71 results on '"Heather J. Dalton"'
Search Results
2. Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression
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Willem W. Overwijk, Anil K. Sood, Rajesha Rupaimoole, Jean M. Hansen, Nicholas B. Jennings, Michael McGuire, Min Soon Cho, Sherry Y. Wu, Gabriel Lopez-Berestein, Michael Andreeff, Hong Mu, Robert L. Coleman, Vianey Gonzalez-Villasana, Guillermo N. Armaiz-Pena, Wei Hu, Menashe Bar-Eli, Yared Hailemichael, Shaolin Ma, Robert R. Langley, Yasmin A. Lyons, Prahlad T. Ram, Rebecca A. Previs, Lingegowda S. Mangala, Sunila Pradeep, and Heather J. Dalton
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0301 basic medicine ,Cancer Research ,Cell Survival ,Antineoplastic Agents ,Drug resistance ,Biology ,Article ,Mice ,03 medical and health sciences ,Immune system ,Downregulation and upregulation ,In vivo ,Cell Line, Tumor ,Neoplasms ,Tumor Microenvironment ,medicine ,Animals ,Humans ,Macrophage ,Promoter Regions, Genetic ,Cell Proliferation ,Tumor microenvironment ,Neovascularization, Pathologic ,Macrophages ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,Blockade ,Gene Expression Regulation, Neoplastic ,Disease Models, Animal ,Receptors, Vascular Endothelial Growth Factor ,030104 developmental biology ,Oncology ,Drug Resistance, Neoplasm ,Immunology ,Female - Abstract
Purpose: VEGF-targeted therapies have modest efficacy in cancer patients, but acquired resistance is common. The mechanisms underlying such resistance are poorly understood. Experimental Design: To evaluate the potential role of immune cells in the development of resistance to VEGF blockade, we first established a preclinical model of adaptive resistance to anti-VEGF therapy. Additional in vitro and in vivo studies were carried out to characterize the role of macrophages in such resistance. Results: Using murine cancer models of adaptive resistance to anti-VEGF antibody (AVA), we found a previously unrecognized role of macrophages in such resistance. Macrophages were actively recruited to the tumor microenvironment and were responsible for the emergence of AVA resistance. Depletion of macrophages following emergence of resistance halted tumor growth and prolonged survival of tumor-bearing mice. In a macrophage-deficient mouse model, resistance to AVA failed to develop, but could be induced by injection of macrophages. Downregulation of macrophage VEGFR-1 and VEGFR-3 expression accompanied upregulation of alternative angiogenic pathways, facilitating escape from anti-VEGF therapy. Conclusions: These findings provide a new understanding of the mechanisms underlying the modest efficacy of current antiangiogenesis therapies and identify new opportunities for combination approaches for ovarian and other cancers. Clin Cancer Res; 23(22); 7034–46. ©2017 AACR.
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- 2017
3. Erythropoietin Stimulates Tumor Growth via EphB4
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Shyon Haghpeykar, Jean M. Hansen, Rebecca L. Stone, Chiyi Xiong, Alpa M. Nick, Sunila Pradeep, Kshipra M. Gharpure, Gabriel Lopez-Berestein, Guillermo N. Armaiz-Pena, Mien Chie Hung, Chun Li, Edna M. Mora, Cristian Rodriguez-Aguayo, Sherry Y. Wu, Archana S. Nagaraja, Martin Stein, Hee Dong Han, Rebecca A. Previs, Anil K. Sood, Blake W. Goodman, Kyunghee Noh, Masato Nishimura, Robert L. Coleman, Armin Schneider, Min Soon Cho, Chad V. Pecot, Rajesha Rupaimoole, Jie Huang, Lingegowda S. Mangala, Bulent Ozpolat, Yunfei Wen, Jinsong Liu, Pablo E. Vivas-Mejia, Stephan Brock, Padmavathi Jaladurgam, John E. Ladbury, Diana L. Urbauer, Koji Matsuo, Heather J. Dalton, Carola Krüger, Christopher G. Danes, David B. Jackson, Loren J. Stagg, Wei Hu, Behrouz Zand, and S. Neslihan Alpay
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Adult ,STAT3 Transcription Factor ,Cancer Research ,Blotting, Western ,Receptor, EphB4 ,Mice, Nude ,Breast Neoplasms ,Kaplan-Meier Estimate ,Article ,Young Adult ,Breast cancer ,Mediator ,Cell Line, Tumor ,hemic and lymphatic diseases ,Receptors, Erythropoietin ,medicine ,Animals ,Humans ,STAT3 ,Erythropoietin ,Aged ,Aged, 80 and over ,Ovarian Neoplasms ,biology ,Reverse Transcriptase Polymerase Chain Reaction ,Cancer ,Cell Biology ,Middle Aged ,medicine.disease ,Recombinant Proteins ,Erythropoietin receptor ,Gene Expression Regulation, Neoplastic ,Mice, Inbred C57BL ,Oncology ,Tumor progression ,Immunology ,Cancer cell ,Disease Progression ,MCF-7 Cells ,biology.protein ,Cancer research ,Female ,Protein Binding ,medicine.drug - Abstract
SummaryWhile recombinant human erythropoietin (rhEpo) has been widely used to treat anemia in cancer patients, concerns about its adverse effects on patient survival have emerged. A lack of correlation between expression of the canonical EpoR and rhEpo’s effects on cancer cells prompted us to consider the existence of an alternative Epo receptor. Here, we identified EphB4 as an Epo receptor that triggers downstream signaling via STAT3 and promotes rhEpo-induced tumor growth and progression. In human ovarian and breast cancer samples, expression of EphB4 rather than the canonical EpoR correlated with decreased disease-specific survival in rhEpo-treated patients. These results identify EphB4 as a critical mediator of erythropoietin-induced tumor progression and further provide clinically significant dimension to the biology of erythropoietin.
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- 2015
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4. Sustained Adrenergic Signaling Promotes Intratumoral Innervation Through Bdnf Induction
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Archana S. Nagaraja, Monika Haemmerle, Morgan Taylor, Danielle M. Herder, Stephen T. C. Wong, Merve Ozcan, Nouara C. Sadaoui, Mariella De Biasi, Frank C. Marini, Prahlad T. Ram, Lingegowda S. Mangala, Heather J. Dalton, Steve W. Cole, Wei Hu, Kshipra M. Gharpure, Susan K. Lutgendorf, Hee Dong Han, Anil K. Sood, Vasudha Sehgal, Sherry Y. Wu, Sunila Pradeep, Rebecca A. Previs, Yu Kang, Rajesha Rupaimoole, Erika L. Spaeth, Xiaoyun Xu, Myrthala Moreno-Smith, R.L. Dood, Behrouz Zand, Cristian Rodriguez-Aguayo, Tatiana Ortiz, Julie K. Allen, Guillermo N. Armaiz-Pena, Gabriel Lopez-Berestein, Justin Bottsford-Miller, and Temel Onkoloji
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0301 basic medicine ,Cancer Research ,Adrenergic ,Receptor tyrosine kinase ,Mice ,Norepinephrine ,03 medical and health sciences ,Neurotrophic factors ,Cell Line, Tumor ,Neoplasms ,Cyclic AMP ,Tumor Microenvironment ,Animals ,Guanine Nucleotide Exchange Factors ,Humans ,Receptor, trkB ,Medicine ,Peripheral Nerves ,Receptor ,Intratumoral innervation ,Feedback, Physiological ,Brain-derived neurotrophic factor ,Tumor microenvironment ,Membrane Glycoproteins ,biology ,business.industry ,Brain-Derived Neurotrophic Factor ,Bdnf induction ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Oncology ,Adrenergic signaling ,Receptors, Adrenergic, beta-3 ,biology.protein ,Cancer research ,Female ,Biyokimya. Hücre biyolojisi. Hücre genetiği ,Signal transduction ,business ,Signal Transduction ,Neurotrophin - Abstract
Mounting clinical and preclinical evidence supports a key role for sustained adrenergic signaling in the tumor microenvironment as a driver of tumor growth and progression. However, the mechanisms by which adrenergic neurotransmitters are delivered to the tumor microenvironment are not well understood. Here we present evidence for a feed-forward loop whereby adrenergic signaling leads to increased tumoral innervation. In response to catecholamines, tumor cells produced brain-derived neurotrophic factor (BDNF) in an ADRB3/cAMP/Epac/JNK-dependent manner. Elevated BDNF levels in the tumor microenvironment increased innervation by signaling through host neurotrophic receptor tyrosine kinase 2 receptors. In patients with cancer, high tumor nerve counts were significantly associated with increased BDNF and norepinephrine levels and decreased overall survival. Collectively, these data describe a novel pathway for tumor innervation, with resultant biological and clinical implications. Significance: Sustained adrenergic signaling promotes tumor growth and metastasis through BDNF-mediated tumoral innervation. Cancer Res; 78(12); 3233–42. ©2018 AACR.
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- 2018
5. PTEN Expression as a Predictor of Response to Focal Adhesion Kinase Inhibition in Uterine Cancer
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Rebecca A. Previs, Duangmani Thanapprapasr, Piotr L. Dorniak, Robert L. Coleman, Wei Hu, Heather J. Dalton, Rouba Ali-Fehmi, Jean M. Hansen, Anil K. Sood, Guillermo N. Armaiz-Pena, Rajesha Rupaimoole, Jie Huang, and Cristina Ivan
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Cancer Research ,Blotting, Western ,Aminopyridines ,Mice, Nude ,Biology ,Hydroxamic Acids ,Article ,Predictive Value of Tests ,Uterine cancer ,Cell Line, Tumor ,medicine ,Animals ,Humans ,PTEN ,Viability assay ,Phosphorylation ,Cell Proliferation ,Neovascularization, Pathologic ,Cell growth ,PTEN Phosphohydrolase ,Cancer ,Transfection ,Prognosis ,medicine.disease ,Immunohistochemistry ,Xenograft Model Antitumor Assays ,Platelet Endothelial Cell Adhesion Molecule-1 ,Ki-67 Antigen ,Oncology ,Apoptosis ,Focal Adhesion Protein-Tyrosine Kinases ,Mutation ,Uterine Neoplasms ,Cancer research ,biology.protein ,Female ,Topotecan ,Proto-Oncogene Proteins c-akt ,medicine.drug - Abstract
PTEN is known to be frequently mutated in uterine cancer and also dephosphorylates FAK. Here, we examined the impact of PTEN alterations on the response to treatment with a FAK inhibitor (GSK2256098). In vitro and in vivo therapeutic experiments were carried out using PTEN-mutated and PTEN-wild-type models of uterine cancer alone and in combination with chemotherapy. Treatment with GSK2256098 resulted in greater inhibition of pFAKY397 in PTEN-mutated (Ishikawa) than in PTEN-wild-type (Hec1A) cells. Ishikawa cells were more sensitive to GSK2256098 than the treated Hec1A cells. Ishikawa cells were transfected with a wild-type PTEN construct and pFAKY397 expression was unchanged after treatment with GSK2256098. Decreased cell viability and enhanced sensitivity to chemotherapy (paclitaxel and topotecan) in combination with GSK2256098 was observed in Ishikawa cells as compared with Hec1a cells. In the Ishikawa orthoptopic murine model, treatment with GSK2256098 resulted in lower tumor weights and fewer metastases than mice inoculated with Hec1A cells. Tumors treated with GSK2256098 had lower microvessel density (CD31), less cellular proliferation (Ki67), and higher apoptosis (TUNEL) rates in the Ishikawa model when compared with the Hec1a model. From a large cohort of evaluable patients, increased FAK and pFAKY397 expression levels were significantly related to poor overall survival. Moreover, PTEN levels were inversely related to pFAKY397 expression. These preclinical data demonstrate that PTEN-mutated uterine cancer responds better to FAK inhibition than does PTEN wild-type cancer. Therefore, PTEN could be a biomarker for predicting response to FAK-targeted therapy during clinical development. Mol Cancer Ther; 14(6); 1466–75. ©2015 AACR.
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- 2015
6. Adrenergic regulation of monocyte chemotactic protein 1 leads to enhanced macrophage recruitment and ovarian carcinoma growth
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Vianey Gonzalez-Villasana, Koji Matsuo, Anil K. Sood, Archana S. Nagaraja, Rebecca A. Previs, Nicholas B. Jennings, Guillermo N. Armaiz-Pena, Piotr L. Dorniak, Nouara C. Sadaoui, Jean M. Hansen, Susan K. Lutgendorf, Rebecca L. Stone, Jesusa M.G. Arevalo, Gabriel Lopez-Berestein, Steve W. Cole, Heather J. Dalton, and Cristian Rodriguez-Aguayo
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medicine.medical_specialty ,Epinephrine ,CD14 ,Mice, Nude ,Adrenergic ,Enzyme-Linked Immunosorbent Assay ,Kaplan-Meier Estimate ,CCL2 ,Biology ,Real-Time Polymerase Chain Reaction ,Mice ,Norepinephrine ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Humans ,Chemokine CCL2 ,030304 developmental biology ,Ovarian Neoplasms ,0303 health sciences ,Tumor microenvironment ,CD68 ,Macrophages ,Monocyte ,Carcinoma ,medicine.disease ,3. Good health ,Chemotaxis, Leukocyte ,ovarian cancer ,Endocrinology ,medicine.anatomical_structure ,Oncology ,Tumor progression ,030220 oncology & carcinogenesis ,MCP1 ,Female ,monocytes ,Ovarian cancer ,catecholamines ,Stress, Psychological ,Research Paper - Abstract
Increased adrenergic signaling facilitates tumor progression, but the underlying mechanisms remain poorly understood. We examined factors responsible for stress-mediated effects on monocyte/macrophage recruitment into the tumor microenvironment, and the resultant effects on tumor growth. In vitro, MCP1 was significantly increased after catecholamine exposure, which was mediated by cAMP and PKA. Tumor samples from mice subjected to daily restraint stress had elevated MCP1 gene and protein levels, increased CD14+ cells, and increased infiltration of CD68+ cells. hMCP1 siRNA-DOPC nanoparticles significantly abrogated daily restraint stress-induced tumor growth and inhibited infiltration of CD68+ and F4/80+ cells. In ovarian cancer patients, elevated peripheral blood monocytes and tumoral macrophages were associated with worse overall survival. Collectively, we demonstrate that increased adrenergic signaling is associated with macrophage infiltration and mediated by tumor cell-derived MCP1 production.
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- 2014
7. Role of YAP1 as a Marker of Sensitivity to Dual AKT and P70S6K Inhibition in Ovarian and Uterine Malignancies
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Kshipra M. Gharpure, Cristina Ivan, Anil K. Sood, Sarah L. Linesch, Kyunghee Noh, Jie Huang, Rebecca A. Previs, Monika Haemmerle, Rajesha Rupaimoole, Lingegowda S. Mangala, Michael J. Wagner, Michael McGuire, Guillermo N. Armaiz-Pena, Sunila Pradeep, Heather J. Dalton, Sherry Y. Wu, Archana S. Nagaraja, Yasmin A. Lyons, Piotr L. Dorniak, Justyna Filant, and Jean M. Hansen
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0301 basic medicine ,Oncology ,Cancer Research ,Angiogenesis ,Uterus ,AKT1 ,Angiogenesis Inhibitors ,Apoptosis ,Kaplan-Meier Estimate ,chemistry.chemical_compound ,0302 clinical medicine ,Antineoplastic Combined Chemotherapy Protocols ,Ovarian Neoplasms ,Ribosomal Protein S6 Kinases, 70-kDa ,Articles ,Tumor Burden ,Bevacizumab ,medicine.anatomical_structure ,Paclitaxel ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,Female ,medicine.drug ,medicine.medical_specialty ,Mice, Nude ,Biology ,Inhibitory Concentration 50 ,03 medical and health sciences ,Uterine cancer ,Cell Line, Tumor ,Internal medicine ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Protein Kinase Inhibitors ,Adaptor Proteins, Signal Transducing ,Cell Proliferation ,Cancer ,YAP-Signaling Proteins ,Phosphoproteins ,medicine.disease ,Antineoplastic Agents, Phytogenic ,Xenograft Model Antitumor Assays ,030104 developmental biology ,Endocrinology ,chemistry ,Ovarian cancer ,Proto-Oncogene Proteins c-akt ,Transcription Factors - 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
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- 2017
8. Activity of bevacizumab-containing regimens in recurrent low-grade serous ovarian or peritoneal cancer: A single institution experience
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David M. Gershenson, Priya Bhosale, Nicole D. Fleming, Charlotte C. Sun, Heather J. Dalton, and Kathleen M. Schmeler
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Sorafenib ,Adult ,Niacinamide ,medicine.medical_specialty ,Bevacizumab ,Databases, Factual ,Paclitaxel ,Serous carcinoma ,Gastroenterology ,Deoxycytidine ,Article ,Disease-Free Survival ,Carboplatin ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Progression-free survival ,Cyclophosphamide ,Peritoneal Neoplasms ,Aged ,Retrospective Studies ,Aged, 80 and over ,Ovarian Neoplasms ,030219 obstetrics & reproductive medicine ,business.industry ,Aromatase Inhibitors ,Phenylurea Compounds ,Obstetrics and Gynecology ,Cancer ,Retrospective cohort study ,Middle Aged ,medicine.disease ,Gemcitabine ,Surgery ,Serous fluid ,Oncology ,030220 oncology & carcinogenesis ,Female ,Neoplasm Recurrence, Local ,business ,Ovarian cancer ,Neoplasms, Cystic, Mucinous, and Serous ,medicine.drug - Abstract
Objective The aim of this study was to evaluate the activity of bevacizumab in a cohort of women with recurrent low-grade serous carcinoma of the ovary or peritoneum. Methods This single-institution retrospective study assessed all patients at MD Anderson Cancer Center with recurrent low-grade serous ovarian or peritoneal cancer who received bevacizumab from 2007 to 2016. Study endpoints included best response, median progression-free survival, median overall survival, and toxicity. Results Forty patients received 45 separate "patient-regimens." Most received bevacizumab in combination with chemotherapy. Complete response (CR) was seen in 7.5%, while 40% had partial responses (PR) and 30% achieved stable disease (SD). Disease progression occurred in nine patients (22.5%). Overall response rate (CR+PR) to bevacizumab-containing regimens was 47.5%. Clinical benefit (CR+PR+SD) was seen in 77.5% of patients. Median progression free survival was 10.2months (95% CI 7.9, 12.4). Median overall survival was 34.6months (95% CI 29.5, 39.7). Fifteen patients discontinued bevacizumab related to toxicity. Conclusions Bevacizumab, most often in combination with chemotherapy, has activity in recurrent low-grade ovarian cancer and should be considered a treatment option for these patients. Further investigation into the most effective chemotherapeutic agent in combination with bevacizumab is warranted.
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- 2017
9. Inhibiting Nuclear Phospho-Progesterone Receptor Enhances Antitumor Activity of Onapristone in Uterine Cancer
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Monika Haemmerle, Yan Huang, Russell Broaddus, Dahai Jiang, Cristina Ivan, Heather J. Dalton, Fangrong Shen, Rebecca A. Previs, Anil K. Sood, Robert L. Coleman, Yunjie Sun, Archana S. Nagaraja, R.L. Dood, Lingegowda S. Mangala, Jean M. Hansen, Sunila Pradeep, Wei Hu, Jie Huang, Nicholas B. Jennings, Michael McGuire, and Kyunghee Noh
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0301 basic medicine ,Cancer Research ,Mice, Nude ,Antineoplastic Agents ,Gonanes ,Article ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Uterine cancer ,Cell Line, Tumor ,Progesterone receptor ,Medicine ,Animals ,Humans ,Receptor ,Trametinib ,business.industry ,Antagonist ,Cancer ,medicine.disease ,030104 developmental biology ,Oncology ,Cell culture ,030220 oncology & carcinogenesis ,Uterine Neoplasms ,Cancer research ,Phosphorylation ,Female ,business ,Receptors, Progesterone - Abstract
Although progesterone receptor (PR)–targeted therapies are modestly active in patients with uterine cancer, their underlying molecular mechanisms are not well understood. The clinical use of such therapies is limited because of the lack of biomarkers that predict response to PR agonists (progestins) or PR antagonists (onapristone). Thus, understanding the underlying molecular mechanisms of action will provide an advance in developing novel combination therapies for cancer patients. Nuclear translocation of PR has been reported to be ligand-dependent or -independent. Here, we identified that onapristone, a PR antagonist, inhibited nuclear translocation of ligand-dependent or -independent (EGF) phospho-PR (S294), whereas trametinib inhibited nuclear translocation of EGF-induced phospho-PR (S294). Using orthotopic mouse models of uterine cancer, we demonstrated that the combination of onapristone and trametinib results in superior antitumor effects in uterine cancer models compared with either monotherapy. These synergistic effects are, in part, mediated through inhibiting the nuclear translocation of EGF-induced PR phosphorylation in uterine cancer cells. Targeting MAPK-dependent PR activation with onapristone and trametinib significantly inhibited tumor growth in preclinical uterine cancer models and is worthy of further clinical investigation. Mol Cancer Ther; 17(2); 464–73. ©2017 AACR.
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- 2017
10. Notch3 Pathway Alterations in Ovarian Cancer
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Tao Liu, Sunila Pradeep, Vasudha Sehgal, Prahlad T. Ram, Lingegowda S. Mangala, Ju Seog Lee, Hee Dong Han, Heather J. Dalton, Wei Hu, Susan L. Tucker, Sherry Y. Wu, Rajesha Rupaimoole, Keith A. Baggerly, Yunjie Sun, Jinsong Liu, Robert L. Coleman, Rebecca A. Previs, Cristina Ivan, Anil K. Sood, Takahito Miyake, Chad V. Pecot, Gabriel Lopez-Berestein, Jie Huang, Justin Bottsford-Miller, Alpa M. Nick, Yu Kang, and Behrouz Zand
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Dynamins ,Cancer Research ,Paclitaxel ,endocrine system diseases ,Notch signaling pathway ,Mice, Nude ,Apoptosis ,Kaplan-Meier Estimate ,Biology ,Endocytosis ,Article ,Transcriptome ,Mice ,Downregulation and upregulation ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Serrate-Jagged Proteins ,RNA, Small Interfering ,Receptor, Notch3 ,Oligonucleotide Array Sequence Analysis ,Ovarian Neoplasms ,Receptors, Notch ,Calcium-Binding Proteins ,Membrane Proteins ,medicine.disease ,Antineoplastic Agents, Phytogenic ,Xenograft Model Antitumor Assays ,Tumor Burden ,Cell biology ,Serous fluid ,Oncology ,Gene Knockdown Techniques ,Cancer research ,Intercellular Signaling Peptides and Proteins ,Jagged-1 Protein ,Female ,Neoplasms, Cystic, Mucinous, and Serous ,Ovarian cancer - Abstract
The Notch pathway plays an important role in the growth of high-grade serous ovarian (HGS-OvCa) and other cancers, but its clinical and biologic mechanisms are not well understood. Here, we found that the Notch pathway alterations are prevalent and significantly related to poor clinical outcome in patients with ovarian cancer. Particularly, Notch3 alterations, including amplification and upregulation, were highly associated with poor patient survival. Targeting Notch3 inhibited ovarian cancer growth and induced apoptosis. Importantly, we found that dynamin-mediated endocytosis was required for selectively activating Jagged-1–mediated Notch3 signaling. Cleaved Notch3 expression was the critical determinant of response to Notch-targeted therapy. Collectively, these data identify previously unknown mechanisms underlying Notch3 signaling and identify new, biomarker-driven approaches for therapy. Cancer Res; 74(12); 3282–93. ©2014 AACR.
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- 2014
11. Focal adhesion kinase
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Keith A. Baggerly, Angela Sanguino, Duangmani Thanapprapasr, Gabriel Lopez-Berestein, Alpa M. Nick, Rebecca L. Stone, Robert L. Coleman, Rehan Akbani, Susan K. Lutgendorf, Justin Bottsford-Miller, Koen DeGeest, Lixia Diao, Guillermo N. Armaiz-Pena, Heather J. Dalton, Anil K. Sood, Yu Kang, and Behrouz Zand
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Cancer Research ,Indoles ,Angiogenesis ,medicine.drug_class ,Gene Dosage ,Mice, Nude ,Angiogenesis Inhibitors ,Carcinoma, Ovarian Epithelial ,Tyrosine-kinase inhibitor ,Metastasis ,Focal adhesion ,Cell Movement ,Animals ,Humans ,Medicine ,Neoplasms, Glandular and Epithelial ,Neoplasm Metastasis ,Phosphorylation ,Protein Kinase Inhibitors ,Cell Proliferation ,Ovarian Neoplasms ,Pharmacology ,Tube formation ,Sulfonamides ,Neovascularization, Pathologic ,business.industry ,Cell growth ,Endothelial Cells ,medicine.disease ,Endothelial stem cell ,Oncology ,Focal Adhesion Protein-Tyrosine Kinases ,Cancer research ,Tyrosine ,Molecular Medicine ,Female ,business ,Ovarian cancer ,Research Paper - Abstract
This investigation describes the clinical significance of phosphorylated focal adhesion kinase (FAK) at the major activating tyrosine site (Y397) in epithelial ovarian cancer (EOC) cells and tumor-associated endothelial cells. FAK gene amplification as a mechanism for FAK overexpression and the effects of FAK tyrosine kinase inhibitor VS-6062 on tumor growth, metastasis, and angiogenesis were examined. FAK and phospho-FAKY397 were quantified in tumor (FAK-T; pFAK-T) and tumor-associated endothelial (FAK-endo; pFAK-endo) cell compartments of EOCs using immunostaining and qRT-PCR. Associations between expression levels and clinical variables were evaluated. Data from The Cancer Genome Atlas were used to correlate FAK gene copy number and expression levels in EOC specimens. The in vitro and in vivo effects of VS-6062 were assayed in preclinical models. FAK-T and pFAK-T overexpression was significantly associated with advanced stage disease and increased microvessel density (MVD). High MVD was observed in tumors with elevated endothelial cell FAK (59%) and pFAK (44%). Survival was adversely affected by FAK-T overexpression (3.03 vs 2.06 y, P = 0.004), pFAK-T (2.83 vs 1.78 y, P < 0.001), and pFAK-endo (2.33 vs 2.17 y, P = 0.005). FAK gene copy number was increased in 34% of tumors and correlated with expression levels (P < 0.001). VS-6062 significantly blocked EOC and endothelial cell migration as well as endothelial cell tube formation in vitro. VS-6062 reduced mean tumor weight by 56% (P = 0.005), tumor MVD by 40% (P = 0.0001), and extraovarian metastasis (P < 0.01) in orthotopic EOC mouse models. FAK may be a unique therapeutic target in EOC given the dual anti-angiogenic and anti-metastatic potential of FAK inhibitors.
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- 2014
12. Cross-talk between EphA2 and BRaf/CRaf Is a Key Determinant of Response to Dasatinib
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Sunila Pradeep, Anil K. Sood, Chad V. Pecot, Huang L, Jie Huang, Russell Broaddus, Yu Kang, Michael T. Deavers, Tao Liu, Chunhua Lu, Hee Dong Han, Nicholas B. Jennings, Wei Hu, Heather J. Dalton, Justin Bottsford-Miller, Duangmani Thanapprapasr, Behrouz Zand, Robert L. Coleman, Rajesha Rupaimoole, Bryan Fellman, Diana L. Urbauer, and Ju Won Roh
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Proto-Oncogene Proteins B-raf ,MAPK/ERK pathway ,Cancer Research ,Dasatinib ,Biology ,Article ,Mice ,Cell Line, Tumor ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,PTEN ,Protein Kinase Inhibitors ,PI3K/AKT/mTOR pathway ,Kinase ,Receptor, EphA2 ,Cancer ,Reverse phase protein lysate microarray ,medicine.disease ,EPH receptor A2 ,Gene Expression Regulation, Neoplastic ,Proto-Oncogene Proteins c-raf ,Thiazoles ,Pyrimidines ,Oncology ,Uterine Neoplasms ,biology.protein ,Cancer research ,Female ,Protein Multimerization ,medicine.drug - Abstract
Purpose: EphA2 is an attractive therapeutic target because of its diverse roles in cancer growth and progression. Dasatinib is a multikinase inhibitor that targets EphA2 and other kinases. However, reliable predictive markers and a better understanding of the mechanisms of response to this agent are needed. Experimental design: The effects of dasatinib on human uterine cancer cell lines were examined using a series of in vitro experiments, including MTT, Western blot analysis, and plasmid transfection. In vivo, an orthotopic mouse model of uterine cancer was utilized to identify the biologic effects of dasatinib. Molecular markers for response prediction and the mechanisms relevant to response to dasatinib were identified by using reverse phase protein array (RPPA), immunoprecipitation, and double immunofluorescence staining. Results: We show that high levels of CAV-1, EphA2 phosphorylation at S897, and the status of PTEN are key determinants of dasatinib response in uterine carcinoma. A set of markers essential for dasatinib response was also identified and includes CRaf, pCRafS338, pMAPKT202/Y204 (mitogen-activated protein kinase [MAPK] pathway), pS6S240/244, p70S6kT389 (mTOR pathway), and pAKTS473. A novel mechanism for response was discovered whereby high expression level of CAV-1 at the plasma membrane disrupts the BRaf/CRaf heterodimer and thus inhibits the activation of MAPK pathway during dasatinib treatment. Conclusions: Our in vitro and in vivo results provide a new understanding of EphA2 targeting by dasatinib and identify key predictors of therapeutic response. These findings have implications for ongoing dasatinib-based clinical trials. Clin Cancer Res; 20(7); 1846–55. ©2014 AACR.
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- 2014
13. Racial disparities in cervical cancer: Worse than we thought
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John H. Farley and Heather J. Dalton
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Cervical cancer ,Cancer Research ,medicine.medical_specialty ,business.industry ,Racial Groups ,MEDLINE ,Alternative medicine ,Uterine Cervical Neoplasms ,Health Status Disparities ,medicine.disease ,White People ,Black or African American ,03 medical and health sciences ,0302 clinical medicine ,Text mining ,Oncology ,030220 oncology & carcinogenesis ,Family medicine ,medicine ,Humans ,Female ,030212 general & internal medicine ,Healthcare Disparities ,business - Published
- 2016
14. Targeting Src and Tubulin in Mucinous Ovarian Carcinoma
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Anil K. Sood, Chad V. Pecot, Hyun Jin Choi, Jian H. Song, Sunila Pradeep, Tao Liu, Michael Frumovitz, Cristina Ivan, Wei Hu, David G. Hangauer, Nicholas B. Jennings, Takahito Miyake, Behrouz Zand, Heather J. Dalton, Gary E. Gallick, Keith A. Baggerly, Yu Kang, Jie Huang, Chunhua Lu, Yunfei Wen, Justin Bottsford-Miller, and Robert L. Coleman
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Oncology ,Cancer Research ,medicine.medical_specialty ,Organoplatinum Compounds ,Cell Survival ,Pyridines ,Morpholines ,Mice, Nude ,Antineoplastic Agents ,Apoptosis ,Biology ,Microtubules ,Article ,Inhibitory Concentration 50 ,Mice ,In vivo ,Cell Line, Tumor ,Internal medicine ,Ovarian carcinoma ,Acetamides ,medicine ,Animals ,Humans ,PTEN ,Cell Proliferation ,Ovarian Neoplasms ,Cell growth ,Cell Cycle ,PTEN Phosphohydrolase ,Cancer ,Drug Synergism ,Cell cycle ,medicine.disease ,Adenocarcinoma, Mucinous ,Xenograft Model Antitumor Assays ,Tubulin Modulators ,Tumor Burden ,Oxaliplatin ,src-Family Kinases ,biology.protein ,Cancer research ,Female ,Protein Multimerization ,Ovarian cancer ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Purpose: To investigate the antitumor effects of targeting Src and tubulin in mucinous ovarian carcinoma. Experimental Design: The in vitro and in vivo effects and molecular mechanisms of KX-01, which inhibits Src pathway and tubulin polymerization, were examined in mucinous ovarian cancer models. Results: In vitro studies using RMUG-S and RMUG-L cell lines showed that KX-01 inhibited cell proliferation, induced apoptosis, arrested the cell cycle at the G2–M phase, and enhanced the cytotoxicity of oxaliplatin in the KX-01–sensitive cell line, RMUG-S. In vivo studies showed that KX-01 significantly decreased tumor burden in RMUG-S and RMUG-L mouse models relative to untreated controls, and the effects were greater when KX-01 was combined with oxaliplatin. KX-01 alone and in combination with oxaliplatin significantly inhibited tumor growth by reducing cell proliferation and inducing apoptosis in vivo. PTEN knock-in experiments in RMUG-L cells showed improved response to KX-01. Reverse phase protein array analysis showed that in addition to blocking downstream molecules of Src family kinases, KX-01 also activated acute stress-inducing molecules. Conclusion: Our results showed that targeting both the Src pathway and tubulin with KX-01 significantly inhibited tumor growth in preclinical mucinous ovarian cancer models, suggesting that this may be a promising therapeutic approach for patients with mucinous ovarian carcinoma. Clin Cancer Res; 19(23); 6532–43. ©2013 AACR.
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- 2013
15. Antiangiogenic agents as a maintenance strategy for advanced epithelial ovarian cancer
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Dana M. Chase, Bradley J. Monk, John H. Farley, Heather J. Dalton, and Ivor Benjamin
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Vascular Endothelial Growth Factor A ,Oncology ,medicine.medical_specialty ,Bevacizumab ,Angiogenesis Inhibitors ,Carcinoma, Ovarian Epithelial ,Pharmacology ,Antibodies, Monoclonal, Humanized ,Pazopanib ,chemistry.chemical_compound ,Maintenance therapy ,Internal medicine ,medicine ,Clinical endpoint ,Animals ,Humans ,Molecular Targeted Therapy ,Neoplasms, Glandular and Epithelial ,Ovarian Neoplasms ,Clinical Trials as Topic ,Taxane ,business.industry ,Ovary ,Hematology ,Carboplatin ,Clinical trial ,chemistry ,Female ,Nintedanib ,business ,medicine.drug - Abstract
Bevacizumab is the first antiangiogenic agent to have demonstrated benefit as first-line and maintenance therapy in epithelial ovarian cancer (EOC), with the Gynecologic Oncology Group 218 and ICON 7 phase III trials revealing significantly prolonged progression-free survival (PFS) for carboplatin/paclitaxel plus bevacizumab followed by bevacizumab maintenance versus carboplatin/paclitaxel alone. Results are forthcoming from several phase III maintenance trials of investigational antiangiogenic agents, each evaluating PFS as the primary endpoint: AGO-OVAR12/LUME-Ovar1 (nintedanib [BIBF 1120]), AGO-OVAR16 (pazopanib), and TRINOVA-1, -2, and -3 (AMG 386). Here we review available data and ongoing clinical trials of investigational antiangiogenic agents as maintenance therapy for EOC. Current controversies, including uncertainties regarding the (1) most appropriate clinical trial endpoints, (2) optimal dosing, duration, and timing of therapy (e.g., with first-line chemotherapy and/or as maintenance monotherapy), and (3) feasibility, tolerability, and cost of adding these agents to platinum/taxane regimens are also highlighted.
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- 2013
16. Trabectedin as a New Chemotherapy Option in the Treatment of Relapsed Platinum Sensitive Ovarian Cancer
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Bradley J. Monk, Ivor Benjamin, Heather J. Dalton, and Adnan Tanovic
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Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Antineoplastic Agents ,Dioxoles ,Neutropenia ,Pharmacology ,Ecteinascidia turbinata ,Recurrence ,Tetrahydroisoquinolines ,Internal medicine ,Drug Discovery ,medicine ,Humans ,media_common.cataloged_instance ,European union ,Trabectedin ,media_common ,Ovarian Neoplasms ,Chemotherapy ,Ifosfamide ,biology ,business.industry ,Soft tissue sarcoma ,medicine.disease ,biology.organism_classification ,Female ,Ovarian cancer ,business ,medicine.drug - Abstract
Trabectedin (ET-743, Yondelis®) is a novel marine antineoplastic alkaloid with a unique mechanism of action. The active substance trabectedin, a tetrahydroisoquinoline alkaloid, is a natural product originally isolated from the Caribbean sea squirt, Ecteinascidia turbinata and is currently manufactured by total synthesis. Trabectedin is licensed by the Spanish pharmaceutical drug company, PharmaMar and co-developed by Johnson & Johnson Pharmaceutical Research and Development, L.L.C., pursuant to a licensing agreement with PharmaMar. Trabectedin is the first anticancer marine-derived drug to be approved by the European Union. In 2007, trabectedin obtained marketing authorization from the European Commission and in many other countries worldwide for the treatment of patients with advanced soft tissue sarcoma (STS) after failure of anthracyclines and ifosfamide, or for those patients who are unsuitable to receive these agents. Based on the recently reported results of a large phase III study (OVA-301) comparing pegylated liposomal doxorubicin (PLD) alone with a combination of PLD and trabectedin in patients with recurrent ovarian cancer, in 2009 the European Commission granted marketing authorization for trabectedin combined with PLD for the treatment of patients with relapsed platinum-sensitive ovarian cancer. The results from OVA-301 showed that the combination of trabectedin and PLD improves progression-free survival and overall response rate over PLD alone with acceptable tolerance in the second-line treatment of recurrent ovarian cancer. In addition, an enhanced activity of trabectedin combined with PLD was observed in platinum sensitive patients, especially in those with a platinum-free interval ranging from 6 to 12 months. Overall, trabectedin-induced toxicities are mainly hematological and hepatic, with grade 3/4 neutropenia and thrombocytopenia observed in approximately 50% and 13% of patients, respectively, and grade 3/4 elevation of liver aminotransferases observed in 40-50% of patients treated with trabectedin. Current efforts are focused on the evaluation of the role of trabectedin in prolonging the platinum-free interval and the identification of predictive factors for patients treated with trabectedin as well as in the development of new trabectedin-based combinations.
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- 2012
17. An economic analysis of dose dense weekly paclitaxel plus carboplatin versus every-3-week paclitaxel plus carboplatin in the treatment of advanced ovarian cancer
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Ivor Benjamin, Xinhua Yu, John K. Chan, L. Hu, Heather J. Dalton, Bradley J. Monk, and Daniel S. Kapp
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Oncology ,medicine.medical_specialty ,Paclitaxel ,Cost-Benefit Analysis ,medicine.medical_treatment ,Disease-Free Survival ,Drug Administration Schedule ,Drug Costs ,Carboplatin ,chemistry.chemical_compound ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,health care economics and organizations ,Proportional Hazards Models ,Ovarian Neoplasms ,Chemotherapy ,Proportional hazards model ,business.industry ,Hazard ratio ,Obstetrics and Gynecology ,Combination chemotherapy ,Middle Aged ,medicine.disease ,Markov Chains ,Regimen ,Models, Economic ,chemistry ,Female ,Ovarian cancer ,business - Abstract
Objective Compared with every-3-week paclitaxel (q3T) plus carboplatin, dose-dense weekly paclitaxel (ddT) plus carboplatin improved the survival of ovarian cancer patients. We performed a cost analysis comparing these two regimens. Methods Using a Markov decision model, an acceptable incremental cost-effectiveness ratio (ICER) per progression-free life-year saved (PFLYS) was estimated. Cost of drugs, growth colony-stimulating factors, and transfusions were derived from Medicare reimbursement data. Survival and rates of complications were estimated based on the clinical trial. Results Using a body weight and surface area of an average woman age 63, the estimated cost per cycle of ddT was $107 vs. $80 for q3T. The costs per cycle of combination chemotherapy including treatment administration were $873 for ddT and $535 for q3T. With a median progression-free survival (PFS) of 28months with ddT vs. 17.2months with q3T, the ICER was $5809 per PFLYS for ddT compared with q3T arm. Using a maximum ICER of $100,000 per LYS as cost-effective threshold, the ddT regimen was cost-effective. The ICER was most sensitive to the hazard rate for difference in PFS between the two regimens. A 4-month difference in PFS resulted in a $1200 change of ICER per PFLYS. The ICER was also sensitive to overall survival difference, rate of hematological toxicity, and rate of discontinuation. Conclusions In this economic model, dose-dense weekly paclitaxel is a cost-effective treatment option for advanced ovarian cancer.
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- 2012
18. Endometrial cancer surgery in Arizona: A statewide analysis of access to care
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Heather J. Dalton, Ivor Benjamin, Leslie Cayco, James Balducci, Yue Qiu, and William G. Johnson
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Adult ,medicine.medical_specialty ,Adolescent ,Databases, Factual ,Medical Oncology ,Health Services Accessibility ,Young Adult ,Gynecologic Surgical Procedures ,medicine ,Humans ,Private insurance ,Aged ,Patterns of care ,business.industry ,Endometrial cancer ,Surgical care ,Significant difference ,Arizona ,Obstetrics and Gynecology ,Middle Aged ,medicine.disease ,Endometrial Neoplasms ,Surgery ,Cross-Sectional Studies ,Oncology ,Gynecology ,Workforce ,Current Procedural Terminology ,Female ,business ,Medicaid ,Insurance coverage - Abstract
To investigate access to surgical care for endometrial cancer in Arizona.The Arizona HealthQuery (AZHQ) data warehouse with claims information on over 7 million patients in Arizona was searched using the International Classification of Disease (ICD-9) codes and Current Procedural Terminology (CPT) codes for endometrial cancer surgery from 2005 to 2008. Coordinates were gathered for patients and hospital to determine the distance traveled, race, insurance and annual caseload per hospital/surgeon were collected. Distance traveled was local (50 miles) or distant (≥ 50 miles) and served as the primary independent variable. Secondary variables included age, race, insurance, surgeon annual volume, and hospital annual volume. Logistic regression for distance traveled was performed for insurance coverage, race, hospital volume, and surgeon volume and expressed as an odds ratio.There were 1532 endometrial cancer surgeries performed at 67 hospitals by 242 surgeons in 15 counties. Most (61%) were performed by high-volume surgeons. Approximately 1 in 5 (19%) of patients traveled greater than 50 miles. Medicare insured patients were twice (OR=2.07, 95% CI=1.38-3.13) and Medicaid patients were three times (OR=3.41, 95% CI=1.89-6.15) as likely to travel over 50 miles. No significant difference was found between uninsured and privately insured patients (OR=0.87, 95% CI=0.45-1.68). Patients were more likely to travel to a high volume facility (OR 2.39, 95% CI=1.26-4.51). Hispanics (OR=2.72, 95% CI=1.72-4.32) and Native Americans (OR=8.60, 95% CI=3.43-21.52) were more likely to travel compared to Caucasians.In Arizona significantly different patterns of care are seen for endometrial cancer surgery based upon insurance coverage, race, surgeon and hospital. Patients travel farther to a high-volume hospital and high-volume surgeon. Hispanics or Native Americans travel farther for care when compared with Caucasians. Patients on government funded insurance plans travel farther for care than patients covered by private insurance or those lacking insurance.
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- 2011
19. PRO-105, a phase II open-label study of NUC-1031 in patients with platinum-resistant ovarian cancer
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Michelle Lockley, Bradley J. Monk, Heather J. Dalton, Susana Banerjee, Charlie Gourley, Jonathan Krell, and Joseph Buscema
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Cancer Research ,Chemotherapy ,endocrine system diseases ,business.industry ,medicine.medical_treatment ,Treatment options ,Phosphoramidate ,medicine.disease ,female genital diseases and pregnancy complications ,Gemcitabine ,03 medical and health sciences ,fluids and secretions ,0302 clinical medicine ,Oncology ,Open label study ,030220 oncology & carcinogenesis ,Cancer research ,Medicine ,In patient ,business ,Ovarian cancer ,medicine.drug ,Platinum resistant - Abstract
TPS5612Background: Patients with platinum-resistant ovarian cancer, following ≥3 lines of chemotherapy have limited treatment options. NUC-1031, a phosphoramidate transformation of gemcitabine, is ...
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- 2018
20. XPO1/CRM1 Inhibition Causes Antitumor Effects by Mitochondrial Accumulation of eIF5A
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David H. Hawke, John E. Wiktorowicz, Sharon Shacham, Archana S. Nagaraja, Morgan Taylor, Rebecca A. Previs, Kshipra M. Gharpure, Sherry Y. Wu, Dilara McCauley, Robert L. Coleman, Heather J. Dalton, Rajesha Rupaimoole, Behrouz Zand, Tao Liu, Yu Kang, Takeshi Hisamatsu, Anil K. Sood, Takahito Miyake, Sunila Pradeep, Yunfei Wen, Min Soon Cho, and Wei Hu
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Proteomics ,Cancer Research ,Programmed cell death ,Active Transport, Cell Nucleus ,Fluorescent Antibody Technique ,Mice, Nude ,Receptors, Cytoplasmic and Nuclear ,Antineoplastic Agents ,Apoptosis ,Mitochondrion ,Biology ,Karyopherins ,Transfection ,Article ,Mice ,Peptide Initiation Factors ,Tandem Mass Spectrometry ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Electrophoresis, Gel, Two-Dimensional ,Enzyme Inhibitors ,RNA, Small Interfering ,Ovarian Neoplasms ,Cancer ,Mammary Neoplasms, Experimental ,RNA-Binding Proteins ,medicine.disease ,Immunohistochemistry ,Xenograft Model Antitumor Assays ,Mitochondria ,Oncology ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Cancer cell ,Cancer research ,Topotecan ,Female ,Signal transduction ,Ovarian cancer ,medicine.drug ,Chromatography, Liquid ,Signal Transduction - Abstract
Purpose: XPO1 inhibitors have shown promise for cancer treatment, and yet the underlying mechanisms for the antitumor effects are not well understood. In this study, we explored the usefulness of selective inhibitors of nuclear export (SINE) compounds that are specific inhibitors of XPO1. Experimental Design: We used proteomic analysis in XPO1 inhibitor–treated ovarian cancer cell lines and examined antitumor effects in ovarian and breast cancer mouse models. We also studied the effects of XPO1 inhibitor in combination with chemotherapeutic agents. Results: XPO1 inhibitor treatment substantially increased the percentage of apoptotic cells (60%) after 72 hours of incubation. XPO1 inhibitor promoted the accumulation of eIF5A in mitochondria, leading to cancer cell death. Topotecan showed the greatest synergistic effect with XPO1 inhibitor. XPO1 inhibitors prevented the translocation of IGF2BP1 from the nucleus to the cytoplasm, thereby permitting the localization of eIF5A in the mitochondria. This process was p53, RB, and FOXO independent. Significant antitumor effects were observed with XPO1 inhibitor monotherapy in orthotopic ovarian (P < 0.001) and breast (P < 0.001) cancer mouse models, with a further decrease in tumor burden observed in combination with topotecan or paclitaxel (P < 0.05). This mitochondrial accumulation of eIF5A was highly dependent on the cytoplasmic IGF2BP1 levels. Conclusions: We have unveiled a new understanding of the role of eIF5A and IGF2BP1 in XPO1 inhibitor–mediated cell death and support their clinical development for the treatment of ovarian and other cancers. Our data also ascertain the combinations of XPO1 inhibitors with specific chemotherapy drugs for therapeutic trials. Clin Cancer Res; 21(14); 3286–97. ©2015 AACR.
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- 2015
21. Dll4 Inhibition plus Aflibercept Markedly Reduces Ovarian Tumor Growth
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Rajesha Rupaimoole, Nicholas B. Jennings, Robert L. Coleman, Archana S. Nagaraja, Limin Hu, Michael McGuire, Anil K. Sood, Jie Huang, Xiao Yun Yang, Tao Liu, Yunjie Sun, Alpa M. Nick, Robert B. Jaffe, Rebecca A. Previs, Yu Kang, Wei Hu, and Heather J. Dalton
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0301 basic medicine ,Cancer Research ,Cell Survival ,medicine.medical_treatment ,Recombinant Fusion Proteins ,GATA3 Transcription Factor ,Pharmacology ,Antibodies, Monoclonal, Humanized ,Article ,03 medical and health sciences ,Ovarian tumor ,Mice ,0302 clinical medicine ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,Aflibercept ,Cell Proliferation ,Ovarian Neoplasms ,Chemotherapy ,business.industry ,Intracellular Signaling Peptides and Proteins ,Cancer ,Antibodies, Monoclonal ,Membrane Proteins ,medicine.disease ,Xenograft Model Antitumor Assays ,Blockade ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Receptors, Vascular Endothelial Growth Factor ,Oncology ,Docetaxel ,Apoptosis ,030220 oncology & carcinogenesis ,Cancer research ,cardiovascular system ,Female ,business ,Ovarian cancer ,Neoplasm Transplantation ,medicine.drug - Abstract
Delta-like ligand 4 (Dll4), one of the Notch ligands, is overexpressed in ovarian cancer, especially in tumors resistant to anti-VEGF therapy. Here, we examined the biologic effects of dual anti-Dll4 and anti-VEGF therapy in ovarian cancer models. Using Dll4-Fc blockade and anti-Dll4 antibodies (murine REGN1035 and human REGN421), we evaluated the biologic effects of Dll4 inhibition combined with aflibercept or chemotherapy in orthotopic mouse models of ovarian cancer. We also examined potential mechanisms by which dual Dll4 and VEGF targeting inhibit tumor growth using immunohistochemical staining for apoptosis and proliferation markers. Reverse-phase protein arrays were used to identify potential downstream targets of Dll4 blockade. Dual targeting of VEGF and Dll4 with murine REGN1035 showed superior antitumor effects in ovarian cancer models compared with either monotherapy. In the A2780 model, REGN1035 (targets murine Dll4) or REGN421 (targets human Dll4) reduced tumor weights by 62% and 82%, respectively; aflibercept alone reduced tumor weights by 90%. Greater therapeutic effects were observed for Dll4 blockade (REGN1035) combined with either aflibercept or docetaxel (P < 0.05 for the combination vs. aflibercept). The superior antitumor effects of REGN1035 and aflibercept were related to increased apoptosis in tumor cells compared with the monotherapy. We also found that GATA3 expression was significantly increased in tumor stroma from the mice treated with REGN1035 combined with docetaxel or aflibercept, suggesting an indirect effect of these combination treatments on the tumor stroma. These findings identify that dual targeting of Dll4 and VEGF is an attractive therapeutic approach. Mol Cancer Ther; 15(6); 1344–52. ©2016 AACR.
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- 2015
22. Differential Platelet Levels Affect Response to Taxane-Based Therapy in Ovarian Cancer
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Alpa M. Nick, Hyun Jin Choi, Vahid Afshar-Kharghan, Behrouz Zand, Anil K. Sood, Justin Bottsford-Miller, Min Soon Cho, Chad V. Pecot, Sunila Pradeep, Rebecca L. Stone, Rebecca A. Previs, Erin K. Crane, Wei Hu, Monika Haemmerle, Heather J. Dalton, and Susan K. Lutgendorf
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Oncology ,Adult ,Bridged-Ring Compounds ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Article ,Internal medicine ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Animals ,Humans ,Platelet ,Aged ,Retrospective Studies ,Aged, 80 and over ,Ovarian Neoplasms ,Chemotherapy ,Taxane ,Thrombocytosis ,business.industry ,Platelet Count ,Cancer ,Thrombosis ,Middle Aged ,medicine.disease ,Xenograft Model Antitumor Assays ,Tumor Burden ,Disease Models, Animal ,Platelet transfusion ,Endocrinology ,Treatment Outcome ,Docetaxel ,Drug Resistance, Neoplasm ,Disease Progression ,Female ,Taxoids ,Neoplasm Recurrence, Local ,business ,Ovarian cancer ,Biomarkers ,medicine.drug - Abstract
Purpose: We hypothesized that platelet levels during therapy could serve as a biomarker for response to therapy and that manipulation of platelet levels could impact responsiveness to chemotherapy. Experimental Design: The medical records of patients with recurrent or progressive ovarian cancer were retrospectively queried for changes in platelet and CA-125 levels during primary therapy. In vitro coculture experiments and in vivo orthotopic models of human ovarian cancer in mice were used to test the effect of modulating platelet levels on tumor growth and responsiveness to docetaxel. Results: Thrombocytosis at the diagnosis of ovarian cancer was correlated with decreased interval to progression (P = 0.05) and median overall survival (P = 0.007). Mean platelet levels corrected during primary therapy and rose at recurrence. Contrary to treatment-responsive patients, in a cohort of patients refractory to primary therapy, platelet levels did not normalize during therapy. In A2780, HeyA8, and SKOV3-ip1 ovarian cancer cell lines, platelet coculture protected against apoptosis (P < 0.05). In orthotopic models of human ovarian cancer, platelet depletion resulted in 70% reduced mean tumor weight (P < 0.05). Compared with mice treated with docetaxel, mice treated with both docetaxel and platelet-depleting antibody had a 62% decrease in mean tumor weight (P = 0.04). Platelet transfusion increased mean aggregate tumor weight 2.4-fold (P < 0.05), blocked the effect of docetaxel on tumor growth (P = 0.55) and decreased tumor cell apoptosis. Pretransfusion aspirinization of the platelets blocked the growth-promoting effects of transfusion. Conclusions: Platelet-driven effects of chemotherapy response may explain clinical observations. Clin Cancer Res; 21(3); 602–10. ©2014 AACR.
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- 2015
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23. Therapeutic Silencing of KRAS using Systemically Delivered siRNAs
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Salma H. Azam, Scott Kopetz, Sherry Y. Wu, Heather J. Dalton, Archana S. Nagaraja, Rajat Bhattacharya, Rajesha Rupaimoole, Anil K. Sood, Anshumaan Maharaj, Chad V. Pecot, Trent A. Waugh, Cristian Rodriguez-Aguayo, Kshipra M. Gharpure, Vianey Gonzalez-Villasana, Takeshi Hisamatsu, Lee M. Ellis, Gabriel Lopez-Berestein, Justyna Filant, Seth Bellister, Maria Pia Morelli, and Behrouz Zand
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Cancer Research ,Small interfering RNA ,endocrine system diseases ,Colorectal cancer ,Gene Expression ,Biology ,medicine.disease_cause ,Article ,Metastasis ,Mice ,Cell Line, Tumor ,Neoplasms ,medicine ,Gene silencing ,Animals ,Humans ,Gene Silencing ,RNA, Small Interfering ,Lung cancer ,neoplasms ,Gene Transfer Techniques ,Cancer ,medicine.disease ,Molecular biology ,Primary tumor ,Xenograft Model Antitumor Assays ,digestive system diseases ,respiratory tract diseases ,Disease Models, Animal ,Oncology ,Liposomes ,Cancer research ,ras Proteins ,Nanoparticles ,Female ,RNA Interference ,KRAS - Abstract
Despite being among the most common oncogenes in human cancer, to date, there are no effective clinical options for inhibiting KRAS activity. We investigated whether systemically delivered KRAS siRNAs have therapeutic potential in KRAS-mutated cancer models. We identified KRAS siRNA sequences with notable potency in knocking down KRAS expression. Using lung and colon adenocarcinoma cell lines, we assessed antiproliferative effects of KRAS silencing in vitro. For in vivo experiments, we used a nanoliposomal delivery platform, DOPC, for systemic delivery of siRNAs. Various lung and colon cancer models were used to determine efficacy of systemic KRAS siRNA based on tumor growth, development of metastasis, and downstream signaling. KRAS siRNA sequences induced >90% knockdown of KRAS expression, significantly reducing viability in mutant cell lines. In the lung cancer model, KRAS siRNA treatment demonstrated significant reductions in primary tumor growth and distant metastatic disease, while the addition of CDDP was not additive. Significant reductions in Ki-67 indices were seen in all treatment groups, whereas significant increases in caspase-3 activity were only seen in the CDDP treatment groups. In the colon cancer model, KRAS siRNA reduced tumor KRAS and pERK expression. KRAS siRNAs significantly reduced HCP1 subcutaneous tumor growth, as well as outgrowth of liver metastases. Our studies demonstrate a proof-of-concept approach to therapeutic KRAS targeting using nanoparticle delivery of siRNA. This study highlights the potential translational impact of therapeutic RNA interference, which may have broad applications in oncology, especially for traditional “undruggable” targets. Mol Cancer Ther; 13(12); 2876–85. ©2014 AACR.
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- 2014
24. Protein profiling of ovarian cancers by immunohistochemistry to identify potential target pathways
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R. Bender, Ivor Benjamin, Bradley J. Monk, Dana M. Chase, D. Loesch, A. Alacron, John H. Farley, and Heather J. Dalton
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Oncology ,Chemotherapy ,medicine.medical_specialty ,Pathology ,business.industry ,Research ,medicine.medical_treatment ,Obstetrics and Gynecology ,Histology ,medicine.disease ,Immunohistochemistry ,Protein profiling ,Serous fluid ,Ovarian cancer ,Internal medicine ,Gene expression ,Cancer research ,medicine ,Biomarker (medicine) ,business ,Clear cell - Abstract
Background To determine the protein expression profile (PEP) of primary and recurrent ovarian cancer patients in order to predict therapeutic targets for chemotherapy. Methods Tissue samples were submitted for PEP in two formats, including formalin-fixed paraffin-embedded tissue for immunohistochemistry (IHC) and fresh frozen tissue for oligonucleotide microarray (MA) gene expression assays. Specimens were analyzed for 18 protein markers and 88 MA genes. A series of Generalized Linear Models (GLM) was used to predict the proportion of positive results by histology for each biomarker. Results Four hundred and twenty-eight specimens were analyzed for IHC and 67 specimens for MA analysis. The majority of specimens, 82%, were serous histology and 35.3% of specimens were poorly differentiated. Sixty percent of specimens were advanced stage, 62% were from a primary diagnosis, and 53% were obtained from a metastatic site. BCRP, ER, MGMT, and RRM1 proteins were overexpressed in 85%, 47%, 93%, and 47% of serous carcinomas, respectively. The MGMT and RRM1 biomarkers were significantly overexpressed in serous (p
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- 2014
25. Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer
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Gabriel Lopez-Berestein, Anil K. Sood, Huamin Wang, Bulent Ozpolat, Cristina Ivan, Guermarie Velazquez-Torres, Vianey Gonzalez-Villasana, Rebecca A. Previs, Heather J. Dalton, Burcu Aslan, Ricardo J. Fernandez-de Thomas, Enrique Fuentes-Mattei, Cristian Rodriguez-Aguayo, Sunila Pradeep, Paloma Monroig, Pinar Kanlikilicer, George A. Calin, and Nermin Kahraman
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rac1 GTP-Binding Protein ,Cancer Research ,Paclitaxel ,Angiogenesis ,p38 mitogen-activated protein kinases ,medicine.medical_treatment ,Blotting, Western ,Mice, Nude ,RAC1 ,Antineoplastic Agents ,Biology ,Matrix metalloproteinase ,Transfection ,Zoledronic Acid ,p38 Mitogen-Activated Protein Kinases ,Article ,Neovascularization ,Mice ,In vivo ,Albumins ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Ovarian Neoplasms ,Diphosphonates ,Neovascularization, Pathologic ,Cell growth ,Imidazoles ,Immunohistochemistry ,Xenograft Model Antitumor Assays ,High-Throughput Screening Assays ,Cytokine ,Oncology ,p21-Activated Kinases ,Cancer research ,Matrix Metalloproteinase 2 ,Female ,medicine.symptom ,Signal Transduction - Abstract
Purpose: Zoledronic acid is being increasingly recognized for its antitumor properties, but the underlying functions are not well understood. In this study, we hypothesized that zoledronic acid inhibits ovarian cancer angiogenesis preventing Rac1 activation. Experimental Design: The biologic effects of zoledronic acid were examined using a series of in vitro [cell invasion, cytokine production, Rac1 activation, reverse-phase protein array, and in vivo (orthotopic mouse models)] experiments. Results: There was significant inhibition of ovarian cancer (HeyA8-MDR and OVCAR-5) cell invasion as well as reduced production of proangiogenic cytokines in response to zoledronic acid treatment. Furthermore, zoledronic acid inactivated Rac1 and decreased the levels of Pak1/p38/matrix metalloproteinase-2 in ovarian cancer cells. In vivo, zoledronic acid reduced tumor growth, angiogenesis, and cell proliferation and inactivated Rac1 in both HeyA8-MDR and OVCAR-5 models. These in vivo antitumor effects were enhanced in both models when zoledronic acid was combined with nab-paclitaxel. Conclusions: Zoledronic acid has robust antitumor and antiangiogenic activity and merits further clinical development as ovarian cancer treatment. Clin Cancer Res; 21(9); 2127–37. ©2015 AACR.
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- 2014
26. Dual Metronomic Chemotherapy with Nab-Paclitaxel and Topotecan Has Potent Antiangiogenic Activity in Ovarian Cancer
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William M. Merritt, Anil K. Sood, Sunila Pradeep, Jean M. Hansen, Alpa M. Nick, Guillermo N. Armaiz-Pena, Robert L. Coleman, Ashley Davis, Rebecca A. Previs, Yvonne G. Lin, Robert R. Langley, and Heather J. Dalton
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Cancer Research ,Combination therapy ,Paclitaxel ,Angiogenesis ,Angiogenesis Inhibitors ,Apoptosis ,Pharmacology ,Article ,chemistry.chemical_compound ,Mice ,In vivo ,Albumins ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,Medicine ,Animals ,Humans ,Cell Proliferation ,Tube formation ,Ovarian Neoplasms ,Neovascularization, Pathologic ,business.industry ,medicine.disease ,Metronomic Chemotherapy ,Xenograft Model Antitumor Assays ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,Administration, Metronomic ,Cancer research ,Topotecan ,Female ,business ,Ovarian cancer ,medicine.drug - Abstract
There is growing recognition of the important role of metronomic chemotherapy in cancer treatment. On the basis of their unique antiangiogenic effects, we tested the efficacy of nab-paclitaxel, which stimulates thrombospondin-1, and topotecan, which inhibits hypoxia-inducible factor 1-α, at metronomic dosing for the treatment of ovarian carcinoma. In vitro and in vivo SKOV3ip1, HeyA8, and HeyA8-MDR (taxane-resistant) orthotopic models were used to examine the effects of metronomic nab-paclitaxel and metronomic topotecan. We examined cell proliferation (Ki-67), apoptosis (cleaved caspase-3), and angiogenesis (microvessel density, MVD) in tumors obtained at necropsy. In vivo therapy experiments demonstrated treatment with metronomic nab-paclitaxel alone and in combination with metronomic topotecan resulted in significant reductions in tumor weight (62% in the SKOV3ip1 model, P < 0.01 and 96% in the HeyA8 model, P < 0.03) compared with vehicle (P < 0.01). In the HeyA8-MDR model, metronomic monotherapy with either cytotoxic agent had modest effects on tumor growth, but combination therapy decreased tumor burden by 61% compared with vehicle (P < 0.03). The greatest reduction in MVD (P < 0.05) and proliferation was seen in combination metronomic therapy groups. Combination metronomic therapy resulted in prolonged overall survival in vivo compared with other groups (P < 0.001). Tube formation was significantly inhibited in RF-24 endothelial cells exposed to media conditioned with metronomic nab-paclitaxel alone and media conditioned with combination metronomic nab-paclitaxel and metronomic topotecan. The combination of metronomic nab-paclitaxel and metronomic topotecan offers a novel, highly effective therapeutic approach for ovarian carcinoma that merits further clinical development. Mol Cancer Ther; 14(12); 2677–86. ©2015 AACR.
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- 2014
27. Hematogenous metastasis of ovarian cancer: Rethinking mode of spread
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Li Huang, Alpa M. Nick, Heather J. Dalton, Hyun Jin Choi, Carolyn S. Hall, Isaiah J. Fidler, J. A. Mayer, Jinsong Liu, Sang Cheul Oh, Robert L. Coleman, Cristian Rodriguez-Aguayo, Vasudha Sehgal, Pradeep Chaluvally-Raghavan, Masato Nishimura, Hee Dong Han, Prahlad T. Ram, Behrouz Zand, Ju Seog Lee, Lingegowda S. Mangala, Rajesha Rupaimoole, Min Soon Cho, Farideh Z. Bischoff, Gabriel Lopez-Berestein, Seung W. Kim, Anil K. Sood, Chad V. Pecot, Ho-Jeong Lee, Sunila Pradeep, Sun Jin Kim, Takahito Miyake, Thiruvengadam Arumugam, and Sherry Y. Wu
- Subjects
Cancer Research ,Time Factors ,endocrine system diseases ,Receptor, ErbB-3 ,Carcinoma, Ovarian Epithelial ,Metastasis ,Mice ,0302 clinical medicine ,Cell Movement ,ERBB3 ,Neoplasms, Glandular and Epithelial ,Peritoneal Neoplasms ,Ovarian Neoplasms ,0303 health sciences ,Neoplastic Cells, Circulating ,female genital diseases and pregnancy complications ,3. Good health ,Oncology ,030220 oncology & carcinogenesis ,Ovarian cancer cells ,Female ,RNA Interference ,Omentum ,Signal Transduction ,endocrine system ,Parabiosis ,Neuregulin-1 ,Mice, Nude ,Biology ,Transfection ,Article ,03 medical and health sciences ,Cell Line, Tumor ,Carcinoma ,medicine ,Animals ,Humans ,Neoplasm Invasiveness ,030304 developmental biology ,Cell Proliferation ,Hematogenous metastasis ,Cell Biology ,medicine.disease ,Xenograft Model Antitumor Assays ,body regions ,Mice, Inbred C57BL ,Omental metastasis ,Immunology ,Cancer research ,Ovarian cancer - Abstract
SummaryOvarian cancer has a clear predilection for metastasis to the omentum, but the underlying mechanisms involved in ovarian cancer spread are not well understood. Here, we used a parabiosis model that demonstrates preferential hematogenous metastasis of ovarian cancer to the omentum. Our studies revealed that the ErbB3-neuregulin 1 (NRG1) axis is a dominant pathway responsible for hematogenous omental metastasis. Elevated levels of ErbB3 in ovarian cancer cells and NRG1 in the omentum allowed for tumor cell localization and growth in the omentum. Depletion of ErbB3 in ovarian cancer impaired omental metastasis. Our results highlight hematogenous metastasis as an important mode of ovarian cancer metastasis. These findings have implications for designing alternative strategies aimed at preventing and treating ovarian cancer metastasis.
- Published
- 2014
28. Clodronate inhibits tumor angiogenesis in mouse models of ovarian cancer
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Sunila Pradeep, Archana S. Nagaraja, Hernan G. Vasquez, Jie Huang, Yunfei Wen, Nicole M Reusser, Anil K. Sood, Takahito Miyake, Kshipra M. Gharpure, Vianey Gonzalez-Villasana, Gabriel Lopez-Berestein, Rajesha Rupaimoole, Wei Hu, Nicholas B. Jennings, and Heather J. Dalton
- Subjects
Cancer Research ,Pathology ,medicine.medical_specialty ,Angiogenesis ,Angiogenesis Inhibitors ,Biology ,Metastasis ,In vivo ,Cell Movement ,Cell Line, Tumor ,medicine ,Macrophage ,Animals ,Humans ,Pharmacology ,Ovarian Neoplasms ,Tumor microenvironment ,Bone Density Conservation Agents ,Macrophages ,Cancer ,Endothelial Cells ,medicine.disease ,Mice, Inbred C57BL ,Oncology ,Cancer research ,Molecular Medicine ,Clodronic acid ,Cytokines ,Female ,Clodronic Acid ,Ovarian cancer ,medicine.drug ,Research Paper - Abstract
Purpose Bisphosphonates have been shown to inhibit and deplete macrophages. The effects of bisphosphonates on other cell types in the tumor microenvironment have been insufficiently studied. Here, we sought to determine the effects of bisphosphonates on ovarian cancer angiogenesis and growth via their effect on the microenvironment, including macrophage, endothelial and tumor cell populations. Experimental Design Using in vitro and in vivo models, we examined the effects of clodronate on angiogenesis and macrophage density, and the overall effect of clodronate on tumor size and metastasis. Results Clodronate inhibited the secretion of pro-angiogenic cytokines by endothelial cells and macrophages, and decreased endothelial migration and capillary tube formation. In treated mice, clodronate significantly decreased tumor size, number of tumor nodules, number of tumor-associated macrophages and tumor capillary density. Conclusions Clodronate is a potent inhibitor of tumor angiogenesis. These results highlight clodronate as a potential therapeutic for cancer.
- Published
- 2014
29. Molecular biomarkers of residual disease after surgical debulking of high-grade serous ovarian cancer
- Author
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Cristina Ivan, Bulent Ozpolat, Keith A. Baggerly, Sherry Y. Wu, Jamie Guenthoer, Erin K. Crane, Gabriel Lopez-Berestein, Wei Hu, Shelley M. Herbrich, Heather J. Dalton, Alpa M. Nick, Rajesha Rupaimoole, Robert L. Coleman, Susan L. Tucker, Kshipra M. Gharpure, Anil K. Sood, and Anna K. Unruh
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Neoplasm, Residual ,Disease ,Bioinformatics ,Residual ,Fatty Acid-Binding Proteins ,Real-Time Polymerase Chain Reaction ,Article ,Cohort Studies ,symbols.namesake ,Internal medicine ,medicine ,Biomarkers, Tumor ,Humans ,RNA, Messenger ,Fisher's exact test ,Ovarian Neoplasms ,business.industry ,Reverse Transcriptase Polymerase Chain Reaction ,Alcohol Dehydrogenase ,Cancer ,Cytoreduction Surgical Procedures ,Debulking ,medicine.disease ,Prognosis ,Cystadenocarcinoma, Serous ,Survival Rate ,Serous fluid ,Quartile ,Cohort ,symbols ,Female ,Neoplasm Grading ,business ,Follow-Up Studies - Abstract
Purpose: Residual disease following primary cytoreduction is associated with adverse overall survival in patients with epithelial ovarian cancer. Accurate identification of patients at high risk of residual disease has been elusive, lacking external validity and prompting many to undergo unnecessary surgical exploration. Our goal was to identify and validate molecular markers associated with high rates of residual disease. Methods: We interrogated two publicly available datasets from chemonaïve primary high-grade serous ovarian tumors for genes overexpressed in patients with residual disease and significant at a 10% false discovery rate (FDR) in both datasets. We selected genes with wide dynamic range for validation in an independent cohort using quantitative RT-PCR to assay gene expression, followed by blinded prediction of a patient subset at high risk for residual disease. Predictive success was evaluated using a one-sided Fisher exact test. Results: Forty-seven probe sets met the 10% FDR criterion in both datasets. These included FABP4 and ADH1B, which tracked tightly, showed dynamic ranges >16-fold and had high expression levels associated with increased incidence of residual disease. In the validation cohort (n = 139), FABP4 and ADH1B were again highly correlated. Using the top quartile of FABP4 PCR values as a prespecified threshold, we found 30 of 35 cases of residual disease in the predicted high-risk group (positive predictive value = 86%) and 54 of 104 among the remaining patients (P = 0.0002; OR, 5.5). Conclusion: High FABP4 and ADH1B expression is associated with significantly higher risk of residual disease in high-grade serous ovarian cancer. Patients with high tumoral levels of these genes may be candidates for neoadjuvant chemotherapy. Clin Cancer Res; 20(12); 3280–8. ©2014 AACR.
- Published
- 2014
30. Biologic effects of platelet-derived growth factor receptor α blockade in uterine cancer
- Author
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Robert L. Coleman, Ju Seog Lee, Vasudha Sehgal, Heather J. Dalton, Xiaoyun Yang, Jie Huang, Nicholas B. Jennings, Hee Dong Han, Anil K. Sood, Ju Won Roh, Sun Joo Lee, Rebecca A. Previs, Duangmani Thanapprapasr, Koji Matsuo, Behrouz Zand, Ashley Davis, Prahlad T. Ram, Bo Hwa Sohn, Wei Hu, and Justin Bottsford-Miller
- Subjects
Cancer Research ,Receptor, Platelet-Derived Growth Factor alpha ,Angiogenesis ,Cell Survival ,Blotting, Western ,Mice, Nude ,Antineoplastic Agents ,Apoptosis ,Biology ,Growth factor receptor ,Uterine cancer ,Cell Line, Tumor ,medicine ,Animals ,Humans ,Viability assay ,Phosphorylation ,Protein kinase B ,Cell Proliferation ,Oligonucleotide Array Sequence Analysis ,Neovascularization, Pathologic ,Cell growth ,Cancer ,Antibodies, Monoclonal ,Drug Synergism ,medicine.disease ,Immunohistochemistry ,Xenograft Model Antitumor Assays ,Gene Expression Regulation, Neoplastic ,Oncology ,Uterine Neoplasms ,biology.protein ,Cancer research ,Female ,Mitogen-Activated Protein Kinases ,Transcriptome ,Proto-Oncogene Proteins c-akt ,Platelet-derived growth factor receptor ,Signal Transduction - Abstract
Purpose: Platelet-derived growth factor receptor α (PDGFRα) expression is frequently observed in many kinds of cancer and is a candidate for therapeutic targeting. This preclinical study evaluated the biologic significance of PDGFRα and PDGFRα blockade (using a fully humanized monoclonal antibody, 3G3) in uterine cancer. Experimental Design: Expression of PDGFRα was examined in uterine cancer clinical samples and cell lines, and biologic effects of PDGFRα inhibition were evaluated using in vitro (cell viability, apoptosis, and invasion) and in vivo (orthotopic) models of uterine cancer. Results: PDGFRα was highly expressed and activated in uterine cancer samples and cell lines. Treatment with 3G3 resulted in substantial inhibition of PDGFRα phosphorylation and of downstream signaling molecules AKT and mitogen-activated protein kinase (MAPK). Cell viability and invasive potential of uterine cancer cells were also inhibited by 3G3 treatment. In orthotopic mouse models of uterine cancer, 3G3 monotherapy had significant antitumor effects in the PDGFRα-positive models (Hec-1A, Ishikawa, Spec-2) but not in the PDGFRα-negative model (OVCA432). Greater therapeutic effects were observed for 3G3 in combination with chemotherapy than for either drug alone in the PDGFRα-positive models. The antitumor effects of therapy were related to increased apoptosis and decreased proliferation and angiogenesis. Conclusions: These findings identify PDGFRα as an attractive target for therapeutic development in uterine cancer. Clin Cancer Res; 20(10); 2740–50. ©2014 AACR.
- Published
- 2014
31. Monocyte subpopulations in angiogenesis
- Author
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Guillermo N. Armaiz-Pena, Menashe Bar-Eli, Vianey Gonzalez-Villasana, Heather J. Dalton, Gabriel Lopez-Berestein, and Anil K. Sood
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Cancer Research ,Tumor microenvironment ,Neovascularization, Pathologic ,Extramural ,Angiogenesis ,Monocyte ,Cancer ,Biology ,Malignancy ,medicine.disease ,Monocytes ,Article ,Neovascularization ,medicine.anatomical_structure ,Oncology ,Neoplasms ,Immunology ,medicine ,Cancer research ,Tumor Microenvironment ,Animals ,Humans ,medicine.symptom - Abstract
Growing understanding of the role of the tumor microenvironment in angiogenesis has brought monocyte-derived cells into focus. Monocyte subpopulations are an increasingly attractive therapeutic target in many pathologic states, including cancer. Before monocyte-directed therapies can be fully harnessed for clinical use, understanding of monocyte-driven angiogenesis in tissue development and homeostasis, as well as malignancy, is required. Here, we provide an overview of the mechanisms by which monocytic subpopulations contribute to angiogenesis in tissue and tumor development, highlight gaps in our existing knowledge, and discuss opportunities to exploit these cells for clinical benefit. Cancer Res; 74(5); 1287–93. ©2014 AACR.
- Published
- 2014
32. In vitro chemoresponse in metachronous pairs of gyneclologic cancers
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Matthew Burrell, Fernando O. Recio, Candace K McClure, Rodney P. Rocconi, Bradley J. Monk, James Fiorica, Heather J. Dalton, and John L Levocchio
- Subjects
Cisplatin ,Oncology ,Chemotherapy ,medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Research ,Recurrent ovarian ,Drug resistance ,Gemcitabine ,Carboplatin ,chemistry.chemical_compound ,Paclitaxel ,chemistry ,Docetaxel ,Internal medicine ,medicine ,Topotecan ,Cross-resistance ,business ,Gynecologic cancer ,medicine.drug - Abstract
Background While most gynecologic cancers respond to first-line cytotoxic chemotherapy, treatment of recurrent disease is frequently associated with acquired drug resistance. In order to find an in vitro surrogate of this clinical phenomenon, a tumor chemoresponse assay was studied. Methods/Materials Patients who had tissue submitted for repeated chemoresponse testing were identified through a retrospective search. Sixty-three patients met inclusion criteria (chemoresponse testing completed at primary diagnosis and upon recurrence of disease and assays completed ≥90 days apart). The Wilcoxon signed-rank test was used to compare chemoresponse, represented as a response index (RI), between primary and recurrent measurements. In a secondary analysis, response was categorized and coded as Responsive = 3, Intermediately Responsive = 2 and Non-Responsive = 1, and the paired t-test was used to compare chemoresponse between primary and recurrent measurement. Results Median time between primary and recurrent tumor testing was 309 days (IQR 208–422). Drugs tested included carboplatin, cisplatin, docetaxel, doxorubicin, gemcitabine, paclitaxel, topotecan, and combination carboplatin/gemcitabine and carboplatin/paclitaxel. There were no differences in chemoresponse between primary and recurrent measurement when chemoresponse was represented by RI scores; although a trend toward increased resistance to paclitaxel upon recurrence was noted. When chemoresponse was analyzed as a continuous variable corresponding to categorized response, a significant shift toward increased resistance to paclitaxel at recurrence, and a marginally significant trend toward increased resistance to carboplatin at recurrence, were observed. Conclusions We observed a trend toward increased chemoresistance at recurrence for paclitaxel, and a marginally significant trend toward increased chemoresistance to carboplatin, but no change in chemoresponsiveness between primary diagnosis and recurrence of disease for other common chemotherapy drugs, including common second-line agents such as doxorubicin, gemcitabine, and topotecan.
- Published
- 2014
33. Role of focal adhesion kinase in regulating YB-1-mediated paclitaxel resistance in ovarian cancer
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Anil K. Sood, Chad V. Pecot, Jianfei Huang, Cristina Ivan, Jie Huang, Yunfei Wen, Takahito Miyake, Sunila Pradeep, Tao Liu, Yu Kang, Morgan Taylor, Rajesha Rupaimoole, Sherry Y. Wu, Chunhua Lu, Behrouz Zand, Wei Hu, Jinsong Liu, Heather J. Dalton, and Nicholas B. Jennings
- Subjects
Cancer Research ,Paclitaxel ,Cell Survival ,medicine.medical_treatment ,Mice, Nude ,Apoptosis ,Drug resistance ,Biology ,Focal adhesion ,chemistry.chemical_compound ,Mice ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Odds Ratio ,Animals ,Humans ,Organic Chemicals ,Phosphorylation ,Cell Proliferation ,Ovarian Neoplasms ,Chemotherapy ,Sulfonamides ,medicine.disease ,Antineoplastic Agents, Phytogenic ,Xenograft Model Antitumor Assays ,Oncology ,chemistry ,Drug Resistance, Neoplasm ,Focal Adhesion Kinase 1 ,Pyrazines ,Immunology ,Cancer cell ,Benzamides ,Cancer research ,Female ,Y-Box-Binding Protein 1 ,Ovarian cancer ,Tyrosine kinase ,Proto-Oncogene Proteins c-akt - Abstract
We previously found focal adhesion kinase (FAK) inhibition sensitizes ovarian cancer to taxanes; however, the mechanisms are not well understood.We characterized the biologic response of taxane-resistant and taxane-sensitive ovarian cancer models to a novel FAK inhibitor (VS-6063). We used reverse-phase protein arrays (RPPA) to identify novel downstream targets in taxane-resistant cell lines. Furthermore, we correlated clinical and pathological data with nuclear and cytoplasmic expression of FAK and YB-1 in 105 ovarian cancer samples. Statistical tests were two-sided, and P values were calculated with Student t test or Fisher exact test.We found that VS-6063 inhibited FAK phosphorylation at the Tyr397 site in a time- and dose-dependent manner. The combination of VS-6063 and paclitaxel markedly decreased proliferation and increased apoptosis, which resulted in 92.7% to 97.9% reductions in tumor weight. RPPA data showed that VS-6063 reduced levels of AKT and YB-1 in taxane-resistant cell lines. FAK inhibition enhanced chemosensitivity in taxane-resistant cells by decreasing YB-1 phosphorylation and subsequently CD44 in an AKT-dependent manner. In human ovarian cancer samples, nuclear FAK expression was associated with increased nuclear YB-1 expression (χ²) = 37.7; P.001). Coexpression of nuclear FAK and YB-1 was associated with statistically significantly worse median overall survival (24.9 vs 67.3 months; hazard ratio = 2.64; 95% confidence interval = 1.38 to 5.05; P = .006).We have identified a novel pathway whereby FAK inhibition with VS-6063 overcomes YB-1-mediated paclitaxel resistance by an AKT-dependent pathway. These findings have implications for clinical trials aimed at targeting FAK.
- Published
- 2013
34. Modeling bad behavior: Overcoming anti-VEGF resistance in vivo
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Jean M. Hansen, Anil K. Sood, B. Zand, W. Hu, Robert L. Coleman, Rajesha Rupaimoole, Rebecca A. Previs, Alpa M. Nick, Sunila Pradeep, and Heather J. Dalton
- Subjects
Anti vegf ,Oncology ,business.industry ,In vivo ,Cancer research ,Obstetrics and Gynecology ,Medicine ,business - Published
- 2016
35. Two to tango: Biological activity and companion predictive markers for a novel dual AKT and P70S6K inhibitor in ovarian and uterine malignancies
- Author
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Guillermo N. Armaiz-Pena, Anil K. Sood, Jean M. Hansen, Robert L. Coleman, W. Hu, Heather J. Dalton, Jie Huang, Rebecca A. Previs, and Cristina Ivan
- Subjects
Pathology ,medicine.medical_specialty ,Oncology ,P70S6 kinase ,business.industry ,medicine ,Cancer research ,Obstetrics and Gynecology ,Biological activity ,DUAL (cognitive architecture) ,business ,Protein kinase B - Published
- 2016
36. Improving hormonal therapy in uterine cancer: Efficacy of onapristone (phosphor-PR) and trametinib
- Author
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Jean M. Hansen, Alpa M. Nick, Robert L. Coleman, W. Hu, Anil K. Sood, Yan Huang, Jie Huang, Rebecca A. Previs, Sunila Pradeep, and Heather J. Dalton
- Subjects
Oncology ,Trametinib ,medicine.medical_specialty ,Uterine cancer ,business.industry ,Internal medicine ,medicine ,Obstetrics and Gynecology ,Hormonal therapy ,medicine.disease ,business ,Onapristone - Published
- 2016
37. Role of Increased n-acetylaspartate Levels in Cancer
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Rajesha Rupaimoole, Guillermo N. Armaiz-Pena, Michael A. Davies, Menashe Bar Eli, Lifeng Yang, Wei Hu, Alpa M. Nick, Behrouz Zand, Christopher McCullough, Gabriel Lopez-Berestein, Lingegowda S. Mangala, Ying Wang, Archana S. Nagaraja, Michele Guindani, Einav Shoshan, Susan K. Lutgendorf, Keith A. Baggerly, Kshipra M. Gharpure, Takashi Mitamura, Deepak Nagrath, Joelle Baddour, Anil K. Sood, Jinsong Liu, Abhinav Achreja, Chad V. Pecot, Heather J. Dalton, Pratip K. Bhattacharya, Rebecca A. Previs, Niki M. Zacharias, Sherry Y. Wu, Cristian Rodriguez-Aguayo, Sunila Pradeep, and Cristina Ivan
- Subjects
0301 basic medicine ,Cancer Research ,Pathology ,medicine.medical_specialty ,Cell Survival ,Apoptosis ,Kaplan-Meier Estimate ,Biology ,Gene Expression Regulation, Enzymologic ,Article ,Mice ,03 medical and health sciences ,Acetyltransferases ,Tandem Mass Spectrometry ,Uterine cancer ,Cell Line, Tumor ,Biomarkers, Tumor ,medicine ,Animals ,Humans ,Gene silencing ,Chromatography, High Pressure Liquid ,Cell Proliferation ,Ovarian Neoplasms ,Aspartic Acid ,Cell growth ,Melanoma ,Ovary ,medicine.disease ,Cystadenocarcinoma, Serous ,Gene Expression Regulation, Neoplastic ,030104 developmental biology ,Oncology ,Cancer cell ,Cancer research ,FOXM1 ,Female ,Neoplasm Grading ,Ovarian cancer - Abstract
The clinical and biological effects of metabolic alterations in cancer are not fully understood.In high-grade serous ovarian cancer (HGSOC) samples (n = 101), over 170 metabolites were profiled and compared with normal ovarian tissues (n = 15). To determine NAT8L gene expression across different cancer types, we analyzed the RNA expression of cancer types using RNASeqV2 data available from the open access The Cancer Genome Atlas (TCGA) website (http://www.cbioportal.org/public-portal/). Using NAT8L siRNA, molecular techniques and histological analysis, we determined cancer cell viability, proliferation, apoptosis, and tumor growth in in vitro and in vivo (n = 6-10 mice/group) settings. Data were analyzed with the Student's t test and Kaplan-Meier analysis. Statistical tests were two-sided.Patients with high levels of tumoral NAA and its biosynthetic enzyme, aspartate N-acetyltransferase (NAT8L), had worse overall survival than patients with low levels of NAA and NAT8L. The overall survival duration of patients with higher-than-median NAA levels (3.6 years) was lower than that of patients with lower-than-median NAA levels (5.1 years, P = .03). High NAT8L gene expression in other cancers (melanoma, renal cell, breast, colon, and uterine cancers) was associated with worse overall survival. NAT8L silencing reduced cancer cell viability (HEYA8: control siRNA 90.61% ± 2.53, NAT8L siRNA 39.43% ± 3.00, P.001; A2780: control siRNA 90.59% ± 2.53, NAT8L siRNA 7.44% ± 1.71, P.001) and proliferation (HEYA8: control siRNA 74.83% ± 0.92, NAT8L siRNA 55.70% ± 1.54, P.001; A2780: control siRNA 50.17% ± 4.13, NAT8L siRNA 26.52% ± 3.70, P.001), which was rescued by addition of NAA. In orthotopic mouse models (ovarian cancer and melanoma), NAT8L silencing reduced tumor growth statistically significantly (A2780: control siRNA 0.52 g ± 0.15, NAT8L siRNA 0.08 g ± 0.17, P.001; HEYA8: control siRNA 0.79 g ± 0.42, NAT8L siRNA 0.24 g ± 0.18, P = .008, A375-SM: control siRNA 0.55 g ± 0.22, NAT8L siRNA 0.21 g ± 0.17 g, P = .001). NAT8L silencing downregulated the anti-apoptotic pathway, which was mediated through FOXM1.These findings indicate that the NAA pathway has a prominent role in promoting tumor growth and represents a valuable target for anticancer therapy.Altered energy metabolism is a hallmark of cancer (1). Proliferating cancer cells have much greater metabolic requirements than nonproliferating differentiated cells (2,3). Moreover, altered cancer metabolism elevates unique metabolic intermediates, which can promote cancer survival and progression (4,5). Furthermore, emerging evidence suggests that proliferating cancer cells exploit alternative metabolic pathways to meet their high demand for energy and to accumulate biomass (6-8).
- Published
- 2016
38. Epigenetic analysis of the Notch superfamily in high-grade serous ovarian cancer
- Author
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Wei Hu, Gabriel Lopez-Berestein, Robert L. Coleman, Behrouz Zand, Anil K. Sood, Keith A. Baggerly, Justin Bottsford-Miller, Tao Liu, Alpa M. Nick, Jie Huang, Cristina Ivan, and Heather J. Dalton
- Subjects
Epigenomics ,endocrine system diseases ,Notch signaling pathway ,Biology ,Bioinformatics ,Article ,microRNA ,Gene expression ,Humans ,Cyclin D1 ,Epigenetics ,RNA, Messenger ,Regulation of gene expression ,Ovarian Neoplasms ,Receptors, Notch ,Obstetrics and Gynecology ,Methylation ,DNA Methylation ,Survival Analysis ,Cystadenocarcinoma, Serous ,Gene Expression Regulation, Neoplastic ,PPAR gamma ,MicroRNAs ,Oncology ,DNA methylation ,Core Binding Factor Alpha 2 Subunit ,Female - Abstract
Objectives Gene methylation and other epigenetic modifications of gene regulation have been implicated in the growth of ovarian cancer, but the clinical significance of such modifications in the Notch pathway in high-grade serous ovarian cancer (HGS-OvCa) is not well understood. We used The Cancer Genome Atlas (TCGA) data to study the clinical relevance of epigenetic modifications of Notch superfamily genes. Methods We analyzed the interaction of DNA methylation and miRNAs with gene expression data for Notch superfamily members with the Spearman rank correlation test and explored potential relationships with overall survival (OS) with the log-rank test. We downloaded clinical data, level 3 gene expression data, and level 3 DNA methylation data for 480 patients with stage II–IV HGS-OvCa from the TCGA data portal. Patients were randomly divided into training and validation cohorts for survival analyses. In each set, patients were grouped into percentiles according to methylation and microRNA (miRNA) or messenger RNA (mRNA) levels. We used several algorithms to predict miRNA–mRNA interaction. Results There were significant inverse relationships between methylation status and mRNA expression for PPARG , CCND1 , and RUNX1 . For each of these genes, patients with a lower methylation level and higher expression level had significantly poorer OS than did patients with a higher methylation level and lower expression level. We also found a significant inverse relationship between miRNAs and mRNA expression for CCND1 , PPARG , and RUNX1 . By further analyzing the effect of miRNAs on gene expression and OS, we found that patients with higher levels of CCND1 , PPARG , and RUNX1 expression and lower expression levels of their respective miRNAs (502-5p, 128, and 215/625) had significantly poorer OS. Conclusions Epigenetic alterations of multiple Notch target genes and pathway interacting genes ( PPARG , CCND1 , and RUNX1 ) may relate to activation of this pathway and poor survival of patients with HGS-OvCa.
- Published
- 2012
39. Taking it up a Notch: Implications for outcomes in endometrial cancer
- Author
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Cristina Ivan, Behrouz Zand, Ashley Davis, Justin Bottsford-Miller, Rebecca A. Previs, Anil K. Sood, Heather J. Dalton, Robert L. Coleman, and Keith A. Baggerly
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Endometrial cancer ,Internal medicine ,medicine ,Obstetrics and Gynecology ,medicine.disease ,business - Published
- 2014
40. More is not always better: Thrombocytosis contributes to impaired chemotherapy response in ovarian cancer
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Anil K. Sood, Ashley Davis, Justin Bottsford-Miller, Rebecca A. Previs, Heather J. Dalton, R.L. Stone, Behrouz Zand, Alpa M. Nick, Vahid Afshar-Kharghan, and Morgan Taylor
- Subjects
Oncology ,medicine.medical_specialty ,Thrombocytosis ,business.industry ,Internal medicine ,Obstetrics and Gynecology ,Medicine ,business ,Ovarian cancer ,medicine.disease ,Chemotherapy response - Published
- 2014
41. Abstract 2273: Mechanistic and functional implications of FABP4 in ovarian cancer metastasis
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Susan L. Tucker, Wei Hu, Bulent Ozpolat, Jamie Guenthoer, Anna K. Unruh, Erin K. Crane, Cristina Ivan, Rajesha Rupaimoole, Keith A. Baggerly, Kshipra M. Gharpure, Sherry Y. Wu, Alpa M. Nick, Gabriel Lopez-Berestein, Shelley M. Herbrich, Heather J. Dalton, Anil K. Sood, and Robert L. Coleman
- Subjects
Oncology ,Cancer Research ,Pathology ,medicine.medical_specialty ,Stromal cell ,business.industry ,medicine.disease ,Debulking ,Metastasis ,Internal medicine ,Gene expression ,Cancer cell ,medicine ,Immunohistochemistry ,Gene silencing ,Ovarian cancer ,business - Abstract
Purpose:The purpose of this study was to identify molecular predictors of residual disease (RD) in high grade serous ovarian cancer (HGSC) and further understand their role in promoting cancer metastasis. Method:The current study analyzed Affymetrix gene expression data of 504 HGSC cases from The Cancer Genome Atlas (TCGA) data to identify differentially expressed genes in tumors from patients with no gross residual disease after surgery (NRD) or presence of RD following initial debulking surgery. It was followed by qRT-PCR analysis of tumor samples for validation purposes. RPPA data of 354 patients from TCGA were analyzed. Immunohistochemical analysis was performed on the patient samples to determine the expression at the protein level (cancer versus stromal cells). Gene array was carried out after overexpressing the selected gene in ovarian cancer cells and the data was analyzed by Ingenuity Pathway Analysis (IPA). In vitro (migration and invasion) and in vivo (orthotopic mouse models) assays were used to determine the biological roles of gene(s) identified from the above analyses. Results: In TCGA data set, 97/107 (90.6%) of the patients with high expression of FABP4 gene had residual disease. In the validation cohort, among the 35 patients predicted to be at high risk for residual disease, 30 (86%) did have residual disease. In contrast, only 54 of the 104 patients with FABP4 values below the decision threshold (52%) had incomplete resection (p = 0.0002). RPPA analysis indicated that expression of FABP4 was positively correlated (Spearman correlation analysis) with expression of several other proteins known to increase tumor cell infiltration and metastasis such as JNK2 (p = 0.194), transglutaminase (p = 0.199), c-kit (p = 0.173), fibronectin (p = 0.364), PKC-A (p = 0.178), collagen-6 (p = 0.197) and paxillin (p = 0.239). It was negatively correlated with E-cadherin (p = -0.246) and claudin-7 (p = -0.201) expression. Immunohistochemical analysis confirmed that apart from endothelial cells and adipocytes, cancer cells also express significant amount of FABP4. In vitro assays showed significant reduction in invasion and migration after silencing FABP4 in HGSC cell lines (p Conclusion:These findings provide a new understanding of ovarian cancer metastasis and identify a potentially important target for therapeutic intervention. Citation Format: Kshipra M. Gharpure, Susan L. Tucker, Shelley M. Herbrich, Anna K. Unruh, Alpa M. Nick, Erin K. Crane, Robert L. Coleman, Jamie Guenthoer, Heather J. Dalton, Sherry Y. Wu, Rajesha Rupaimoole, Gabriel Lopez-Berestein, Bulent Ozpolat, Cristina Ivan, Wei Hu, Keith Baggerly, Anil Sood. Mechanistic and functional implications of FABP4 in ovarian cancer metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2273. doi:10.1158/1538-7445.AM2015-2273
- Published
- 2015
42. Abstract 2359: Adrenergic regulation of MCP-1 leads to enhanced macrophage recruitment and ovarian carcinoma growth
- Author
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Rebecca L. Stone, Anil K. Sood, Archana S. Nagaraja, Rebecca A. Previs, Guillermo N. Armaiz-Pena, Nouara C. Sadaoui, Susan K. Lutgendorf, Cristian Rodriguez-Aguayo, Piotr L. Dorniak, Gabriel Lopez-Berestein, Koji Matsuo, Heather J. Dalton, and Vianey Gonzalez-Villasana
- Subjects
Cancer Research ,Tumor microenvironment ,medicine.medical_specialty ,business.industry ,Monocyte ,CD14 ,Adrenergic ,medicine.disease ,medicine.anatomical_structure ,Endocrinology ,Oncology ,Tumor progression ,White blood cell ,Internal medicine ,Medicine ,Interleukin 8 ,business ,Ovarian cancer - Abstract
Increased adrenergic signaling is known to promote tumor progression, but the underlying mechanisms remain poorly understood. Tumor associated macrophages (TAMs) are key components of the tumor microenvironment that contribute to pro-inflammatory processes and tumor growth. Recently, it has been reported that patients with higher levels of adrenergic signaling have higher counts of MMP-9-producing TAMs. Here, we examined factors responsible for stress-mediated effects on monocyte/macrophage recruitment into the tumor microenvironment and the resultant effects on tumor growth. Conditioned media from norepinephrine- or epinephrine-treated ADRB positive SKOV3ip1 ovarian cancer cells had significantly increased levels of pro-inflammatory cytokines, such as MCP1, fractalkine, IL6, IL8 and VEGF. MCP1, a key modulator of monocyte/macrophage recruitment, gene and protein levels were significantly increased in vitro after catecholamine exposure, which was mediated by cAMP and PKA, while this effect was abrogated by a beta-blocker. SKOV3ip1 tumor samples from mice, subjected to daily restraint stress, had elevated MCP1 gene and protein expression levels, increased CD14+ cells, and increased infiltration of CD68+ cells. Both, propranolol, a non-specific beta-blocker, and hMCP1 siRNA packaged in DOPC nanoparticles significantly abrogated daily restraint stress-induced tumor growth and inhibited infiltration of CD68+ and F4/80+ cells. Of patient samples evaluated (n = 462), 28% had elevated absolute peripheral blood monocyte (>0.7 × 106/μL) and 43% had high peripheral blood monocytes when measured as the percent of white blood cell content (>8%). Elevated peripheral blood monocytes and increased CD68+ cells (>15/hpf) in samples from ovarian cancer patients were significantly associated with advanced disease and worse overall survival. In summary, increased adrenergic signaling is associated with enhanced macrophage infiltration mediated by tumor cell-derived MCP1 production. Citation Format: Guillermo N. Armaiz-Pena, Vianey Gonzalez-Villasana, Archana S. Nagaraja, Cristian Rodriguez-Aguayo, Piotr Dorniak, Rebecca Previs, Nouara Sadaoui, Rebecca Stone, Koji Matsuo, Heather J. Dalton, Susan K. Lutgendorf, Anil K. Sood, Gabriel Lopez-Berestein. Adrenergic regulation of MCP-1 leads to enhanced macrophage recruitment and ovarian carcinoma growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2359. doi:10.1158/1538-7445.AM2015-2359
- Published
- 2015
43. Abstract 1199: Systems-based approach identifies altered carbohydrate metabolism as a predictor of a malignant phenotype in ovarian cancer
- Author
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Tyler J. Moss, Anil K. Sood, Heather J. Dalton, Guillermo N. Armaiz-Pena, Prahlad T. Ram, Rebecca A. Previs, Pratip K. Bhattacharya, Jean M. Hansen, Susan K. Lutgendorf, Rajesha Rupaimoole, Behrouz Zand, and Robert L. Coleman
- Subjects
Cancer Research ,Oncology ,Immunology ,medicine ,Cancer research ,Carbohydrate metabolism ,Biology ,Ovarian cancer ,medicine.disease ,Malignant phenotype - Abstract
Objective: Metabolic changes occur initially at a molecular level, while genetic alterations further contribute to this shift and promote cancer cell survival and proliferation. We sought to identify genomic correlates of metabolic dysregulation in high grade serous ovarian cancer (HGSOC). Methods: We profiled 101 HGSOC samples and 15 normal ovarian tissues samples by LC/MS and GC/MS metabolic profiling; 172 significantly altered metabolites were identified. We classified these metabolites into altered pathways and carried out full-scale gene expression analyses. Results: We compared expression of measured metabolites for normal ovarian tissues and HGSOC and classified them into super pathways. We created a random forest classifier to generate a prediction model using metabolic profiles from normal tissue versus tumor within 3% error. From the random forest classification, the top 10% of significantly altered metabolites included gluconate, ADMA, and NAA. Carbohydrate, amino acid, and lipid super pathways were identified as the most important, with carbohydrate enrichment as significant (p = 0.03). Metabolites from the pentose phosphate pathway (PPP) and glycolysis were identified with this prediction model and found to be globally downregulated. Gene expression for enzymes in the PPP and glycolysis were compared between HGSOC and normal ovary and not found to be different. Gene expression ratios from the rate limiting steps in these pathways were evaluated. No significant difference was identified between gene ratios from normal and tumor tissues (p = 0.22) within our data set, but relative expression was significantly different within The Cancer Genome Atlas (TCGA) data set (p = 0.009). We subsequently generated a network that merged metabolic and gene level changes for enzymes coding for the synthesis and degradation of these metabolites, while accounting for time to recurrence in ovarian cancer patients for each gene within glycolysis and PPP. We then merged the genes identified by our network analysis with data from a whole-genome siRNA synthetic lethality screen (3 HGSOC chemoresistant cell lines). When GPI, the gene that encodes glucose-6-phosphate isomerase (PGI), was silenced, cellular lethality was observed across all cell lines tested. In our network analysis, GPI was among the most upregulated within the carbohydrate pathway within our cohort of ovarian cancer samples. In the TCGA data, ovarian cancer patients with tumoral GPI levels higher than the median had worse overall survival (p = 0.0002). Conclusions: Here, we present a novel systems-based approach using altered metabolites and genes to predict a malignant phenotype specific to HGSOC patients. Altered metabolism, coupled with genomic analyses, identified the most interconnected gene-biochemical networks that will lead to novel biomarkers and therapeutic targets. Citation Format: Rebecca A. Previs, Tyler J. Moss, Behrouz Zand, Rajesha Rupaimoole, Heather J. Dalton, Jean M. Hansen, Guillermo Armaiz-Pena, Susan Lutgendorf, Robert L. Coleman, Pratip Bhattacharya, Prahlad Ram, Anil K. Sood. Systems-based approach identifies altered carbohydrate metabolism as a predictor of a malignant phenotype in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1199. doi:10.1158/1538-7445.AM2015-1199
- Published
- 2015
44. Molecular predictors of response to EphA2 targeted therapy in uterine cancer
- Author
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Robert L. Coleman, Anil K. Sood, Alpa M. Nick, W. Hu, Yunjie Sun, Jie Huang, Russell Broaddus, Rebecca A. Previs, Heather J. Dalton, and Jean M. Hansen
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Oncology ,medicine.medical_specialty ,Uterine cancer ,business.industry ,medicine.medical_treatment ,Internal medicine ,medicine ,Obstetrics and Gynecology ,medicine.disease ,business ,EPH receptor A2 ,Targeted therapy - Published
- 2015
45. Homologous recombination deficiency in endometrioid uterine cancer: An unrecognized phenomenon
- Author
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Anil K. Sood, Robert L. Coleman, Jean M. Hansen, Keith A. Baggerly, Rebecca A. Previs, Ying Wang, Shuhong Wu, Heather J. Dalton, W. Hu, and Behrouz Zand
- Subjects
Genetics ,Oncology ,Uterine cancer ,business.industry ,medicine ,Cancer research ,Obstetrics and Gynecology ,medicine.disease ,Homologous Recombination Deficiency ,business - Published
- 2015
46. Fuel for the fire: Connecting genomics with metabolomics in ovarian cancer
- Author
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Rebecca A. Previs, Robert L. Coleman, Pratip K. Bhattacharya, Prahlad T. Ram, Jean M. Hansen, Susan K. Lutgendorf, Tyler J. Moss, Anil K. Sood, Heather J. Dalton, Behrouz Zand, Rajesha Rupaimoole, and Guillermo N. Armaiz-Pena
- Subjects
Metabolomics ,Oncology ,medicine ,Obstetrics and Gynecology ,Genomics ,Biology ,Ovarian cancer ,medicine.disease ,Bioinformatics - Published
- 2015
47. The FAK of uterine cancer: PTEN expression predicts response of uterine cancer to focal adhesion kinase inhibition
- Author
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Anil K. Sood, Guillermo N. Armaiz-Pena, Behrouz Zand, Rajesha Rupaimoole, R. Ali, Duangmani Thanapprapasr, Jean M. Hansen, W. Hu, Rebecca A. Previs, Robert L. Coleman, Heather J. Dalton, and Jie Huang
- Subjects
Focal adhesion ,Oncology ,biology ,Uterine cancer ,business.industry ,Cancer research ,medicine ,biology.protein ,Obstetrics and Gynecology ,PTEN ,medicine.disease ,business - Published
- 2015
48. Role of increased n-acetylaspartate levels in epithelial ovarian cancer
- Author
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Anil K. Sood, Niki M. Zacharias, Rajesha Rupaimoole, Rebecca A. Previs, Pratip K. Bhattacharya, Heather J. Dalton, Behrouz Zand, Gabriel Lopez-Berestein, Cristian Rodriguez-Aguayo, Jean M. Hansen, and Michele Guindani
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Obstetrics and Gynecology ,Epithelial ovarian cancer ,business ,N-acetylaspartate - Published
- 2015
49. Separating the good, the bad, and the ugly: New directions in genomic prediction of outcome in ovarian cancer
- Author
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Anil K. Sood, Justin Bottsford-Miller, Chad V. Pecot, Heather J. Dalton, Cristina Ivan, Behrouz Zand, Alpa M. Nick, Rajesha Rupaimoole, and W. Hu
- Subjects
Oncology ,business.industry ,Obstetrics and Gynecology ,Medicine ,Bioinformatics ,business ,Ovarian cancer ,medicine.disease ,Outcome (game theory) - Published
- 2013
50. Abstract 2993: Dll4 inhibition plus aflibercept markedly reduces ovarian tumor burden and ascites
- Author
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Jie Huang, Justin Bottsford-Miller, Robert B. Jaffe, Robert L. Coleman, Wei Hu, Anil K. Sood, and Heather J. Dalton
- Subjects
Cancer Research ,medicine.medical_specialty ,business.industry ,Angiogenesis ,GATA3 ,Cancer ,medicine.disease ,Ovarian tumor ,Endocrinology ,Oncology ,In vivo ,Apoptosis ,Internal medicine ,cardiovascular system ,Cancer research ,medicine ,business ,Ovarian cancer ,Aflibercept ,medicine.drug - Abstract
Purpose: To determine the effects of Dll4 blockade with and without aflibercept on ovarian tumor burden and ascites in preclinical models. Methods: Using Dll4-Fc and anti-Dll4 antibodies, we evaluated the biological effects of Dll4 inhibition combined with aflibercept in vivo (orthotopic mouse models of ovarian cancer). Reverse phase protein array (RPPA) analysis was used to identify potential biomarkers of treatment response. Results: To address the biological significance of Dll4 expression in tumor cells versus endothelial cells, we used human and mouse anti-Dll4 antibodies in vivo. In the A2780 model, treatment with mouse (REGN1035) or human (REGN421) anti-Dll4 antibodies reduced tumor weight by 61.5% and 82.4%, respectively, compared to the controls (P < 0.05 for both). Aflibercept alone reduced tumor weight by 90% (p < 0.05). The combinations of REGN1035 plus aflibercept, and REGN421 plus aflibercept resulted in the greatest inhibition of tumor growth, reducing respective tumor weight by 95.8% and 93.9%, compared to the controls (P < 0.05). The anti-tumor effects were related to decreased angiogenesis and increased apoptosis. RPPA analysis revealed that caspase3 and GATA3 were significantly increased; cyclin D1, Bcl-2 and pS6-s240_s244 were decreased in response to Dll4 Inhibition plus aflibercept. Among these, GATA3, a transcription factor for E-cadherin, was significantly induced by Dll4 Inhibition plus aflibercept, resulting in the up-regulation of E-cadherin expression in human cancer cells. Furthermore, GATA3 and E-cadherin expression might be useful as potential biomarkers of response. Conclusions: Dual targeting of Dll4 and VEGF shows promise for inhibiting ovarian tumor growth and may have important clinical implications. Citation Format: Jie Huang, Wei Hu, Heather J. Dalton, Justin Bottsford-Miller, Robert L. Coleman, Robert B. Jaffe, Anil K. Sood. Dll4 inhibition plus aflibercept markedly reduces ovarian tumor burden and ascites. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2993. doi:10.1158/1538-7445.AM2014-2993
- Published
- 2014
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