term>
<term>Paclitaxel (administration & dosage)</term>
<term>Paclitaxel (pharmacology)</term>
<term>Phosphoproteins (metabolism)</term>
<term>Protein Kinase Inhibitors (administration & dosage)</term>
<term>Protein Kinase Inhibitors (pharmacology)</term>
<term>Proto-Oncogene Proteins c-akt (antagonists & inhibitors)</term>
<term>Proto-Oncogene Proteins c-akt (metabolism)</term>
<term>Ribosomal Protein S6 Kinases, 70-kDa (antagonists & inhibitors)</term>
<term>Ribosomal Protein S6 Kinases, 70-kDa (metabolism)</term>
<term>Transcription Factors (MeSH)</term>
<term>Tumor Burden (drug effects)</term>
<term>Uterine Neoplasms (drug therapy)</term>
<term>Uterine Neoplasms (metabolism)</term>
<term>Xenograft Model Antitumor Assays (MeSH)</term>
</keywords>
<keywords scheme="KwdFr" xml:lang="fr"><term>Animaux (MeSH)</term>
<term>Antinéoplasiques d'origine végétale (administration et posologie)</term>
<term>Antinéoplasiques d'origine végétale (pharmacologie)</term>
<term>Apoptose (effets des médicaments et des substances chimiques)</term>
<term>Bévacizumab (administration et posologie)</term>
<term>Bévacizumab (pharmacologie)</term>
<term>Charge tumorale (effets des médicaments et des substances chimiques)</term>
<term>Concentration inhibitrice 50 (MeSH)</term>
<term>Estimation de Kaplan-Meier (MeSH)</term>
<term>Facteurs de transcription (MeSH)</term>
<term>Femelle (MeSH)</term>
<term>Humains (MeSH)</term>
<term>Inhibiteurs de l'angiogenèse (administration et posologie)</term>
<term>Inhibiteurs de l'angiogenèse (pharmacologie)</term>
<term>Inhibiteurs de protéines kinases (administration et posologie)</term>
<term>Inhibiteurs de protéines kinases (pharmacologie)</term>
<term>Lignée cellulaire tumorale (MeSH)</term>
<term>Marqueurs biologiques tumoraux (métabolisme)</term>
<term>Paclitaxel (administration et posologie)</term>
<term>Paclitaxel (pharmacologie)</term>
<term>Phosphoprotéines (métabolisme)</term>
<term>Prolifération cellulaire (effets des médicaments et des substances chimiques)</term>
<term>Protocoles de polychimiothérapie antinéoplasique (pharmacologie)</term>
<term>Protéines adaptatrices de la transduction du signal (métabolisme)</term>
<term>Protéines proto-oncogènes c-akt (antagonistes et inhibiteurs)</term>
<term>Protéines proto-oncogènes c-akt (métabolisme)</term>
<term>Ribosomal Protein S6 Kinases, 70-kDa (antagonistes et inhibiteurs)</term>
<term>Ribosomal Protein S6 Kinases, 70-kDa (métabolisme)</term>
<term>Souris nude (MeSH)</term>
<term>Tests d'activité antitumorale sur modèle de xénogreffe (MeSH)</term>
<term>Tumeurs de l'ovaire (métabolisme)</term>
<term>Tumeurs de l'ovaire (traitement médicamenteux)</term>
<term>Tumeurs de l'utérus (métabolisme)</term>
<term>Tumeurs de l'utérus (traitement médicamenteux)</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="administration & dosage" xml:lang="en"><term>Angiogenesis Inhibitors</term>
<term>Antineoplastic Agents, Phytogenic</term>
<term>Bevacizumab</term>
<term>Paclitaxel</term>
<term>Protein Kinase Inhibitors</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Proto-Oncogene Proteins c-akt</term>
<term>Ribosomal Protein S6 Kinases, 70-kDa</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Adaptor Proteins, Signal Transducing</term>
<term>Biomarkers, Tumor</term>
<term>Phosphoproteins</term>
<term>Proto-Oncogene Proteins c-akt</term>
<term>Ribosomal Protein S6 Kinases, 70-kDa</term>
</keywords>
<keywords scheme="MESH" type="chemical" qualifier="pharmacology" xml:lang="en"><term>Angiogenesis Inhibitors</term>
<term>Antineoplastic Agents, Phytogenic</term>
<term>Bevacizumab</term>
<term>Paclitaxel</term>
<term>Protein Kinase Inhibitors</term>
</keywords>
<keywords scheme="MESH" qualifier="administration et posologie" xml:lang="fr"><term>Antinéoplasiques d'origine végétale</term>
<term>Bévacizumab</term>
<term>Inhibiteurs de l'angiogenèse</term>
<term>Inhibiteurs de protéines kinases</term>
<term>Paclitaxel</term>
</keywords>
<keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Protéines proto-oncogènes c-akt</term>
<term>Ribosomal Protein S6 Kinases, 70-kDa</term>
</keywords>
<keywords scheme="MESH" qualifier="drug effects" xml:lang="en"><term>Apoptosis</term>
<term>Cell Proliferation</term>
<term>Tumor Burden</term>
</keywords>
<keywords scheme="MESH" qualifier="drug therapy" xml:lang="en"><term>Ovarian Neoplasms</term>
<term>Uterine Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="effets des médicaments et des substances chimiques" xml:lang="fr"><term>Apoptose</term>
<term>Charge tumorale</term>
<term>Prolifération cellulaire</term>
</keywords>
<keywords scheme="MESH" qualifier="metabolism" xml:lang="en"><term>Ovarian Neoplasms</term>
<term>Uterine Neoplasms</term>
</keywords>
<keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Marqueurs biologiques tumoraux</term>
<term>Phosphoprotéines</term>
<term>Protéines adaptatrices de la transduction du signal</term>
<term>Protéines proto-oncogènes c-akt</term>
<term>Ribosomal Protein S6 Kinases, 70-kDa</term>
<term>Tumeurs de l'ovaire</term>
<term>Tumeurs de l'utérus</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacologie" xml:lang="fr"><term>Antinéoplasiques d'origine végétale</term>
<term>Bévacizumab</term>
<term>Inhibiteurs de l'angiogenèse</term>
<term>Inhibiteurs de protéines kinases</term>
<term>Paclitaxel</term>
<term>Protocoles de polychimiothérapie antinéoplasique</term>
</keywords>
<keywords scheme="MESH" qualifier="pharmacology" xml:lang="en"><term>Antineoplastic Combined Chemotherapy Protocols</term>
</keywords>
<keywords scheme="MESH" qualifier="traitement médicamenteux" xml:lang="fr"><term>Tumeurs de l'ovaire</term>
<term>Tumeurs de l'utérus</term>
</keywords>
<keywords scheme="MESH" xml:lang="en"><term>Animals</term>
<term>Cell Line, Tumor</term>
<term>Female</term>
<term>Humans</term>
<term>Inhibitory Concentration 50</term>
<term>Kaplan-Meier Estimate</term>
<term>Mice, Nude</term>
<term>Transcription Factors</term>
<term>Xenograft Model Antitumor Assays</term>
</keywords>
<keywords scheme="MESH" xml:lang="fr"><term>Animaux</term>
<term>Concentration inhibitrice 50</term>
<term>Estimation de Kaplan-Meier</term>
<term>Facteurs de transcription</term>
<term>Femelle</term>
<term>Humains</term>
<term>Lignée cellulaire tumorale</term>
<term>Souris nude</term>
<term>Tests d'activité antitumorale sur modèle de xénogreffe</term>
</keywords>
</textClass>
</profileDesc>
</teiHeader>
<front><div type="abstract" xml:lang="en"><p><b>Background</b>
</p>
<p>The PI3K/AKT/P70S6K pathway is an attractive therapeutic target in ovarian and uterine malignancies because of its high rate of deregulation and key roles in tumor growth. Here, we examined the biological effects of MSC2363318A, which is a novel inhibitor of AKT1, AKT3, and P70S6K.</p>
</div>
<div type="abstract" xml:lang="en"><p><b>Methods</b>
</p>
<p>Orthotopic murine models of ovarian and uterine cancer were utilized to study the effect of MSC2363318A on survival and regression. For each cell line, 10 mice were treated in each of the experimental arms tested. Moreover, in vitro experiments in 21 cell lines (MTT, immunoblot analysis, plasmid transfection, reverse phase protein array [RPPA]) were carried out to characterize underlying mechanisms and potential biomarkers of response. All statistical tests were two-sided.</p>
</div>
<div type="abstract" xml:lang="en"><p><b>Results</b>
</p>
<p>MSC2363318A decreased tumor growth and metastases in multiple murine orthotopic models of ovarian (SKOV3ip1, HeyA8, and Igrov1) and uterine (Hec1a) cancer by reducing proliferation and angiogenesis and increasing cell death. Statistically significant prolonged overall survival was achieved with combination MSC2363318A and paclitaxel in the SKUT2 (endometrioid) uterine cancer mouse model ( P <  .001). Mice treated with combination MSC2363318A and paclitaxel had the longest overall survival (mean = 104.2 days, 95% confidence interval [CI] = 97.0 to 111.4) compared with those treated with vehicle (mean = 61.9 days, 95% CI = 46.3 to 77.5), MSC2363318A alone (mean = 89.7 days, 95% CI = 83.0 to 96.4), and paclitaxel alone (mean = 73.6 days, 95% CI = 53.4 to 93.8). Regression and stabilization of established tumors in the Ishikawa (endometrioid) uterine cancer model was observed in mice treated with combination MSC2363318A and paclitaxel. Synergy between MSC2363318A and paclitaxel was observed in vitro in cell lines that had an IC50 of 5 µM or greater. RPPA results identified YAP1 as a candidate marker to predict cell lines that were most sensitive to MSC2363318A (R = 0.54, P =  .02). After establishment of a murine ovarian cancer model of adaptive anti-angiogenic resistance (SKOV3ip1-luciferase), we demonstrate that resensitization to bevacizumab occurs with the addition of MSC2363318A, resulting in improved overall survival ( P =  .01) using the Kaplan-Meier method. Mice treated with bevacizumab induction followed by MSC2363318A had the longest overall survival (mean = 66.0 days, 95% CI = 53.9 to 78.1) compared with mice treated with control (mean = 42.0 days, 95% CI = 31.4 to 52.6) and bevacizumab-sensitive mice (mean = 47.2 days; 95% CI = 37.5 to 56.9).</p>
</div>
<div type="abstract" xml:lang="en"><p><b>Conclusions</b>
</p>
<p>MSC2363318A has therapeutic efficacy in multiple preclinical models of ovarian and uterine cancer. These findings support clinical development of a dual AKT/P70S6K inhibitor.</p>
</div>
</front>
</TEI>
<pubmed><MedlineCitation Status="MEDLINE" Owner="NLM"><PMID Version="1">28376174</PMID>
<DateCompleted><Year>2017</Year>
<Month>05</Month>
<Day>24</Day>
</DateCompleted>
<DateRevised><Year>2020</Year>
<Month>05</Month>
<Day>02</Day>
</DateRevised>
<Article PubModel="Print"><Journal><ISSN IssnType="Electronic">1460-2105</ISSN>
<JournalIssue CitedMedium="Internet"><Volume>109</Volume>
<Issue>7</Issue>
<PubDate><Year>2017</Year>
<Month>07</Month>
<Day>01</Day>
</PubDate>
</JournalIssue>
<Title>Journal of the National Cancer Institute</Title>
<ISOAbbreviation>J Natl Cancer Inst</ISOAbbreviation>
</Journal>
<ArticleTitle>Role of YAP1 as a Marker of Sensitivity to Dual AKT and P70S6K Inhibition in Ovarian and Uterine Malignancies.</ArticleTitle>
<ELocationID EIdType="doi" ValidYN="Y">10.1093/jnci/djw296</ELocationID>
<Abstract><AbstractText Label="Background">The PI3K/AKT/P70S6K pathway is an attractive therapeutic target in ovarian and uterine malignancies because of its high rate of deregulation and key roles in tumor growth. Here, we examined the biological effects of MSC2363318A, which is a novel inhibitor of AKT1, AKT3, and P70S6K.</AbstractText>
<AbstractText Label="Methods">Orthotopic murine models of ovarian and uterine cancer were utilized to study the effect of MSC2363318A on survival and regression. For each cell line, 10 mice were treated in each of the experimental arms tested. Moreover, in vitro experiments in 21 cell lines (MTT, immunoblot analysis, plasmid transfection, reverse phase protein array [RPPA]) were carried out to characterize underlying mechanisms and potential biomarkers of response. All statistical tests were two-sided.</AbstractText>
<AbstractText Label="Results">MSC2363318A decreased tumor growth and metastases in multiple murine orthotopic models of ovarian (SKOV3ip1, HeyA8, and Igrov1) and uterine (Hec1a) cancer by reducing proliferation and angiogenesis and increasing cell death. Statistically significant prolonged overall survival was achieved with combination MSC2363318A and paclitaxel in the SKUT2 (endometrioid) uterine cancer mouse model ( P <  .001). Mice treated with combination MSC2363318A and paclitaxel had the longest overall survival (mean = 104.2 days, 95% confidence interval [CI] = 97.0 to 111.4) compared with those treated with vehicle (mean = 61.9 days, 95% CI = 46.3 to 77.5), MSC2363318A alone (mean = 89.7 days, 95% CI = 83.0 to 96.4), and paclitaxel alone (mean = 73.6 days, 95% CI = 53.4 to 93.8). Regression and stabilization of established tumors in the Ishikawa (endometrioid) uterine cancer model was observed in mice treated with combination MSC2363318A and paclitaxel. Synergy between MSC2363318A and paclitaxel was observed in vitro in cell lines that had an IC50 of 5 µM or greater. RPPA results identified YAP1 as a candidate marker to predict cell lines that were most sensitive to MSC2363318A (R = 0.54, P =  .02). After establishment of a murine ovarian cancer model of adaptive anti-angiogenic resistance (SKOV3ip1-luciferase), we demonstrate that resensitization to bevacizumab occurs with the addition of MSC2363318A, resulting in improved overall survival ( P =  .01) using the Kaplan-Meier method. Mice treated with bevacizumab induction followed by MSC2363318A had the longest overall survival (mean = 66.0 days, 95% CI = 53.9 to 78.1) compared with mice treated with control (mean = 42.0 days, 95% CI = 31.4 to 52.6) and bevacizumab-sensitive mice (mean = 47.2 days; 95% CI = 37.5 to 56.9).</AbstractText>
<AbstractText Label="Conclusions">MSC2363318A has therapeutic efficacy in multiple preclinical models of ovarian and uterine cancer. These findings support clinical development of a dual AKT/P70S6K inhibitor.</AbstractText>
<CopyrightInformation>© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.</CopyrightInformation>
</Abstract>
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<Initials>RA</Initials>
<AffiliationInfo><Affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</Affiliation>
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<AffiliationInfo><Affiliation>Department of Basic Sciences, Division of Pharmacology, Ponce Health Sciences University, Ponce, Puerto Rico.</Affiliation>
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<AffiliationInfo><Affiliation>Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</Affiliation>
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<AffiliationInfo><Affiliation>Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</Affiliation>
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<AffiliationInfo><Affiliation>Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.</Affiliation>
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<Acronym>GM</Acronym>
<Agency>NIGMS NIH HHS</Agency>
<Country>United States</Country>
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<Acronym>CA</Acronym>
<Agency>NCI NIH HHS</Agency>
<Country>United States</Country>
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<Grant><GrantID>R01 CA109298</GrantID>
<Acronym>CA</Acronym>
<Agency>NCI NIH HHS</Agency>
<Country>United States</Country>
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<Grant><GrantID>T32 CA101642</GrantID>
<Acronym>CA</Acronym>
<Agency>NCI NIH HHS</Agency>
<Country>United States</Country>
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<MedlineTA>J Natl Cancer Inst</MedlineTA>
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<ISSNLinking>0027-8874</ISSNLinking>
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<Reference><Citation>PLoS One. 2014 Mar 12;9(3):e91770</Citation>
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<Reference><Citation>Nature. 2007 Jul 26;448(7152):439-44</Citation>
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<name sortKey="Huang, Jie" sort="Huang, Jie" uniqKey="Huang J" first="Jie" last="Huang">Jie Huang</name>
<name sortKey="Ivan, Cristina" sort="Ivan, Cristina" uniqKey="Ivan C" first="Cristina" last="Ivan">Cristina Ivan</name>
<name sortKey="Linesch, Sarah L" sort="Linesch, Sarah L" uniqKey="Linesch S" first="Sarah L" last="Linesch">Sarah L. Linesch</name>
<name sortKey="Lyons, Yasmin" sort="Lyons, Yasmin" uniqKey="Lyons Y" first="Yasmin" last="Lyons">Yasmin Lyons</name>
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Role of YAP1 as a Marker of Sensitivity to Dual AKT and P70S6K Inhibition in Ovarian and Uterine Malignancies.

Role of YAP1 as a Marker of Sensitivity to Dual AKT and P70S6K Inhibition in Ovarian and Uterine Malignancies.

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