131 results on '"Heather J. Dalton"'
Search Results
2. Antagonism of Tumoral Prolactin Receptor Promotes Autophagy-Related Cell Death
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Yunfei Wen, Behrouz Zand, Bulent Ozpolat, Miroslaw J. Szczepanski, Chunhua Lu, Erkan Yuca, Amy R. Carroll, Neslihan Alpay, Chandra Bartholomeusz, Ibrahim Tekedereli, Yu Kang, Rajesha Rupaimoole, Chad V. Pecot, Heather J. Dalton, Anadulce Hernandez, Anna Lokshin, Susan K. Lutgendorf, Jinsong Liu, Walter N. Hittelman, Wen Y. Chen, Gabriel Lopez-Berestein, Marta Szajnik, Naoto T. Ueno, Robert L. Coleman, and Anil K. Sood
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Biology (General) ,QH301-705.5 - Abstract
Summary: Therapeutic upregulation of macroautophagy in cancer cells provides an alternative mechanism for cell death. Prolactin (PRL) and its receptor (PRLR) are considered attractive therapeutic targets because of their roles as growth factors in tumor growth and progression. We utilized G129R, an antagonist peptide of PRL, to block activity of the tumoral PRL/PRLR axis, which resulted in inhibition of tumor growth in orthotopic models of human ovarian cancer. Prolonged treatment with G129R induced the accumulation of redundant autolysosomes in 3D cancer spheroids, leading to a type II programmed cell death. This inducible autophagy was a noncanonical beclin-1-independent pathway and was sustained by an astrocytic phosphoprotein (PEA-15) and protein kinase C zeta interactome. Lower levels of tumoral PRL/PRLR in clinical samples were associated with longer patient survival. Our findings provide an understanding of the mechanisms of tumor growth inhibition through targeting PRL/PRLR and may have clinical implications. : Pharmacological manipulation of autophagy represents a new therapeutic opportunity for cancer. Wen et al. show that blockade of the tumoral PRL/PRLR axis with an antagonist, G129R, induces prolonged autophagy. This inducible autophagy is sustained by the PEA-15 and PKC zeta interactome and leads to type II programmed cell death. There was an inverse correlation between tumoral PRL/PRLR expression and survival of ovarian cancer patients. This study reveals a previously unrecognized mechanism related to targeting the tumoral PRL/PRLR pathway.
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- 2014
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3. Autocrine Effects of Tumor-Derived Complement
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Min Soon Cho, Hernan G. Vasquez, Rajesha Rupaimoole, Sunila Pradeep, Sherry Wu, Behrouz Zand, Hee-Dong Han, Cristian Rodriguez-Aguayo, Justin Bottsford-Miller, Jie Huang, Takahito Miyake, Hyun-Jin Choi, Heather J. Dalton, Cristina Ivan, Keith Baggerly, Gabriel Lopez-Berestein, Anil K. Sood, and Vahid Afshar-Kharghan
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Biology (General) ,QH301-705.5 - Abstract
We describe a role for the complement system in enhancing cancer growth. Cancer cells secrete complement proteins that stimulate tumor growth upon activation. Complement promotes tumor growth via a direct autocrine effect that is partially independent of tumor-infiltrating cytotoxic T cells. Activated C5aR and C3aR signal through the PI3K/AKT pathway in cancer cells, and silencing the PI3K or AKT gene in cancer cells eliminates the progrowth effects of C5aR and C3aR stimulation. In patients with ovarian or lung cancer, higher tumoral C3 or C5aR mRNA levels were associated with decreased overall survival. These data identify a role for tumor-derived complement proteins in promoting tumor growth, and they therefore have substantial clinical and therapeutic implications.
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- 2014
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- View/download PDF
4. Supplementary Figure 1 from Dual Metronomic Chemotherapy with Nab-Paclitaxel and Topotecan Has Potent Antiangiogenic Activity in Ovarian Cancer
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Anil K. Sood, Robert L. Coleman, Robert R. Langley, Alpa M. Nick, William M. Merritt, Jean M. Hansen, Heather J. Dalton, Sunila Pradeep, Ashley N. Davis, Yvonne G. Lin, Guillermo N. Armaiz-Pena, and Rebecca A. Previs
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Hematologic effects of daily metronomic (MET) nab-paclitaxel.
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- 2023
5. Data from Dll4 Inhibition plus Aflibercept Markedly Reduces Ovarian Tumor Growth
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Anil K. Sood, Robert B. Jaffe, Robert L. Coleman, Nicholas B. Jennings, Alpa M. Nick, Tao Liu, Yu Kang, Archana S. Nagaraja, Rajesha Rupaimoole, Michael McGuire, Yunjie Sun, Xiao-Yun Yang, Heather J. Dalton, Rebecca A. Previs, Limin Hu, Wei Hu, and Jie Huang
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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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- 2023
6. Data from Therapeutic Silencing of KRAS Using Systemically Delivered siRNAs
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Anil K. Sood, Lee M. Ellis, Gabriel Lopez-Berestein, Scott Kopetz, Heather J. Dalton, Behrouz Zand, Vianey Gonzalez-Villasana, Trent A. Waugh, Kshipra M. Gharpure, Maria Pia Morelli, Archana S. Nagaraja, Cristian Rodriguez-Aguayo, Salma Azam, Anshumaan Maharaj, Rajat Bhattacharya, Takeshi Hisamatsu, Rajesha Rupaimoole, Justyna Filant, Seth Bellister, Sherry Y. Wu, and Chad V. Pecot
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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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- 2023
7. Data from PTEN Expression as a Predictor of Response to Focal Adhesion Kinase Inhibition in Uterine Cancer
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Anil K. Sood, Robert L. Coleman, Rouba Ali-Fehmi, Heather J. Dalton, Jie Huang, Rajesha Rupaimoole, Jean M. Hansen, Piotr L. Dorniak, Guillermo N. Armaiz-Pena, Cristina Ivan, Wei Hu, Rebecca A. Previs, and Duangmani Thanapprapasr
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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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- 2023
8. Supplementary Figure 1 from PTEN Expression as a Predictor of Response to Focal Adhesion Kinase Inhibition in Uterine Cancer
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Anil K. Sood, Robert L. Coleman, Rouba Ali-Fehmi, Heather J. Dalton, Jie Huang, Rajesha Rupaimoole, Jean M. Hansen, Piotr L. Dorniak, Guillermo N. Armaiz-Pena, Cristina Ivan, Wei Hu, Rebecca A. Previs, and Duangmani Thanapprapasr
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Mean mouse weights in orthotopic mouse models of uterine cancer.
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- 2023
9. Supplementary Figures 1 - 2 from Therapeutic Silencing of KRAS Using Systemically Delivered siRNAs
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Anil K. Sood, Lee M. Ellis, Gabriel Lopez-Berestein, Scott Kopetz, Heather J. Dalton, Behrouz Zand, Vianey Gonzalez-Villasana, Trent A. Waugh, Kshipra M. Gharpure, Maria Pia Morelli, Archana S. Nagaraja, Cristian Rodriguez-Aguayo, Salma Azam, Anshumaan Maharaj, Rajat Bhattacharya, Takeshi Hisamatsu, Rajesha Rupaimoole, Justyna Filant, Seth Bellister, Sherry Y. Wu, and Chad V. Pecot
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Supplementary figure 1 provides a schematic of DOPC:siRNA nanoliposomal preparation, and Supplementary figure 2 shows tumor volumetric measurements of the A549 orthotopic lung cancer therapeutic experiment described in the main figure 2.
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- 2023
10. Data from Inhibiting Nuclear Phospho-Progesterone Receptor Enhances Antitumor Activity of Onapristone in Uterine Cancer
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Anil K. Sood, Robert L. Coleman, Russell Broaddus, Nicholas B. Jennings, Michael McGuire, Archana S. Nagaraja, Rebecca A. Previs, Heather J. Dalton, Jean M. Hansen, Kyunghee Noh, Lingegowda S. Mangala, Dahai Jiang, Monika Haemmerle, Robert Dood, Sunila Pradeep, Cristina Ivan, Yunjie Sun, Fangrong Shen, Jie Huang, Wei Hu, and Yan Huang
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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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- 2023
11. Data from Dual Metronomic Chemotherapy with Nab-Paclitaxel and Topotecan Has Potent Antiangiogenic Activity in Ovarian Cancer
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Anil K. Sood, Robert L. Coleman, Robert R. Langley, Alpa M. Nick, William M. Merritt, Jean M. Hansen, Heather J. Dalton, Sunila Pradeep, Ashley N. Davis, Yvonne G. Lin, Guillermo N. Armaiz-Pena, and Rebecca A. Previs
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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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- 2023
12. Supplementary Figures 1-6 from Dll4 Inhibition plus Aflibercept Markedly Reduces Ovarian Tumor Growth
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Anil K. Sood, Robert B. Jaffe, Robert L. Coleman, Nicholas B. Jennings, Alpa M. Nick, Tao Liu, Yu Kang, Archana S. Nagaraja, Rajesha Rupaimoole, Michael McGuire, Yunjie Sun, Xiao-Yun Yang, Heather J. Dalton, Rebecca A. Previs, Limin Hu, Wei Hu, and Jie Huang
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Supplementary Figure 1. Representative OVCAR3-inoculated mice after aflibercept, Dll4-Fc, and the combination. Supplementary Figure 2. In vivo study of Dll4 blockade, aflibercept, and docetaxel, alone and in combinations, in A2780 and HeyA8 models. Supplementary Figure 3. Immunohistochemical staining of CX3CL1 in the tumor stroma of mice inoculated with A2780 ovarian cancer cells. Supplementary Figure 4. Quantitative real-time PCR of CX3CL1 expression in A2780 cells cultured with primary dendritic cells isolated from C57/BL6 mice. Supplementary Figure 5. ELISA analysis of plasma IFN-gamma in the mice inoculated with A2780 ovarian cancer cells. Supplementary Figure 6. RT-PCR analysis of E-cadherin expression in tumors (tumor cells and stroma) obtained from A2780 mice treated with a single agent or a combination.
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- 2023
13. Supplementary Figures from Inhibiting Nuclear Phospho-Progesterone Receptor Enhances Antitumor Activity of Onapristone in Uterine Cancer
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Anil K. Sood, Robert L. Coleman, Russell Broaddus, Nicholas B. Jennings, Michael McGuire, Archana S. Nagaraja, Rebecca A. Previs, Heather J. Dalton, Jean M. Hansen, Kyunghee Noh, Lingegowda S. Mangala, Dahai Jiang, Monika Haemmerle, Robert Dood, Sunila Pradeep, Cristina Ivan, Yunjie Sun, Fangrong Shen, Jie Huang, Wei Hu, and Yan Huang
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Supplementary Figure 1. In vitro effects of PR silencing on onapristone sensitivity in PR-high-expressing uterine cancer cell line (Ishikawa). Supplementary Figure 2. In vitro effects of onapristone and trametinib in PR-weak-expressing uterine cancer cell line (SKUT2). Supplementary Figure 3. In vivo effects of therapy with onapristone in uterine cancer model. Supplementary Figure 4. In vivo effect of onapristone, trametinib, and the combination of both drugs on total PR expression in the ISHIKAWA model.
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- 2023
14. Supplementary Figure Legend from Dual Metronomic Chemotherapy with Nab-Paclitaxel and Topotecan Has Potent Antiangiogenic Activity in Ovarian Cancer
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Anil K. Sood, Robert L. Coleman, Robert R. Langley, Alpa M. Nick, William M. Merritt, Jean M. Hansen, Heather J. Dalton, Sunila Pradeep, Ashley N. Davis, Yvonne G. Lin, Guillermo N. Armaiz-Pena, and Rebecca A. Previs
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Hematologic effects of daily metronomic (MET) nab-paclitaxel. White blood count (WBC), hemoglobin, and platelet number were assessed from tumor bearing mice after one, two, and three weeks of treatment.
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- 2023
15. Supplementary Video 2 from Immunotherapy Targeting Folate Receptor Induces Cell Death Associated with Autophagy in Ovarian Cancer
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Anil K. Sood, Robert L. Coleman, Pablo E. Vivas-Mejia, Ju-Seog Lee, Prahlad Ram, Vasudha Sehgal, Heather J. Dalton, Nicholas B. Jennings, Alpa M. Nick, Behrouz Zand, Lingegowda S. Mangala, Cristina Ivan, Wei Hu, Rebecca A. Previs, Whitney S. Graybill, and Yunfei Wen
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Supplementary Video 2. 3-D SKOV3ip1 spheroids expressing pGFP-RFP-LC3 were treated with MORAB-003
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- 2023
16. Data from Molecular Biomarkers of Residual Disease after Surgical Debulking of High-Grade Serous Ovarian Cancer
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Anil K. Sood, Keith A. Baggerly, Wei Hu, Cristina Ivan, Bulent Ozpolat, Gabriel Lopez-Berestein, Rajesha Rupaimoole, Sherry Y. Wu, Heather J. Dalton, Jamie Guenthoer, Robert L. Coleman, Erin K. Crane, Alpa M. Nick, Anna K. Unruh, Shelley M. Herbrich, Kshipra Gharpure, and Susan L. Tucker
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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.
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- 2023
17. Data from Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction
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Anil K. Sood, Mariella De Biasi, Susan K. Lutgendorf, Steve W. Cole, Gabriel Lopez-Berestein, Frank C. Marini, Stephen T.C. Wong, Prahlad T. Ram, Erika L. Spaeth, Vasudha Sehgal, Cristian Rodriguez-Aguayo, Lingegowda S. Mangala, Yu Kang, Myrthala Moreno-Smith, Justin Bottsford-Miller, Wei Hu, Morgan Taylor, Heather J. Dalton, Behrouz Zand, Hee Dong Han, Xiaoyun Xu, Sunila Pradeep, Sherry Y. Wu, Rebecca A. Previs, Rajesha Rupaimoole, Kshipra M. Gharpure, Monika Haemmerle, Danielle M. Herder, Merve Ozcan, Robert Dood, Tatiana Ortiz, Nouara C. Sadaoui, Archana S. Nagaraja, Guillermo N. Armaiz-Pena, and Julie K. Allen
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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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- 2023
18. Supplementary Materials and Methods, Figures 1 - 14, Table 1 from Molecular Biomarkers of Residual Disease after Surgical Debulking of High-Grade Serous Ovarian Cancer
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Anil K. Sood, Keith A. Baggerly, Wei Hu, Cristina Ivan, Bulent Ozpolat, Gabriel Lopez-Berestein, Rajesha Rupaimoole, Sherry Y. Wu, Heather J. Dalton, Jamie Guenthoer, Robert L. Coleman, Erin K. Crane, Alpa M. Nick, Anna K. Unruh, Shelley M. Herbrich, Kshipra Gharpure, and Susan L. Tucker
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PDF file - 2766KB, Supplementary methods and reports describing all data analyses. Supplementary Table 1. Probesets (N=47) and associated genes (N=38) having consistent differences in expression between residual disease (RD) and No-RD patients in the TCGA and Tothill data sets at a 10 percent false discovery rate in each data set. Figure 1. Bivariate plot of two-sample RD-No RD t-values for TCGA and Tothill. The vast majority of the probesets selected show higher expression in RD cases. Lumican (LUM) is the strongest overall. Figure 2. Zoom on the upper quadrant of the bivariate plot of two-sample RD-No RD t-values for TCGA and Tothill, to show the names more clearly. Figure 3. Heatmap of the TCGA Samples using just the 8 probesets passing the 5 percent FDR filter for both TCGA and Tothill. Figure 4. Heatmap of the Tothill Samples using just the 8 probesets passing the 5 percent FDR filter for both TCGA and Tothill. Figure 5. Heatmap of the TCGA Samples using the 47 probesets passing the 10 percent FDR filter for both TCGA and Tothill. Figure 6. Heatmap of the Tothill Samples using the 47 probesets passing the 10 percent FDR filter for both TCGA and Tothill. Figure 7. Correlations in the TCGA data between the 47 probesets selected by 10 percent FDR cutoffs. Figure 8. Correlations in the Tothill data between the 47 probesets selected by 10 percent FDR cutoffs. Figure 9. Dot and density plots for lumican (LUM) in TCGA and Tothill. Figure 10. Dot and density plots for decorin (DCN) in TCGA and Tothill. Figure 11. Dot and density plots for GADD45B in TCGA and Tothill. Figure 12. Dot and density plots for FABP4 in TCGA and Tothill. Figure 13. Dot and density plots for ADH1B in TCGA and Tothill. Figure 14. Dot and density plots for ADIPOQ in TCGA and Tothill.
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- 2023
19. Supplementary Figure Legends (Figures 1-6) from Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer
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Gabriel Lopez-Berestein, Anil K. Sood, George Calin, Bulent Ozpolat, Pinar Kanlikilicer, Huamin Wang, Nermin Kahraman, Sunila Pradeep, Rebecca A. Previs, Guermarie Velazquez-Torres, Paloma del C. Monroig, Burcu Aslan, Ricardo J. Fernandez-de Thomas, Cristian Rodriguez-Aguayo, Heather J. Dalton, Cristina Ivan, Enrique Fuentes-Mattei, and Vianey Gonzalez-Villasana
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Supplementary Figure Legends (Figures 1-6)
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- 2023
20. Figure S2 from Targeting Src and Tubulin in Mucinous Ovarian Carcinoma
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Anil K. Sood, Michael Frumovitz, Robert L. Coleman, David G. Hangauer, Keith A. Baggerly, Gary E. Gallick, Cristina Ivan, Nicholas B. Jennings, Behrouz Zand, Justin Bottsford-Miller, Chad V. Pecot, Chunhua Lu, Yunfei Wen, Jian H. Song, Takahito Miyake, Sunila Pradeep, Yu Kang, Jie Huang, Hyun Jin Choi, Heather J. Dalton, Wei Hu, and Tao Liu
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PDF file 196K, Figure S2. Effects of KX-01 and oxaliplatin on cell proliferation (Ki-67; A), angiogenesis (CD31; B), apoptosis (Cleaved caspase-3; C) RMUG-L model. Original magnification 200x . Bars in the graphs correspond sequentially to the labeled columns of images on the left. Data are shown as mean {plus-minus} standard deviation (error bars). *p
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- 2023
21. Data from Immunotherapy Targeting Folate Receptor Induces Cell Death Associated with Autophagy in Ovarian Cancer
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Anil K. Sood, Robert L. Coleman, Pablo E. Vivas-Mejia, Ju-Seog Lee, Prahlad Ram, Vasudha Sehgal, Heather J. Dalton, Nicholas B. Jennings, Alpa M. Nick, Behrouz Zand, Lingegowda S. Mangala, Cristina Ivan, Wei Hu, Rebecca A. Previs, Whitney S. Graybill, and Yunfei Wen
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Purpose: Cancer cells are highly dependent on folate metabolism, making them susceptible to drugs that inhibit folate receptor activities. Targeting overexpressed folate receptor alpha (FRα) in cancer cells offers a therapeutic opportunity. We investigated the functional mechanisms of MORAB-003 (farletuzumab), a humanized mAb against FRα, in ovarian cancer models.Experimental Design: We first examined FRα expression in an array of human ovarian cancer cell lines and then assessed the in vivo effect of MORAB-003 on tumor growth and progression in several orthotopic mouse models of ovarian cancer derived from these cell lines. Molecular mechanisms of tumor cell death induced by MORAB-003 were investigated by cDNA and protein expression profiling analysis. Mechanistic studies were performed to determine the role of autophagy in MORAB-003–induced cell death.Results: MORAB-003 significantly decreased tumor growth in the high-FRα IGROV1 and SKOV3ip1 models but not in the low-FRα A2780 model. MORAB-003 reduced proliferation, but had no significant effect on apoptosis. Protein expression and cDNA microarray analyses showed that MORAB-003 regulated an array of autophagy-related genes. It also significantly increased expression of LC3 isoform II and enriched autophagic vacuolization. Blocking autophagy with hydroxychloroquine or bafilomycin A1 reversed the growth inhibition induced by MORAB-003. In addition, alteration of FOLR1 gene copy number significantly correlated with shorter disease-free survival in patients with ovarian serous cancer.Conclusions: MORAB-003 displays prominent antitumor activity in ovarian cancer models expressing FRα at high levels. Blockade of folate receptor by MORAB-003 induced sustained autophagy and suppressed cell proliferation. Clin Cancer Res; 21(2); 448–59. ©2014 AACR.
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- 2023
22. Data from Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer
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Gabriel Lopez-Berestein, Anil K. Sood, George Calin, Bulent Ozpolat, Pinar Kanlikilicer, Huamin Wang, Nermin Kahraman, Sunila Pradeep, Rebecca A. Previs, Guermarie Velazquez-Torres, Paloma del C. Monroig, Burcu Aslan, Ricardo J. Fernandez-de Thomas, Cristian Rodriguez-Aguayo, Heather J. Dalton, Cristina Ivan, Enrique Fuentes-Mattei, and Vianey Gonzalez-Villasana
- 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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- 2023
23. Supplementary Video 3 from Immunotherapy Targeting Folate Receptor Induces Cell Death Associated with Autophagy in Ovarian Cancer
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Anil K. Sood, Robert L. Coleman, Pablo E. Vivas-Mejia, Ju-Seog Lee, Prahlad Ram, Vasudha Sehgal, Heather J. Dalton, Nicholas B. Jennings, Alpa M. Nick, Behrouz Zand, Lingegowda S. Mangala, Cristina Ivan, Wei Hu, Rebecca A. Previs, Whitney S. Graybill, and Yunfei Wen
- Abstract
Supplementary Video 3. 3-D SKOV3ip1 spheroids expressing pGFP-LC3 only were treated with MORAB-003
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- 2023
24. Supplementary Figures 1 - 6 and Tables 1 - 10 from Cross-talk between EphA2 and BRaf/CRaf Is a Key Determinant of Response to Dasatinib
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Anil K. Sood, Robert L. Coleman, Russell Broaddus, Michael T. Deavers, Li Huang, Nicholas B. Jennings, Yu Kang, Diana Urbauer, Bryan Fellman, Chunhua Lu, Rajesh Rupaimoole, Chad V. Pecot, Heather J. Dalton, Duangmani Thanapprapasr, Ju-Won Roh, Sunila Pradeep, Behrouz Zand, Hee Dong Han, Tao Liu, Justin Bottsford-Miller, Wei Hu, and Jie Huang
- Abstract
PDF file - 930KB, The supplementary file includes: Figure S1. Effects of dasatinib on uterine and ovarian cancer cells. Figure S2. Effects of dasatinib based on PTEN status. Figure S3. RPPA analysis of expression levels of 176 proteins in uterine cancer cells treated with dasatinib, paclitaxel, or both. Figure S4. Effect of dasatinib on selected proteins in uterine cancer cell lines. Figure S5. Effect of dasatinib on uterine cancer cell lines with or without EphA2 silencing. Figure S6. In vivo effects of dasatinib and paclitaxel on mouse models of uterine carcinoma. Table S1. Candidate predictive markers for response to dasatinib in uterine cancer. Table S2. Basal expression levels of putative dasatinib response markers in human normal uterine and uterine cancer samples. Table S3. Proteins that differed among controls and treated SPEC-2 cells Table S4. Mean fold change of proteins in SPEC-2 cell line Table S5. Proteins that differed among controls and treated SKUT-2 cells Table S6. Mean fold change of proteins in SKUT-2 cell line Table S7. Proteins that differed among controls and treated HEC1-A cells Table S8. Mean fold change of proteins in HEC1-A cell line Table S9. Proteins that differed among controls and treated Ishikawa cells Table S10. Mean fold change of proteins in Ishikawa cell line.
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- 2023
25. Supplemental Table 2 from Differential Platelet Levels Affect Response to Taxane-Based Therapy in Ovarian Cancer
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Anil K. Sood, Vahid Afshar-Kharghan, Susan K. Lutgendorf, Wei Hu, Erin King Crane, Chad V. Pecot, Rebecca A. Previs, Behrouz Zand, Sunila Pradeep, Alpa M. Nick, Monika Haemmerle, Min Soon Cho, Rebecca L. Stone, Heather J. Dalton, Hyun-Jin Choi, and Justin Bottsford-Miller
- Abstract
Supplemental Table 2: Patterns of platelet level changes through treatment and surveillance until recurrence.
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- 2023
26. Data from Biologic Effects of Platelet-Derived Growth Factor Receptor α Blockade in Uterine Cancer
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Anil K. Sood, Robert L. Coleman, Prahlad Ram, Ju-Seog Lee, Koji Matsuo, Ashley N. Davis, Rebecca A. Previs, Heather J. Dalton, Behrouz Zand, Justin Bottsford-Miller, Duangmani Thanapprapasr, Sun Joo Lee, Hee Dong Han, Bo Hwa Sohn, Vasudha Sehgal, Nicholas B. Jennings, XiaoYun Yang, Wei Hu, Jie Huang, and Ju-Won Roh
- 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.
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- 2023
27. Supplementary Figures 1 - 3 from Biologic Effects of Platelet-Derived Growth Factor Receptor α Blockade in Uterine Cancer
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Anil K. Sood, Robert L. Coleman, Prahlad Ram, Ju-Seog Lee, Koji Matsuo, Ashley N. Davis, Rebecca A. Previs, Heather J. Dalton, Behrouz Zand, Justin Bottsford-Miller, Duangmani Thanapprapasr, Sun Joo Lee, Hee Dong Han, Bo Hwa Sohn, Vasudha Sehgal, Nicholas B. Jennings, XiaoYun Yang, Wei Hu, Jie Huang, and Ju-Won Roh
- Abstract
PDF file - 959KB, Supplementary Figure 1. PDGFRalpha expression and activation in patients with uterine cancer. Supplementary Figure 2. In vivo therapeutic and biological effects of PDGFRalpha blockade (3G3) on uterine cancer. Supplementary 3. Network analysis of angiogenesis factors down-regulated by 3G3 treatment in PDGFRalpha-positive cells and PDGFRalpha-negative cells.
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- 2023
28. Supplementary Figures 1-6 from Rac1/Pak1/p38/MMP-2 Axis Regulates Angiogenesis in Ovarian Cancer
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Gabriel Lopez-Berestein, Anil K. Sood, George Calin, Bulent Ozpolat, Pinar Kanlikilicer, Huamin Wang, Nermin Kahraman, Sunila Pradeep, Rebecca A. Previs, Guermarie Velazquez-Torres, Paloma del C. Monroig, Burcu Aslan, Ricardo J. Fernandez-de Thomas, Cristian Rodriguez-Aguayo, Heather J. Dalton, Cristina Ivan, Enrique Fuentes-Mattei, and Vianey Gonzalez-Villasana
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Supplementary Figures 1-6. Supplementary Figure S1: In vivo and in vitro effects of ZA on apoptosis. Supplementary Figure S2: Nab-paclitaxel inhibits tube formation.Supplementary Figure S3: RPPA analysis in HeyA8 MDR treated with ZA. Supplementary Figure S4: Functional changes induced by ZA in HeyA8 MDR. Supplementary Figure S5: ZA decreases angiogenic factors. Supplementary Figure S6: ZA inhibits cell invasion
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- 2023
29. Supplementary information from Targeting Src and Tubulin in Mucinous Ovarian Carcinoma
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Anil K. Sood, Michael Frumovitz, Robert L. Coleman, David G. Hangauer, Keith A. Baggerly, Gary E. Gallick, Cristina Ivan, Nicholas B. Jennings, Behrouz Zand, Justin Bottsford-Miller, Chad V. Pecot, Chunhua Lu, Yunfei Wen, Jian H. Song, Takahito Miyake, Sunila Pradeep, Yu Kang, Jie Huang, Hyun Jin Choi, Heather J. Dalton, Wei Hu, and Tao Liu
- Abstract
PDF file 106K, Table S1. Molecules whose expression significantly differed between cells treated with KX-01 and control cells in RMUG-S cells Table S2. Molecules whose expression significantly differed between cells treated with KX-01 and control cells in RMUG-L cells
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- 2023
30. Supplementary Movie 2 from Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction
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Anil K. Sood, Mariella De Biasi, Susan K. Lutgendorf, Steve W. Cole, Gabriel Lopez-Berestein, Frank C. Marini, Stephen T.C. Wong, Prahlad T. Ram, Erika L. Spaeth, Vasudha Sehgal, Cristian Rodriguez-Aguayo, Lingegowda S. Mangala, Yu Kang, Myrthala Moreno-Smith, Justin Bottsford-Miller, Wei Hu, Morgan Taylor, Heather J. Dalton, Behrouz Zand, Hee Dong Han, Xiaoyun Xu, Sunila Pradeep, Sherry Y. Wu, Rebecca A. Previs, Rajesha Rupaimoole, Kshipra M. Gharpure, Monika Haemmerle, Danielle M. Herder, Merve Ozcan, Robert Dood, Tatiana Ortiz, Nouara C. Sadaoui, Archana S. Nagaraja, Guillermo N. Armaiz-Pena, and Julie K. Allen
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CARS imaging of ex vivo ovarian cancer samples
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- 2023
31. Data from Targeting Src and Tubulin in Mucinous Ovarian Carcinoma
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Anil K. Sood, Michael Frumovitz, Robert L. Coleman, David G. Hangauer, Keith A. Baggerly, Gary E. Gallick, Cristina Ivan, Nicholas B. Jennings, Behrouz Zand, Justin Bottsford-Miller, Chad V. Pecot, Chunhua Lu, Yunfei Wen, Jian H. Song, Takahito Miyake, Sunila Pradeep, Yu Kang, Jie Huang, Hyun Jin Choi, Heather J. Dalton, Wei Hu, and Tao Liu
- 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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- 2023
32. Figures S1-S6, Table S1-S3 from Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction
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Anil K. Sood, Mariella De Biasi, Susan K. Lutgendorf, Steve W. Cole, Gabriel Lopez-Berestein, Frank C. Marini, Stephen T.C. Wong, Prahlad T. Ram, Erika L. Spaeth, Vasudha Sehgal, Cristian Rodriguez-Aguayo, Lingegowda S. Mangala, Yu Kang, Myrthala Moreno-Smith, Justin Bottsford-Miller, Wei Hu, Morgan Taylor, Heather J. Dalton, Behrouz Zand, Hee Dong Han, Xiaoyun Xu, Sunila Pradeep, Sherry Y. Wu, Rebecca A. Previs, Rajesha Rupaimoole, Kshipra M. Gharpure, Monika Haemmerle, Danielle M. Herder, Merve Ozcan, Robert Dood, Tatiana Ortiz, Nouara C. Sadaoui, Archana S. Nagaraja, Guillermo N. Armaiz-Pena, and Julie K. Allen
- Abstract
Fig. S1. Sustained adrenergic signaling increases nerve counts in tumors. Fig. S2. Characterization of tumoral innervation. Fig. S3. NE induces BDNF expression. Fig. S4. NE-induced BDNF expression is mediated by ADRB3/Epac/Jnk. Fig. S5. BDNF increases nerve counts. Fig. S6. Adrenergic-mediated mTrkB activation leads to increased in vivo tumor nodule counts. Table S1. Alteration in pathways associated with neuronal growth and function after NE treatment (HeyA8 and SKOV3ip1 cells). Table S2. Association of Clinicopathologic variables with BDNF protein expression. Table S3. Association of Clinicopathologic variables with Nerve Counts.
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- 2023
33. Supplemental Methods from Differential Platelet Levels Affect Response to Taxane-Based Therapy in Ovarian Cancer
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Anil K. Sood, Vahid Afshar-Kharghan, Susan K. Lutgendorf, Wei Hu, Erin King Crane, Chad V. Pecot, Rebecca A. Previs, Behrouz Zand, Sunila Pradeep, Alpa M. Nick, Monika Haemmerle, Min Soon Cho, Rebecca L. Stone, Heather J. Dalton, Hyun-Jin Choi, and Justin Bottsford-Miller
- Abstract
Supplemental Methods. The supplementary methods section describes in greater detail how platelets were isolated from whole mouse blood, how the in vitro apoptosis assay was performed, how cleaved caspace 3 immunohistochemistry was performed, how platelet transfusion was performed, and how aspirinization of platelets prior to transfusion was performed. The supplementary data includes a table detailing the demographic characteristics of the patients included in the clinical component of the work as well as the details of platelet change over the course of primary therapy.
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- 2023
34. Supplementary Video 1 from Immunotherapy Targeting Folate Receptor Induces Cell Death Associated with Autophagy in Ovarian Cancer
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Anil K. Sood, Robert L. Coleman, Pablo E. Vivas-Mejia, Ju-Seog Lee, Prahlad Ram, Vasudha Sehgal, Heather J. Dalton, Nicholas B. Jennings, Alpa M. Nick, Behrouz Zand, Lingegowda S. Mangala, Cristina Ivan, Wei Hu, Rebecca A. Previs, Whitney S. Graybill, and Yunfei Wen
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Supplementary Video 1. 3-D SKOV3ip1 spheroids expressing pGFP-RFP-LC3 were treated with control IgG
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- 2023
35. Data from Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression
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Anil K. Sood, Robert L. Coleman, Gabriel Lopez-Berestein, Prahlad Ram, Willem Overwijk, Menashe Bar-Eli, Michael Andreeff, Hong Mu, Robert Langley, Wei Hu, Nicholas B. Jennings, Lingegowda S. Mangala, Sherry Y. Wu, Min Soon Cho, Vianey Gonzalez-Villasana, Rajesha Rupaimoole, Jean Marie Hansen, Rebecca A. Previs, Guillermo N. Armaiz-Pena, Yasmin Lyons, Shaolin MA, Yared Hailemichael, Michael McGuire, Sunila Pradeep, and Heather J. Dalton
- 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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- 2023
36. Supplementary figures S1-5, Tables S1-5 from XPO1/CRM1 Inhibition Causes Antitumor Effects by Mitochondrial Accumulation of eIF5A
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Anil K. Sood, Robert L. Coleman, John E. Wiktorowicz, David H. Hawke, Dilara McCauley, Sharon Shacham, Tao Liu, Yu Kang, Takeshi Hisamatsu, Morgan L. Taylor, Rebecca A. Previs, Heather J. Dalton, Min Soon Cho, Wei Hu, Archana S. Nagaraja, Kshipra M. Gharpure, Yunfei Wen, Behrouz Zand, Rajesha Rupaimoole, Sherry Y. Wu, Sunila Pradeep, and Takahito Miyake
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Supplementary Figures S1-5, Tables S1-5. Figure S1 The Cytotoxic Effect of KPT-185 is Tumor Suppressor-independent. Figure S2 Combination Index of KPT-185 with Chemotherapeutic Agents. Figure S3 1D Gel Analysis of Cytoplasmic Protein. Figure S4 Effects of Selinexor (KPT-330) in an Ovarian Cancer Mouse Model. Figure S5 The Efficacy of Selinexor (KPT-330) on Tumor Regression and Metastasis Table S1 p53 status and IC50 concentration of KPT-185 after 72 hours of incubation in human cancer cell lines Table S2 Combination index (CI) of KPT-185 with cytotoxic agents Table S3 Proteins showing altered mitochondrial localization after treatment with KPT-185 Table S4 1D Proteomic analysis of cytoplasmic proteins immunoprecipitated with eIF5A Table S5 siRNA Sequences
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- 2023
37. Supplementary Figures 1-5, Supplementary Experimental Procedures, Supplementary References from Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression
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Anil K. Sood, Robert L. Coleman, Gabriel Lopez-Berestein, Prahlad Ram, Willem Overwijk, Menashe Bar-Eli, Michael Andreeff, Hong Mu, Robert Langley, Wei Hu, Nicholas B. Jennings, Lingegowda S. Mangala, Sherry Y. Wu, Min Soon Cho, Vianey Gonzalez-Villasana, Rajesha Rupaimoole, Jean Marie Hansen, Rebecca A. Previs, Guillermo N. Armaiz-Pena, Yasmin Lyons, Shaolin MA, Yared Hailemichael, Michael McGuire, Sunila Pradeep, and Heather J. Dalton
- Abstract
S Figure 1 (A) C57BL/6 mice that received intra-peritoneal injections of IG10 cells were randomly assigned to one of two groups (control or B20 treatment). S Figure 2 (A) Bar graph represents the CD11b+/F4/80+ macrophages in tumor tissue by FACS analysis. S Figure 3 Anti-VEGF therapyââ,¬â€œresistant macrophages have heightened viability, migration, and invasion. S Figure 4 (A) Bar graph represents the percentage of viability of B20 treated macrophages. S Figure 5. VEGFR1-positive macrophages increase the effectiveness of anti-VEGF therapy.
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- 2023
38. Supplementary Movie 1 from Sustained Adrenergic Signaling Promotes Intratumoral Innervation through BDNF Induction
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Anil K. Sood, Mariella De Biasi, Susan K. Lutgendorf, Steve W. Cole, Gabriel Lopez-Berestein, Frank C. Marini, Stephen T.C. Wong, Prahlad T. Ram, Erika L. Spaeth, Vasudha Sehgal, Cristian Rodriguez-Aguayo, Lingegowda S. Mangala, Yu Kang, Myrthala Moreno-Smith, Justin Bottsford-Miller, Wei Hu, Morgan Taylor, Heather J. Dalton, Behrouz Zand, Hee Dong Han, Xiaoyun Xu, Sunila Pradeep, Sherry Y. Wu, Rebecca A. Previs, Rajesha Rupaimoole, Kshipra M. Gharpure, Monika Haemmerle, Danielle M. Herder, Merve Ozcan, Robert Dood, Tatiana Ortiz, Nouara C. Sadaoui, Archana S. Nagaraja, Guillermo N. Armaiz-Pena, and Julie K. Allen
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CARS imaging of ex vivo ovarian cancer samples
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- 2023
39. Supplemental Table 1 from Differential Platelet Levels Affect Response to Taxane-Based Therapy in Ovarian Cancer
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Anil K. Sood, Vahid Afshar-Kharghan, Susan K. Lutgendorf, Wei Hu, Erin King Crane, Chad V. Pecot, Rebecca A. Previs, Behrouz Zand, Sunila Pradeep, Alpa M. Nick, Monika Haemmerle, Min Soon Cho, Rebecca L. Stone, Heather J. Dalton, Hyun-Jin Choi, and Justin Bottsford-Miller
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Supplemental Table 1: Patient Demographics.
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- 2023
40. TableS1 from Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression
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Anil K. Sood, Robert L. Coleman, Gabriel Lopez-Berestein, Prahlad Ram, Willem Overwijk, Menashe Bar-Eli, Michael Andreeff, Hong Mu, Robert Langley, Wei Hu, Nicholas B. Jennings, Lingegowda S. Mangala, Sherry Y. Wu, Min Soon Cho, Vianey Gonzalez-Villasana, Rajesha Rupaimoole, Jean Marie Hansen, Rebecca A. Previs, Guillermo N. Armaiz-Pena, Yasmin Lyons, Shaolin MA, Yared Hailemichael, Michael McGuire, Sunila Pradeep, and Heather J. Dalton
- Abstract
Table S1
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- 2023
41. Data from Differential Platelet Levels Affect Response to Taxane-Based Therapy in Ovarian Cancer
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Anil K. Sood, Vahid Afshar-Kharghan, Susan K. Lutgendorf, Wei Hu, Erin King Crane, Chad V. Pecot, Rebecca A. Previs, Behrouz Zand, Sunila Pradeep, Alpa M. Nick, Monika Haemmerle, Min Soon Cho, Rebecca L. Stone, Heather J. Dalton, Hyun-Jin Choi, and Justin Bottsford-Miller
- 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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- 2023
42. Supplementary Table 3 from Notch3 Pathway Alterations in Ovarian Cancer
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Anil K. Sood, Robert L. Coleman, Keith A. Baggerly, Gabriel Lopez-Berestein, Susan L. Tucker, Jinsong Liu, Prahlad Ram, Vasudha Sehgal, Ju-Seog Lee, Sherry Y. Wu, Alpa M. Nick, Chad V. Pecot, Yu Kang, Behrouz Zand, Justin Bottsford-Miller, Hee Dong Han, Rebecca A. Previs, Rajesh Rupaimoole, Sunila Pradeep, Heather J. Dalton, Takahito Miyake, Lingegowda S. Mangala, Jie Huang, Yunjie Sun, Cristina Ivan, Tao Liu, and Wei Hu
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PDF file - 55K, Correlation between key transcription factors and Notch3 overexpression.
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- 2023
43. Supplementary Figures 1 - 5 from Notch3 Pathway Alterations in Ovarian Cancer
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Anil K. Sood, Robert L. Coleman, Keith A. Baggerly, Gabriel Lopez-Berestein, Susan L. Tucker, Jinsong Liu, Prahlad Ram, Vasudha Sehgal, Ju-Seog Lee, Sherry Y. Wu, Alpa M. Nick, Chad V. Pecot, Yu Kang, Behrouz Zand, Justin Bottsford-Miller, Hee Dong Han, Rebecca A. Previs, Rajesh Rupaimoole, Sunila Pradeep, Heather J. Dalton, Takahito Miyake, Lingegowda S. Mangala, Jie Huang, Yunjie Sun, Cristina Ivan, Tao Liu, and Wei Hu
- Abstract
PDF file - 765K, Overall Survival (OS) Analysis in Patients With High-Grade Serous Ovarian Cancer HGS-OvCa (S1); In Vitro Functional Studies of Notch3 siRNA or GSI and combined with Paclitaxel in OvCa Cells (S2); qRT-PCR Analysis of Expression of Gamma-Secretase Complex in Ovarian Cancer Cells (S3); In vitro effects of blocking endocytosis on Jagged-1/Notch3 pathway in cancer cells (S4); In vivo study of Notch3 siRNA in orthotopic mouse models of ovarian cancer (S5).
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- 2023
44. Supplementary Table 4 from Notch3 Pathway Alterations in Ovarian Cancer
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Anil K. Sood, Robert L. Coleman, Keith A. Baggerly, Gabriel Lopez-Berestein, Susan L. Tucker, Jinsong Liu, Prahlad Ram, Vasudha Sehgal, Ju-Seog Lee, Sherry Y. Wu, Alpa M. Nick, Chad V. Pecot, Yu Kang, Behrouz Zand, Justin Bottsford-Miller, Hee Dong Han, Rebecca A. Previs, Rajesh Rupaimoole, Sunila Pradeep, Heather J. Dalton, Takahito Miyake, Lingegowda S. Mangala, Jie Huang, Yunjie Sun, Cristina Ivan, Tao Liu, and Wei Hu
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PDF file - 65K, Microarray Analysis of Significantly Down- regulated Genes in OVCAR3 cells With or Without Notch3 Silencing.
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- 2023
45. Supplementary Table 2 from Notch3 Pathway Alterations in Ovarian Cancer
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Anil K. Sood, Robert L. Coleman, Keith A. Baggerly, Gabriel Lopez-Berestein, Susan L. Tucker, Jinsong Liu, Prahlad Ram, Vasudha Sehgal, Ju-Seog Lee, Sherry Y. Wu, Alpa M. Nick, Chad V. Pecot, Yu Kang, Behrouz Zand, Justin Bottsford-Miller, Hee Dong Han, Rebecca A. Previs, Rajesh Rupaimoole, Sunila Pradeep, Heather J. Dalton, Takahito Miyake, Lingegowda S. Mangala, Jie Huang, Yunjie Sun, Cristina Ivan, Tao Liu, and Wei Hu
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PDF file - 183K, The siRNA and Primer Sequences.
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- 2023
46. Supplementary Table 1 from Notch3 Pathway Alterations in Ovarian Cancer
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Anil K. Sood, Robert L. Coleman, Keith A. Baggerly, Gabriel Lopez-Berestein, Susan L. Tucker, Jinsong Liu, Prahlad Ram, Vasudha Sehgal, Ju-Seog Lee, Sherry Y. Wu, Alpa M. Nick, Chad V. Pecot, Yu Kang, Behrouz Zand, Justin Bottsford-Miller, Hee Dong Han, Rebecca A. Previs, Rajesh Rupaimoole, Sunila Pradeep, Heather J. Dalton, Takahito Miyake, Lingegowda S. Mangala, Jie Huang, Yunjie Sun, Cristina Ivan, Tao Liu, and Wei Hu
- Abstract
PDF file - 96K, Notch Pathway Alterations in Patients with HGS-OvCa.
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- 2023
47. Editor's Note: Biologic Effects of Platelet-Derived Growth Factor Receptor α Blockade in Uterine Cancer
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Anil K. Sood, Nicholas B. Jennings, Hee Dong Han, Behrouz Zand, Duangmani Thanapprapasr, Ashley Davis, Sun Joo Lee, Prahlad T. Ram, Bo Hwa Sohn, Heather J. Dalton, Ju Seog Lee, Koji Matsuo, Robert E. Coleman, Xiao Yun Yang, Rebecca A. Previs, Justin Bottsford-Miller, Jie Huang, Wei Hu, Ju Won Roh, and Vasudha Sehgal
- Subjects
CD31 ,Cancer Research ,TUNEL assay ,biology ,business.industry ,α blockade ,Pharmacology ,medicine.disease ,Article ,chemistry.chemical_compound ,Text mining ,Oncology ,Paclitaxel ,chemistry ,Uterine cancer ,medicine ,biology.protein ,business ,Platelet-derived growth factor receptor - Abstract
The editors are publishing this note to alert readers to a concern about [this article][1] ([1][2]). Four sets of identical representative images exist: Fig. 4B Hec-1A/Control and Fig. 4B Hec-1A SD+PDGF-AA+HmIgG; Fig. 5B CD31/3G3 and Supplementary Fig. S2 CD31/Paclitaxel; Fig. 5B TUNEL/PBS and
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- 2021
48. 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
- Subjects
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.
- Published
- 2017
49. Author Correction: Hypoxia-mediated downregulation of miRNA biogenesis promotes tumour progression
- Author
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Mircea Ivan, Li Huang, Kshipra M. Gharpure, Nouara C. Sadaoui, Anil K. Sood, Cristina Ivan, Lingegowda S. Mangala, Behrouz Zand, Guillermo N. Armaiz-Pena, Elizabeth Koch, George A. Calin, Sherry Y. Wu, Morgan Taylor, Milan Radovich, Menashe Bar-Eli, Wei Zhang, Gabriel Lopez-Berestein, Justyna Filant, Rajesha Rupaimoole, Twan van den Beucken, Bradly G. Wouters, Sunila Pradeep, Michael McGuire, Cristian Rodriguez-Aguayo, Chad V. Pecot, Justin Bottsford Miller, Heather J. Dalton, Archana S. Nagaraja, and Chunhua Lu
- Subjects
Multidisciplinary ,business.industry ,Science ,General Physics and Astronomy ,General Chemistry ,Hypoxia (medical) ,Biology ,General Biochemistry, Genetics and Molecular Biology ,Text mining ,Downregulation and upregulation ,medicine ,Cancer research ,lcsh:Q ,medicine.symptom ,lcsh:Science ,MiRNA biogenesis ,business - Abstract
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
- Published
- 2020
50. Erythropoietin Stimulates Tumor Growth via EphB4
- Author
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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.
- Published
- 2015
- Full Text
- View/download PDF
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