Publications by authors named "Nicholas B Jennings"

60 Publications

Immune microenvironment composition in high-grade serous ovarian cancers based on BRCA mutational status.

J Cancer Res Clin Oncol 2021 Dec 2;147(12):3545-3555. Epub 2021 Sep 2.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77054, USA.

Purpose: An in-depth analysis of the tumor microenvironment of ovarian cancer is needed. The purpose of this study was to elucidate the architecture of the immune microenvironment of high-grade serous ovarian cancers (HGSCs) with or without BRCA1 and BRCA2 mutations.

Methods: A cohort of highly annotated HGSC patients with known germline BRCA1 and BRCA2 status was selected, and pretreatment tumor tissue specimens were analyzed with a multiplexed staining technique aimed at detecting lymphocytes, macrophages, and fibroblasts in the whole tumor area and in specific regions including epithelium, stroma, and perivascular areas.

Results: BRCA1- or BRCA2-mutated tumors showed a more immunogenic microenvironment, characterized by a higher abundance of CD8 and PD-L1 cells, than did tumors with wild-type BRCA1 and BRCA2. High numbers of PD-L1 and PD-L1CD8 cells were prognostic for event-free survival (hazard ratio [HR]: 0.41, 95% CI 0.21-0.79, p = 0.008 and HR 0.49, 95% CI 0.26-0.91, p = 0.025, respectively), as were high numbers of epithelial PD-L1 and FAPPD-L1 cells (HR 0.52, 95% CI 0.28-0.96, p = 0.037 and HR 0.27, 95% CI 0.08-0.87, p = 0.029) and CD8 cells (HR 0.51, 95% CI 0.28-0.93, p = 0.027).

Conclusions: This study reveals substantial differences between the immune microenvironment composition of germline BRCA-mutated and BRCA wild-type HGSC.
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http://dx.doi.org/10.1007/s00432-021-03778-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8557133PMC
December 2021

Assessment of In Vivo siRNA Delivery in Cancer Mouse Models.

Methods Mol Biol 2021 ;2372:157-168

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center (MDACC), Houston, TX, USA.

RNA interference (RNAi) has rapidly become a powerful tool for target discovery and therapeutics. Small interfering RNAs (siRNAs) are highly effective in mediating sequence-specific gene silencing. However, the major obstacle for using siRNAs for cancer therapeutics is their systemic delivery from the administration site to target cells in vivo. This chapter describes approaches to deliver siRNA effectively for cancer treatment and discusses in detail the current methods to assess pharmacokinetics and biodistribution of siRNAs in vivo.
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http://dx.doi.org/10.1007/978-1-0716-1697-0_14DOI Listing
January 2022

CD63-mediated cloaking of VEGF in small extracellular vesicles contributes to anti-VEGF therapy resistance.

Cell Rep 2021 08;36(7):109549

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address:

Despite wide use of anti-vascular endothelial growth factor (VEGF) therapy for many solid cancers, most individuals become resistant to this therapy, leading to disease progression. Therefore, new biomarkers and strategies for blocking adaptive resistance of cancer to anti-VEGF therapy are needed. As described here, we demonstrate that cancer-derived small extracellular vesicles package increasing quantities of VEGF and other factors in response to anti-VEGF therapy. The packaging process of VEGF into small extracellular vesicles (EVs) is mediated by the tetraspanin CD63. Furthermore, small EV-VEGF (eVEGF) is not accessible to anti-VEGF antibodies and can trigger intracrine VEGF signaling in endothelial cells. eVEGF promotes angiogenesis and enhances tumor growth despite bevacizumab treatment. These data demonstrate a mechanism where VEGF is partitioned into small EVs and promotes tumor angiogenesis and progression. These findings have clinical implications for biomarkers and therapeutic strategies for ovarian cancer.
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http://dx.doi.org/10.1016/j.celrep.2021.109549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8422976PMC
August 2021

MEK inhibition overcomes resistance to EphA2-targeted therapy in uterine cancer.

Gynecol Oncol 2021 10 11;163(1):181-190. Epub 2021 Aug 11.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America. Electronic address:

Background: Our pilot clinical study of EphA2 inhibitor (dasatinib) plus paclitaxel and carboplatin showed interesting clinical activity in endometrial cancer with manageable toxicity. However, the underlying mechanisms of dasatinib resistance in uterine cancer are unknown. Here, we investigated potential mechanisms underlying resistance to EphA2 inhibitors in uterine cancer and examined the anti-tumor activity of EphA2 inhibitors alone and in combination with a MEK inhibitor.

Methods: We evaluated the antitumor activity of EphA2 inhibitors plus a MEK inhibitor using in vitro and in vivo orthotopic models of uterine cancer.

Results: EphA2 inhibitor induced MAPK in dasatinib-resistant uterine cancer cells (HEC-1A and Ishikawa) and BRAF/CRAF heterodimerization in HEC-1A cells. EphA2 inhibitor and trametinib significantly increased apoptosis in cancer cells resistant to EphA2 inhibitors compared with controls (p < 0.01). An in vivo study with the orthotopic HEC-1A model showed significantly greater antitumor response to combination treatment compared with dasatinib alone (p < 0.01). Combination treatment increased EphrinA1 and BIM along with decreased pMAPK, Jagged 1, and c-MYC expression in dasatinib-resistant cells. In addition, Spearman analysis using the TCGA data revealed that upregulation of EphA2 was significantly correlated with JAG1, MYC, NOTCH1, NOTCH3 and HES1 expression (p < 0.001, r = 0.25-0.43). Specifically, MAP3K15 and the NOTCH family genes were significantly related to poor clinical outcome in patients with uterine cancer.

Conclusions: These findings indicate that the MAPK pathway is activated in dasatinib-resistant uterine cancer cells and that EphrinA1-mediated MEK inhibition overcomes dasatinib resistance. Dual targeting of both EphA2 and MEK, combined with chemotherapy, should be considered for future clinical development.
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http://dx.doi.org/10.1016/j.ygyno.2021.08.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8511168PMC
October 2021

Gain-of-function p53 protein transferred via small extracellular vesicles promotes conversion of fibroblasts to a cancer-associated phenotype.

Cell Rep 2021 02;34(6):108726

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA. Electronic address:

Tumor and stromal interactions consist of reciprocal signaling through cytokines, growth factors, direct cell-cell interactions, and extracellular vesicles (EVs). Small EVs (≤200 nm) have been considered critical messengers of cellular communication during tumor development. Here, we demonstrate that gain-of-function (GOF) p53 protein can be packaged into small EVs and transferred to fibroblasts. GOF p53 protein is selectively bound by heat shock protein 90 (HSP90), a chaperone protein, and packaged into small EVs. Inhibition of HSP90 activity blocks packaging of GOF, but not wild-type, p53 in small EVs. GOF p53-containing small EVs result in their conversion to cancer-associated fibroblasts. In vivo studies reveal that GOF p53-containing small EVs can enhance tumor growth and promote fibroblast transformation into a cancer-associated phenotype. These findings provide a better understanding of the complex interactions between cancer and stromal cells and may have therapeutic implications.
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http://dx.doi.org/10.1016/j.celrep.2021.108726DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957825PMC
February 2021

6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase-2 Regulates TP53-Dependent Paclitaxel Sensitivity in Ovarian and Breast Cancers.

Clin Cancer Res 2019 09 7;25(18):5702-5716. Epub 2019 Aug 7.

Department of Experimental Therapeutics, University of Texas, MD Anderson Cancer Center, Houston, Texas.

Purpose: Paclitaxel is an integral component of primary therapy for breast and epithelial ovarian cancers, but less than half of these cancers respond to the drug. Enhancing the response to primary therapy with paclitaxel could improve outcomes for women with both diseases. Twelve kinases that regulate metabolism were depleted in multiple ovarian and breast cancer cell lines to determine whether they regulate sensitivity to paclitaxel in Sulforhodamine B assays. The effects of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 () depletion on cell metabolomics, extracellular acidification rate, nicotinamide adenine dinucleotide phosphate, reactive oxygen species (ROS), and apoptosis were studied in multiple ovarian and breast cancer cell lines. Four breast and ovarian human xenografts and a breast cancer patient-derived xenograft (PDX) were used to examine the knockdown effect of on tumor cell growth .

Results: Knockdown of inhibited clonogenic growth and enhanced paclitaxel sensitivity in ovarian and breast cancer cell lines with wild-type (wt). Silencing significantly inhibited tumor growth and enhanced paclitaxel sensitivity in four xenografts derived from two ovarian and two breast cancer cell lines, and prolonged survival in a triple-negative breast cancer PDX. Transfection of si increased the glycolysis rate, but decreased the flow of intermediates through the pentose-phosphate pathway in cancer cells with wt, decreasing NADPH. ROS accumulated after knockdown, which stimulated Jun N-terminal kinase and p53 phosphorylation, and induced apoptosis that depended upon upregulation of p21 and Puma.

Conclusions: PFKFB2 is a novel target whose inhibition can enhance the effect of paclitaxel-based primary chemotherapy upon ovarian and breast cancers retaining wt.
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http://dx.doi.org/10.1158/1078-0432.CCR-18-3448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6744996PMC
September 2019

Paclitaxel Sensitivity of Ovarian Cancer Can be Enhanced by Knocking Down Pairs of Kinases that Regulate MAP4 Phosphorylation and Microtubule Stability.

Clin Cancer Res 2018 10 3;24(20):5072-5084. Epub 2018 Jul 3.

Department of Experimental Therapeutics, University of Texas, M.D. Anderson Cancer Center, Houston, Texas.

Most patients with ovarian cancer receive paclitaxel chemotherapy, but less than half respond. Pre-treatment microtubule stability correlates with paclitaxel response in ovarian cancer cell lines. Microtubule stability can be increased by depletion of individual kinases. As microtubule stability can be regulated by phosphorylation of microtubule-associated proteins (MAPs), we reasoned that depletion of pairs of kinases that regulate phosphorylation of MAPs could induce microtubule stabilization and paclitaxel sensitization. Fourteen kinases known to regulate paclitaxel sensitivity were depleted individually in 12 well-characterized ovarian cancer cell lines before measuring proliferation in the presence or absence of paclitaxel. Similar studies were performed by depleting all possible pairs of kinases in six ovarian cancer cell lines. Pairs that enhanced paclitaxel sensitivity across multiple cell lines were studied in depth in cell culture and in two xenograft models. Transfection of siRNA against 10 of the 14 kinases enhanced paclitaxel sensitivity in at least six of 12 cell lines. Dual knockdown of IKBKB/STK39 or EDN2/TBK1 enhanced paclitaxel sensitivity more than silencing single kinases. Sequential knockdown was superior to concurrent knockdown. Dual silencing of IKBKB/STK39 or EDN2/TBK1 stabilized microtubules by inhibiting phosphorylation of p38 and MAP4, inducing apoptosis and blocking cell cycle more effectively than silencing individual kinases. Knockdown of IKBKB/STK39 or EDN2/TBK1 enhanced paclitaxel sensitivity in two ovarian xenograft models. Sequential knockdown of dual kinases increased microtubule stability by decreasing p38-mediated phosphorylation of MAP4 and enhanced response to paclitaxel in ovarian cancer cell lines and xenografts, suggesting a strategy to improve primary therapy. .
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http://dx.doi.org/10.1158/1078-0432.CCR-18-0504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191368PMC
October 2018

Inhibiting Nuclear Phospho-Progesterone Receptor Enhances Antitumor Activity of Onapristone in Uterine Cancer.

Mol Cancer Ther 2018 02 13;17(2):464-473. Epub 2017 Dec 13.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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. .
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5805630PMC
February 2018

Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression.

Clin Cancer Res 2017 Nov 29;23(22):7034-7046. Epub 2017 Aug 29.

Departments of Gynecologic Oncology and Reproductive Medicine,

VEGF-targeted therapies have modest efficacy in cancer patients, but acquired resistance is common. The mechanisms underlying such resistance are poorly understood. 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 and studies were carried out to characterize the role of macrophages in such resistance. 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. 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. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-0647DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690831PMC
November 2017

Adrenergic-mediated increases in INHBA drive CAF phenotype and collagens.

JCI Insight 2017 Aug 17;2(16). Epub 2017 Aug 17.

Department of Gynecologic Oncology and Reproductive Medicine.

Adrenergic signaling is known to promote tumor growth and metastasis, but the effects on tumor stroma are not well understood. An unbiased bioinformatics approach analyzing tumor samples from patients with known biobehavioral profiles identified a prominent stromal signature associated with cancer-associated fibroblasts (CAFs) in those with a high biobehavioral risk profile (high Center for Epidemiologic Studies Depression Scale [CES-D] score and low social support). In several models of epithelial ovarian cancer, daily restraint stress resulted in significantly increased CAF activation and was abrogated by a nonspecific β-blocker. Adrenergic signaling-induced CAFs had significantly higher levels of collagen and extracellular matrix components than control tumors. Using a systems-based approach, we found INHBA production by cancer cells to induce CAFs. Ablating inhibin β A decreased CAF phenotype both in vitro and in vivo. In preclinical models of breast and colon cancers, there were increased CAFs and collagens following daily restraint stress. In an independent data set of renal cell carcinoma patients, there was an association between high depression (CES-D) scores and elevated expression of ACTA2, collagens, and inhibin β A. Collectively, our findings implicate adrenergic influences on tumor stroma as important drivers of CAFs and establish inhibin β A as an important regulator of the CAF phenotype in ovarian cancer.
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http://dx.doi.org/10.1172/jci.insight.93076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5621917PMC
August 2017

Assessment of cost sharing in the Pima County Marketplace.

Health Policy 2017 Jan 8;121(1):50-57. Epub 2016 Nov 8.

University of Arizona Mel and Enid Zuckerman College of Public Health, 1295 N Martin Ave, Tucson, AZ 85724, USA.

The Patient Protection and Affordable Care Act established health insurance marketplaces to allow consumers to make educated decisions about their health care coverage. During the first open enrollment period in 2013, the federally facilitated marketplace in Pima County, Arizona listed 119 plans, making it one of the most competitive markets in the country. This study compares these plans based on differences in consumer cost sharing, including deductibles, co-pays and premiums. Consumer costs were reviewed using specific cases including a normal delivery pregnancy, the management of Type II Diabetes, and the utilization of specialty drugs to treat Hepatitis C. Total cost of care was calculated as the cost of managing the condition or event plus the cost of monthly premiums, evaluated as a single individual age 27. Evaluating a plan on premium alone is not sufficient as cost sharing can dramatically raise the cost of care. A rating system and better cost transparency tools could provider easier access to pertinent information for consumers.
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http://dx.doi.org/10.1016/j.healthpol.2016.10.011DOI Listing
January 2017

Dll4 Inhibition plus Aflibercept Markedly Reduces Ovarian Tumor Growth.

Mol Cancer Ther 2016 06 23;15(6):1344-52. Epub 2016 Mar 23.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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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http://dx.doi.org/10.1158/1535-7163.MCT-15-0144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893925PMC
June 2016

Adrenergic regulation of monocyte chemotactic protein 1 leads to enhanced macrophage recruitment and ovarian carcinoma growth.

Oncotarget 2015 Feb;6(6):4266-73

Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.

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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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414188PMC
http://dx.doi.org/10.18632/oncotarget.2887DOI Listing
February 2015

Immunotherapy targeting folate receptor induces cell death associated with autophagy in ovarian cancer.

Clin Cancer Res 2015 Jan 21;21(2):448-59. Epub 2014 Nov 21.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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.
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http://dx.doi.org/10.1158/1078-0432.CCR-14-1578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4297546PMC
January 2015

Clodronate inhibits tumor angiogenesis in mouse models of ovarian cancer.

Cancer Biol Ther 2014 Aug 19;15(8):1061-7. Epub 2014 May 19.

Department of Gynecologic Oncology and Reproductive Medicine; The University of Texas MD Anderson Cancer Center; Houston, TX USA; Department of Cancer Biology; The University of Texas MD Anderson Cancer Center; Houston, TX USA; Center for RNA Interference and Non-Coding RNA; The University of Texas MD Anderson Cancer Center; Houston, TX USA.

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.
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http://dx.doi.org/10.4161/cbt.29184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4119073PMC
August 2014

Biologic effects of platelet-derived growth factor receptor α blockade in uterine cancer.

Clin Cancer Res 2014 May 14;20(10):2740-50. Epub 2014 Mar 14.

Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine and Cancer Biology, Center for RNA Interference and Non-Coding RNA, the University of Texas MD Anderson Cancer Center, Houston, Texas; University of Southern California, Los Angeles, California; Department of Obstetrics and Gynecology, Dongguk University; Departments of Systems Biology and Obstetrics and Gynecology, Konkuk University, Seoul, Korea; and Department of Obstetrics and Gynecology, Ramathibodi Hospital, Mahidol University, Bangkok, ThailandAuthors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine and Cancer Biology, Center for RNA Interference and Non-Coding RNA, the University of Texas MD Anderson Cancer Center, Houston, Texas; University of Southern California, Los Angeles, California; Department of Obstetrics and Gynecology, Dongguk University; Departments of Systems Biology and Obstetrics and Gynecology, Konkuk University, Seoul, Korea; and Department of Obstetrics and Gynecology, Ramathibodi Hospital, Mahidol University, Bangkok, ThailandAuthors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine and Cancer Biology, Center for RNA Interference and Non-Coding RNA, the University of Texas MD Anderson Cancer Center, Houston, Texas; University of Southern California, Los Angeles, California; Department of Obstetrics and Gynecology, Dongguk University; Departments of Systems Biology and Obstetrics and Gynecology, Konkuk University, Seoul, Korea; and Department of Obstetrics and Gynecology, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand

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.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-2507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4024372PMC
May 2014

Cross-talk between EphA2 and BRaf/CRaf is a key determinant of response to Dasatinib.

Clin Cancer Res 2014 Apr 31;20(7):1846-55. Epub 2014 Jan 31.

Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Hematology and Oncology, Biostatistics, Cancer Biology, and Pathology, and The Center for RNA Interference and Non-Coding RNAs; The University of Texas MD Anderson Cancer Center, Houston, Texas.

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, pCRaf(S338), pMAPK(T202/Y204) (mitogen-activated protein kinase [MAPK] pathway), pS6(S240/244), p70S6k(T389) (mTOR pathway), and pAKT(S473). 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.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-2141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3975695PMC
April 2014

Cystathionine beta-synthase (CBS) contributes to advanced ovarian cancer progression and drug resistance.

PLoS One 2013 13;8(11):e79167. Epub 2013 Nov 13.

Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic Rochester, Minnesota, United States of America.

Background: Epithelial ovarian cancer is the leading cause of gynecologic cancer deaths. Most patients respond initially to platinum-based chemotherapy after surgical debulking, however relapse is very common and ultimately platinum resistance emerges. Understanding the mechanism of tumor growth, metastasis and drug resistant relapse will profoundly impact the therapeutic management of ovarian cancer.

Methods/principal Findings: Using patient tissue microarray (TMA), in vitro and in vivo studies we report a role of of cystathionine-beta-synthase (CBS), a sulfur metabolism enzyme in ovarian carcinoma. We report here that the expression of cystathionine-beta-synthase (CBS), a sulfur metabolism enzyme, is common in primary serous ovarian carcinoma. The in vitro effects of CBS silencing can be reversed by exogenous supplementation with the GSH and H2S producing chemical Na2S. Silencing CBS in a cisplatin resistant orthotopic model in vivo by nanoliposomal delivery of CBS siRNA inhibits tumor growth, reduces nodule formation and sensitizes ovarian cancer cells to cisplatin. The effects were further corroborated by immunohistochemistry that demonstrates a reduction of H&E, Ki-67 and CD31 positive cells in si-RNA treated as compared to scrambled-RNA treated animals. Furthermore, CBS also regulates bioenergetics of ovarian cancer cells by regulating mitochondrial ROS production, oxygen consumption and ATP generation. This study reports an important role of CBS in promoting ovarian tumor growth and maintaining drug resistant phenotype by controlling cellular redox behavior and regulating mitochondrial bioenergetics.

Conclusion: The present investigation highlights CBS as a potential therapeutic target in relapsed and platinum resistant ovarian cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0079167PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827285PMC
July 2014

Targeting SRC and tubulin in mucinous ovarian carcinoma.

Clin Cancer Res 2013 Dec 7;19(23):6532-43. Epub 2013 Oct 7.

Authors' Affiliations: Departments of Gynecologic Oncology and Reproductive Medicine, Genitourinary Medical Oncology, Bioinformatics and Computational Biology, and Cancer Biology; Division of Cancer Medicine; Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas; Kinex Pharmaceuticals LLC, New York State Center of Excellence in Bioinformatics and Life Sciences, Buffalo, New York; Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei; Department of Gynecology, Obstetrics and Gynecology, Hospital of Fudan University, Shanghai, P.R. China.

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.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-1305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852199PMC
December 2013
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