bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A7: Targeting mutant p53 and cell-cell adhesion in ovarian cancer
Authors: Iwanicki Marcin P. , Novak Marian , Zervantonakis Ioannis K. , Ince Tan A. , Drapkin Ronny , Brugge Joan S. 
Published: August 2014

Abstract
One of the most important challenges in the ovarian cancer research is to identify new molecular pathways that can be targeted to kill ovarian cancer cells. High-grade serous ovarian cancer (HGS-OvCa) cells survive, proliferate, and assemble into multicellular clusters that have a capacity to disseminate within the peritoneum. Therefore, it is important to identify specific molecular mechanisms that can be targeted to block survival, growth, and assembly of ovarian cancer multicellular clusters that metastasize within peritoneum. High-grade ovarian tumors originate from the fallopian tube epithelium (FTE) and almost all have mutations in theTP53 gene. The contribution of various mutant p53 proteins (m-p53) to ovarian cancer and whether targeting mutant p53 –dependent molecular mechanisms in ovarian cancer is poorly understood and of clinical significance. We have developed new methodologies and used them to identify m-p53-dependent pathways that support HGS-OvCa survival, proliferation and assembly of multicellular aggregates under condition mimicking peritoneal suspension. To determine whether mutations in TP53 contribute to the ability of HGS-OvCa cells to survive, proliferate, and assemble into multicellular clusters we introduced different variants of mutant p53 (m-p53) into normal human non-transformed FTE cells. We found that expression of m-p53 variants (R175H; R249S; R273H) in FTE cells promoted survival, growth, and assembly of multicellular clusters under conditions mimicking peritoneal suspension. Interestingly m-p53-driven phenotypes were not induced by the loss of p53 expression; and more importantly, these phenotypes were blocked by the reactivation of p53 pathway with small molecule inhibitor NSC319726. We further found that m-p53 induced phenotypes were dependent on the expression of integrin β 1 (ITGB1). The evidence that activated ITGB1 is enriched at cell's surface of precursors of HGS-OvCa within the fallopian tube and HGS-OvCa isolated from ovarian cancer patients highlighted the relevance of these findings to ovarian cancer. We hypothesize that mutant p53 supports survival, growth, and assembly of multicellular HGS-OvCa clusters through mechanisms in which ITGB1 plays a critical role. Our data indicate that observed phenotypes are the consequence of the m-p53 gain of function mechanisms that are amenable to therapeutic inhibitions and targeting m-p53 in HGS-OvCa might be of clinical significance.
Citation Format: Marcin P. Iwanicki, Marian Novak, Ioannis K. Zervantonakis, Tan A. Ince, Ronny Drapkin, Joan S. Brugge. Targeting mutant p53 and cell-cell adhesion in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A7.
Abstract A74: Microparticles mediate cross-talk between tumoral and endothelial cells and promote the constitution of an angiocrine pro-metastatic niche through Arf6 up regulation
Authors: Pasquier Jennifer , Thawadi Hamda Al. , Kaoud Nadine Abu , Ghiabi Pegah , Maleki Mahtab , Guerrouahen Bella S. , Rafii Arash 
Published: August 2014

Abstract
During the past few years, evidences in the literature point out the crucial role of the microenvironment in tumor growth, resistance to therapy and occurrence of metastatic phenotype. Tumor vessels have been considered for a long time as passive conducts for nutriments but more recently several studies have also demonstrated secretion of pro-tumoral factors by endothelial cells. It seems therefore mandatory to clearly identify the mechanisms mediating cross-talk between tumor cells and endothelial cells.
Here, we hypothetize that tumor cell and endothelium secrete bio-active microparticles (MPs) that are actively uptaken by the other cell type and that are participating to a functional cross-talk. We characterized the cancer cells MPs, using 2 cells lines from breast cancer (MCF7, MDA-MB231) and 2 from ovarian cancer (SKOV3, OVCAR3) and the endothelium secreted MPs using E4orf1-activated endothelium.
Our data show that MPs from mesenchymal-like metastatic cell lines (MDA-MB231 and SKOV3) were able to promote an angiocrine switch of endothelial cells (activation of akt signaling) compared to MPs from epithelial-like cell lines (OVCAR3 and MCF7). The angiocrine switch increased Arf6 expression and functionalized an MP dependent vascular niche enhancing tumor cells pro-metastatic proprieties. We also show that angiocrine endothelial MPs enhanced tumor cells pro-metastatic proprieties and cancer stemness.
All together we demonstrated that cancer cell derived MPs induced or sustain both an angiogenic but also an angiocrine switch of the endothelium. This has great implication in terms of tumor biology as indeed while the emphasis has mainly been on the angiogenic properties, the angiocrine pro-tumoral effect might be the cause for therapeutic resistance as well as residual and recurrent disease.
Citation Format: Jennifer Pasquier, Hamda Al. Thawadi, Nadine Abu Kaoud, Pegah Ghiabi, Mahtab Maleki, Bella S. Guerrouahen, Arash Rafii. Microparticles mediate cross-talk between tumoral and endothelial cells and promote the constitution of an angiocrine pro-metastatic niche through Arf6 up regulation. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A74.
Abstract A84: Metronomic cyclophosphamide, when combined with vaccination, increases the immunogenicity of the vaccine and modulates the tumor microenvironment to provide better anti-tumor activity
Authors: Weir Genevieve M. , Berinstein Neil L. , Hrytsenko Olga , Karkada Mohan , Stanford Marianne M. , Mansour Marc 
Published: August 2014

Abstract
DPX-Survivac is a peptide vaccine targeting the broadly expressed tumor antigen survivin. The vaccine contains a mixture of survivin HLA class I peptides (A1, A2, A3, A24 and B7) formulated in the novel adjuvanting vaccine platform DepoVaxTM. A phase I clinical study performed in advanced ovarian cancer patients (n=19) demonstrated that the combination of metronomic cyclophosphamide (mCPA) and DPX-Survivac exhibited enhanced immune responses by IFN-γ ELISPOT (p&lt;0.015) and increased poly-functional antigen-specific EM/ CM CD8+ T cells, relative to patients treated with vaccine alone. These results were mirrored in a preclinical mouse model in which tumor bearing mice treated with mCPA in combination with a DPX peptide vaccine had increased IFN-γ ELISPOT response and enriched antigen-specific CD8+ T cells. Adoptively transferred T cells from mice treated with the combination of mCPA and vaccine provided a more pronounced anti-tumor effect. Immunophenotyping by flow cytometry indicated that mice treated with mCPA and vaccine had reduced levels of tumor-induced immune suppressor cells, such as myeloid derived suppressor cells, but no effect was seen on regulatory T cells. Analysis of the tumor microenvironment by RT-qPCR revealed that mice treated with combination therapy had increased levels of cytotoxic T lymphocyte (CTL) markers such as granzyme B and IFN-γ. An ovarian tumor model (MOSE) was developed in HLA-A2 transgenic mice to extend these finding to a DPX-survivin vaccine in a relevant animal model. We showed that mCPA increased the levels of CTL markers in the tumor specifically when combined with a DPX-survivin vaccine, in addition to enhancing the immunogenicity of the vaccine. Together, these models allow us to explore novel immune modulator/ vaccine combinations and provide insight into mechanisms that could result in enhanced anti-tumor activity.
Citation Format: Genevieve M. Weir, Neil L. Berinstein, Olga Hrytsenko, Mohan Karkada, Marianne M. Stanford, Marc Mansour. Metronomic cyclophosphamide, when combined with vaccination, increases the immunogenicity of the vaccine and modulates the tumor microenvironment to provide better anti-tumor activity. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A84.
Abstract B27: Melatonin synergistically enhances cisplatin-induced apoptosis via the dephosphorylation of ERK/p90 ribosomal S6 kinase/heat shock protein 27 in SK-OV-3 cells
Authors: Kim Sunghoon , Kim Jihyun , kim bonglee , Kim Junghyo 
Published: August 2014

Abstract
To evaluate melatonin's ability to enhance ovarian cancer cells to cisplatin treatment for ovarian cancer, this study was performed. Melatonin by itself had no significant cytotoxicity against SK-OV-3 cells, while cisplatin suppressed the cell viability in a dose-dependent manner. Combined treatment with cisplatin and melatonin synergistically inhibited the viability of SK-OV-3 cells with the synergism between two drugs (1 &gt; combination index). In contrast, melatonin revealed the protective effect against cisplatin-induced cytotoxicity in OSEN normal ovarian epithelial cells. Cotreatment with cisplatin and melatonin increased the sub-G1 DNA contents and TdT-mediated dUTP nick end-labeling (TUNEL)-positive cells compared with cisplatin control in SK-OV-3 cells, suggesting that melatonin augments cisplatin-induced apoptosis. Consistently, combined treatment of cisplatin and melatonin increased the cleavage of caspase-3 and poly-(ADP-ribose) polymerase (PARP). Importantly, melatonin synergistically inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) along with dephosphorylation of 90-kDa ribosomal S6 kinase (p90RSK) and heat shock protein 27 (HSP27) induced by cisplatin. Furthermore, melatonin remarkably blocked the expression and colocalization of p90RSK and HSP27 by combination treatment with cisplatin. Taken together, our findings demonstrate that melatonin enhances cisplatin-induced apoptosis via the inactivation of ERK/p90RSK/HSP27 cascade in SK-OV-3 cells as a potent synergist to cisplatin treatment.
Citation Format: Sunghoon Kim, Jihyun Kim, bonglee kim, Junghyo Kim. Melatonin synergistically enhances cisplatin-induced apoptosis via the dephosphorylation of ERK/p90 ribosomal S6 kinase/heat shock protein 27 in SK-OV-3 cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B27.
Abstract B31: Aryl hydrocarbon receptor translocation, CYP1A1 induction and ROS formation: pharmacodynamic markers of sensitivity to antitumor Benzothiazole 5F203 in ovarian cancer
Authors: Callero Mariana Alejandra , Luzzani Gabriela , Dios Diana De , Tracey Bradshaw , Perez Andrea Loaiza 
Published: August 2014

Abstract
Ovarian malignancies, the second cause of gynaecological cancer death in developed countries possess poor prognoses. Detected at advanced stages of disease (III and IV), the standard of care is cytoreductive surgery followed by platin- and taxane-based chemotherapy. Intrinsic- or acquired resistance to cytotoxic drugs result in significant risk of recurrence; therefore, the discovery of new molecular targets and more effective therapies remain vital.
2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F203, NSC 703786) lysylamide belongs to a novel mechanistic class of antitumor agents. It elicits activity against ovarian, breast, kidney and colorectal cancer models. We have previously showed 5F203 activates aryl hydrocarbon receptor (AhR) signaling: enhanced CYP1A1 expression and AhR nuclear translocation in sensitive IGROV-1 ovarian cancer cells. This AhR modulation triggers an antiproliferative/pro-apoptotic activity evoking ROS formation, DNA damage and cell cycle arrest prior to apoptosis. In contrast, 5F203 failed to induce CYP1A1 expression, AhR translocation or oxidative stress in 5F203-resistant SKOV-3 cells.
In this work we further investigated 5F 203 antitumor mechanism of action. We found that 5F203 ROS formation was accompanied by JNK, ERK and P38MAPK phosphorylation only in IGROV-1 sensitive cells. In addition, cancer cells have been isolated from ascites fluid of ovarian cancer patients; sensitivity to 5F203 and concurrent AhR signal transduction has been examined. 5F203 induced enhanced CYP1A1 expression, AhR translocation and ROS formation in ascites-isolated ovarian cancer cells that were sensitive to 5F203.
We propose that AhR may represent a new molecular target in the treatment of ovarian tumors and 5F203 may exemplify a potential novel treatment. Finally, our studies demonstrate theranostic pharmacodynamic markers of 5F203 activity and provide additional insight into molecular targets of this novel anticancer agent, which may benefit ovarian cancer patients with limited therapeutic options.
Note: This abstract was not presented at the conference.
Citation Format: Mariana Alejandra Callero, Gabriela Luzzani, Diana De Dios, Bradshaw Tracey, Andrea Loaiza Perez. Aryl hydrocarbon receptor translocation, CYP1A1 induction and ROS formation: pharmacodynamic markers of sensitivity to antitumor Benzothiazole 5F203 in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B31.
Abstract B40: MiR-30c-2-3p participates in a regulatory feedback loop to inhibit the progression of chemoresistant ovarian cancer cells
Authors: Murph Mandi , JIa Wei , Altman Molly , Nguyen Ha 
Published: August 2014

Abstract
Although many patients achieve a period of remission, serous epithelial ovarian carcinoma remains incurable because untreatable chemoresistant disease develops after first-line chemotherapy. The general lack of knowledge in understanding the molecular mechanisms that evolve in chemoresistance and the absence of ‘targetable’ molecules to exploit therapeutically is a major obstacle preventing an improvement in mortality. MicroRNAs (miRNAs) are naturally-produced, small noncoding RNA molecules that modulate gene transcription by fine-tuning messenger RNA (mRNA) expression and acting as mRNA co-repressors or co-activators. The mitogenic lipid, lysophosphatidic acid, and the epidermal growth factor mediate a significant increase in miR-30c-2-3p, which then participates in a regulatory feedback loop to inhibit viability, growth and proliferation of both chemo-sensitive and –resistant cells. Because a single miRNA can target hundreds of transcripts, we wanted to understand which mRNAs are targeted by miR-30c-2-3p and what is the extent of its ability to alter normal processes like survival, growth and proliferation through post-transcriptional modifications. In our study, we uncovered that miR-30c-2-3p targets the oncogene transcript for BCL9, which is a protein that promotes tumor progression, proliferation and metastasis. We hypothesize that the perpetuation of incessant, extracellular, mitogenic signaling overwhelms the anti-growth feedback loop mechanism supported by miR-30c-2-3p. Thus, the growth factor lysophosphatidic acid, which is abundantly present in ascites fluid, is a significant barrier to the successful treatment of chemoresistant ovarian tumors. Our data will demonstrate the effects of lysophosphatidic acid in both in vitro and in vivo models of ovarian cancer. Our long-term goal is to better understand the molecular mechanisms which evolve simultaneously with chemoresistance in ovarian tumor progression.
Citation Format: Mandi Murph, Wei JIa, Molly Altman, Ha Nguyen. MiR-30c-2-3p participates in a regulatory feedback loop to inhibit the progression of chemoresistant ovarian cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B40.
Abstract B52: The bromodomain inhibitor JQ1 enhances cisplatin-mediated cytotoxicity in ovarian cancer cells
Authors: Khabele Dineo , Wilson Andrew J. , Saskowski Jeanette , Hiebert Scott W. 
Published: August 2014

Abstract
Ovarian cancer is the most lethal gynecologic malignancy. The treatment of platinum resistance disease remains an urgent and unmet clinical need. Identification of bromodomain inhibitors to disrupt “reading” of aberrant protein acetylation marks in cancer, leading to down-regulation of lineage-specific oncogenes is an exciting development in epigenetic drug therapy. The oncogenic transcription factor c-MYC (MYC) is amplified in approximately 30-40% of high grade serous ovarian tumors and may be epigenetically deregulated via a “super enhancer” on chromosome 8q24. JQ1, an inhibitor of bromodomain binding, down-regulates MYC expression in MYC-amplified tumors. However, this mechanism appears to be tissue-specific and has not been tested as a method for chemosensitization in ovarian cancer. We hypothesized that JQ1 could be used to enhance cisplatin cytotoxicity in ovarian cancer cells, in part by repression of MYC. Ovarian cancer cell lines were selected after in silico evaluation of publically available, annotated cell line collections. Cell lines with relatively low expression of MYC (IGROV-1 and SKOV3) and relatively high expression, A2780 parental [A2780PAR] and isogenic cisplatin-resistant A2780CP20 cells) were treated with 0.1% DMSO, JQ1, cisplatin or the combination of drugs. Sulforhodamine B (SRB) and clonogenic assays were used to assess effects on cell viability. Apoptosis was evaluated by Western Blot detection of cleaved PARP. Expression of MYC was measured by QPCR and Western Blot. JQ1 reduced cell viability and clonogenicity at sub-micromolar concentrations in the ovarian cancer cell lines examined. Furthermore, JQ1 treatment sensitized ovarian cancer cells, including the resistant A2780CP20, to the growth inhibitory and pro-apoptotic effects of cisplatin. However, the cytotoxic effects of JQ1 were not directly correlated with down-regulation of MYC. First, A2780PAR and A2780CP20 cells expressed the highest basal levels of MYC in our panel, but were not the most sensitive to JQ1-induced anti-tumor effects. Second, JQ1 markedly inhibited MYC expression in A2780PAR, but not A2780CP20 cells, despite relatively similar reduction in growth inhibition by JQ1 alone and combined with cisplatin in these cell lines. Taken together, these novel findings suggest that JQ1 could be used to sensitize ovarian cancer cells to platinum-based therapy. Identifying oncogenic targets of JQ1 other than MYC in ovarian cancer is a priority for further development of bromodomain inhibitors in ovarian cancer.
Citation Format: Dineo Khabele, Andrew J. Wilson, Jeanette Saskowski, Scott W. Hiebert. The bromodomain inhibitor JQ1 enhances cisplatin-mediated cytotoxicity in ovarian cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B52.
Abstract B60: Oovarian mesenchymal stem cells secreted Interleukin-6 promotes the malignant transformation of serous ovarian cancer
Authors: Ding Dah-Ching , Chu Tang-Yuan 
Published: August 2014

Abstract
Purpose: The IL-6/STAT3 signal plays a key role in the progression of serous carcinoma of the ovary. The role of ovarian stroma mesenchymal stem cells involving in this signaling and cancer progression is not known.
Methods: Ovarian mesenchymal stem cells (OvMSC) were derived from ovarian stroma. Surface markers and differentiation ability were characterized. The effect of condition medium (CM) of OvMSC on the transformation of SKOV3 ovarian cancer cells was tested and the level and downstream signalings of IL6 were investigated.
Results: OvMSC had a similar surface marker profiles as bone marrow mesenchymal stem cells, i.e. CD44 (+), CD90 (+) and CD45 (-) and was readily inducible to osteogenic, adipogenic and chondrogenic differentiations. Upon treatment CM of OvMSC, an increase of proliferation, colony formation and tumor sphere formation of SKOV3 cells was noted. The ELISA assay revealed CM of OvMSC had high level of IL-6, which readily activated JAK2 and STAT3 in the cancer cells. Adding of IL-6 blocking antibody to the CM of OvMSC significantly reduced the transformation activity to SKOV3 cells.
Conclusion: IL-6 secreted by OvMSC may be an important transformation signal to the developing ovarian serous carcinoma, the JAK2/STAT3 signaling pathway. The study suggests the possible source of transforming IL-6 from OvMSC in the development of serous ovarian carcinoma.
Citation Format: Dah-Ching Ding, Tang-Yuan Chu. Oovarian mesenchymal stem cells secreted Interleukin-6 promotes the malignant transformation of serous ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B60.
Abstract B69: Preferential transfer of mitochondria from endothelial to cancer cells through tunneling nanotubes modulates chemoresistance
Authors: Pasquier Jennifer , Guerrouahen Bella s. , Thawadi Hamda Al. , Kaoud Nadine Abu , Maleki Mahtab , Foll Frank Le , Rafii Arash 
Published: August 2014

Abstract
Our vision of cancer has changed during the past decades. Indeed tumors are now perceived as complex entities where tumoral and stromal components interact closely. Among the different elements of tumor stroma the cellular component play a primordial role. Bone Marrow derived mesenchymal cells (MSCs) are attracted to tumor sites and support tumor growth. Endothelial cells (ECs) play a major role in angiogenesis. While the literature documents many aspects of the cross talk between stromal and cancer cells, the role of direct hetero-cellular contact is not clearly established.
Recently, Tunneling nanotubes (TnTs) have been shown to support cell-to-cell transfers of plasma membrane components, cytosolic molecules and organelles within cell lines. Herein, we have investigated the formation of heterocellular TnTs between stromal (MSCs and ECs) and cancer cells. We demonstrate that TnTs occur between different cancer cells, stromal cells and cancer-stromal cell lines. We showed that TnTs-like structure occurred in 3D anchorage independent spheroids and also in tumor explant cultures. In our culture condition, TnTs formation occurred after large membrane adhesion. We showed that intercellular transfers of cytoplasmic content occurred similarly between cancer cells and MSCs or ECs, but we highlighted that the exchange of mitochondria occurred preferentially between endothelial cells and cancer cells. We illustrated that the cancer cells acquiring mitochondria displayed chemoresistance.
Our results illustrate the perfusion-independent role of the endothelium by showing a direct endothelial to cancer cell mitochondrial exchange associated to phenotypic modulation. This supports another role of the endothelium in the constitution of the metastatic niche.
Citation Format: Jennifer Pasquier, Bella s. Guerrouahen, Hamda Al. Thawadi, Nadine Abu Kaoud, Mahtab Maleki, Frank Le Foll, Arash Rafii. Preferential transfer of mitochondria from endothelial to cancer cells through tunneling nanotubes modulates chemoresistance. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B69.