bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B57: Sucrose nonfermenting 1-related kinase (SNRK) expression and function in ovarian cancer.
Authors: Bishop Erin A. , Cossette Stephanie M. , Ramchandran Ramani 
Published: May 2016

Abstract
Purpose of study: SNRK is a member of the sucrose nonfermenting (SNF)-related kinase family of serine/threonine kinases with sequence similarity to AMP-activated protein kinase (AMPK). AMPK proteins play a central role in cellular energy regulation. Active AMPK restricts cellular proliferation, growth, and metabolic substrate synthesis, and increases ATP-generating processes, such as glucose and fatty acid oxidation. SNKR has been previously shown to regulate metabolism and to suppress adipocyte inflammation via mTORC1, which is a pathway known to be aberrant in ovarian cancer. SNRK has also been shown to reduce colon cancer cell proliferation and stable knockdown of SNRK increases in vitro colon cancer cell tumorigenicity indicating that SNRK is a regulator of cell proliferation. The goal of this study is to describe the expression and function of SNRK in ovarian cancer and benign cell lines.
Experimental Procedures: The ovarian cancer cell line A2780 was used as well as the benign surface epithelial cell line, IOSE, for comparison. Quantitative PCR and western blot analysis were used to compare SNRK mRNA and protein expression between cell lines. SNRK was knocked down in each cell line using lentiviral transduction. Proliferation, migration, and invasion assays were performed to determine the effects of SNRK knockdown on tumorigenicity. Alterations in metabolism as a result of SNRK knockdown were assessed using the XF Extracellular Flux Analyzer (Seahorse Bioscience). Western blot analysis was used to determine changes in active phosphorylated AMPK (pAMPK) and mTOR protein expression.
Summary of data: IOSE and A2780 cells have similar levels of SNRK mRNA and protein expression. We observed increased proliferation, migration, and invasion in SNRK knockdown cells compared to controls with significant differences seen in the IOSE cells. A2780 and IOSE SNRK knockdown cells have decreased oxygen consumption rates and decreased spare respiratory capacity in the presence of fatty acids as a substrate compared to controls as well as decreased pAMPK and mTOR expression.
Conclusions: Our results show that decreased SNRK levels lead to increased tumorigenicity and impairment in fatty acid oxidation particularly in the benign IOSE cells. Along with these functional changes, a decrease in pAMPK expression is also seen. Our results suggest that SNRK plays a role in regulating growth and metabolism and that this regulation appears to be required in benign ovarian cells, while malignant cells may have the ability to control growth independent of SNRK.
Citation Format: Erin A. Bishop, Stephanie M. Cossette, Ramani Ramchandran. Sucrose nonfermenting 1-related kinase (SNRK) expression and function in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B57.
Abstract B59: The adhesion molecule L1: a new driver in ovarian cancer vasculature.
Authors: Angiolini Francesca , Magrini Elena , Fiore Pier Paolo Di , Cavallaro Ugo 
Published: May 2016

Abstract
Ovarian cancer (OC) represents an outstanding clinical challenge due to its high mortality rate, tumor relapse and chemoresistance. The identification of novel targets and strategies for the treatment of OC is clearly an unmet need in clinical oncology. In this context, drugs that interfere with tumor neovascularization have shown some promising results in recent clinical trials. However, anti-angiogenic therapies in most cases exhibit only transient and insufficient efficacy, resulting in tumor recurrence in patients after several months of treatment.
Thus, the definition of tumor vasculature biomarkers and of druggable molecular targets within cancer-associated angiogenesis will represent a breakthrough in this field.
Our laboratory has obtained compelling evidence that L1, an adhesion molecule that plays a key role in neural development, is aberrantly expressed in tumor vasculature. Furthermore, we have recently reported that vascular L1 plays a pivotal role in tumor angiogenesis and represents a viable target for therapies directed against cancer-associated vessels (Magrini et al., JCI, 2014). However, the functional role of L1 in endothelial cells and its contribution to tumor angiogenesis remain elusive.
Based on the observation that L1 is particularly abundant in OC vasculature as compared to normal tissue, we hypothesized that the loss of endothelial L1 would affect OC development. To test this hypothesis, we have established a syngeneic model of ovarian tumorigenesis in conditional knockout mice with the endothelium-specific ablation of L1. Interestingly, we observed that vascular L1 is causally involved in the peritoneal metastasis of OC, thus implicating L1 in tumor dissemination. In addition, the loss of endothelial L1 results in tumor vessel normalization, a process that has been proposed to enhance the efficacy of systemic chemotherapy.
Mechanistically, L1 emerged as a master regulator of the endothelial transcriptional and signaling activity, and was capable of orchestrating multiple functions of endothelial cells, thus accounting for the aberrant pathophysiology of cancer vessels. We are currently capitalizing on these observations to define the molecular mechanisms underlying such a pleiotropic role on the OC vasculature.
Our data may pave the way to innovative anti-angiogenic and/or vessel-normalizing therapies for the treatment of ovarian cancer.
Citation Format: Francesca Angiolini, Elena Magrini, Pier Paolo Di Fiore, Ugo Cavallaro. The adhesion molecule L1: a new driver in ovarian cancer vasculature. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B59.
Abstract B60: Identification of an ovarian tumor:stromal HH:BMP4 signaling loop critical to ovarian cancer growth and chemotherapy resistance.
Authors: Coffman Lan G. , Choi Yunjung , Mclean Karen , Magliano Marina Pasca di , Allen Benjamin , Buckanovich Ronald J. 
Published: May 2016

Abstract
The ovarian tumor microenvironment is critical to ovarian cancer growth, spread, and survival. We recently identified a novel host cell component of the tumor microenvironment, human ovarian carcinoma-associated mesenchymal stem cells (CA-MSCs). CA-MSCs are of particular interest as they are multi-potent and can differentiate to create many components of the tumor microenvironment including fibroblasts, myofibroblasts and adipocytes. CA-MSCs, compared to normal MSCs, express high levels of BMP proteins and promote tumor growth by increasing numbers of cancer stem-like cells (CSCs). We now define a CA-MSC BMP4: ovarian tumor cell Hedgehog (HH) positive feedback loop critical to the cancer promoting functions of CA-MSCs. We demonstrate that CA-MSC expression of BMP4 is induced by ovarian tumor cell-secreted Hedgehog (HH). Reciprocally, CA-MSC-derived BMP4 increases ovarian tumor cell HH expression creating a positive feedback loop. Interruption of this loop with either a HH pathway inhibitor (IPI-926 or LDE-225) or BMP4 blocking antibody decreases the induction of CA-MSC-derived BMP4 and tumor-derived HH. This signaling loop is critical to the pro-tumorigenic effects of CA-MSCs as HH inhibition blocked CA-MSC-mediated tumorigenesis and reduced the number of CSCs. Additionally, HH inhibition reversed CA-MSC -induced chemotherapy resistance leading to significant cisplatin response in established platinum-resistant tumors. Collectively, we define a critical positive feedback loop between CA-MSC-derived BMP4 and ovarian tumor cell-secreted HH providing further support for clinical targeting of the HH pathway, particularly in combination with platinum-based chemotherapy, in ovarian cancer.
Citation Format: Lan G. Coffman, Yunjung Choi, Karen Mclean, Marina Pasca di Magliano, Benjamin Allen, Ronald J. Buckanovich. Identification of an ovarian tumor:stromal HH:BMP4 signaling loop critical to ovarian cancer growth and chemotherapy resistance. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B60.
Abstract B73: The monoterpene, citral, increases intracellular oxygen radicals and inhibits cancer cell proliferation by inducing apoptosis and endoplasmic reticulum stress .
Authors: Kapur Arvinder , Felder Mildred , Fass Lucas , kaur Justanjyot , Czarnecki Austin , Rathi Kavya , Patankar Manish 
Published: May 2016

Abstract
The terpene-enriched steam distilled extract of ginger rhizomes has potent anti-tumor activity. Screening of the components of ginger extract demonstrated citral, a commonly used food flavoring agent, as the major monoterpene that inhibits proliferation of human and murine cancer cell lines A2780, ECC-1, OVCAR-3, SKOV-3, ID8 and MOVCAR. Citral initiates a rapid decrease in intracellular levels of glutathione and a corresponding increase in oxygen radicals. In wild-type p53-expressing ECC-1 cells, citral treatment increases phosphorylation of the Ser-15 residue of p53 and causes apoptosis. Inhibition of intracellular oxygen radicals by N-acetylcysteine and p53 activity by pifithrin-α inhibits citral-induced apoptosis in ECC-1 cells. Apoptosis in mutant p53 (Arg248Glu) expressing OVCAR-3 cells was also inhibited by N-acetylcysteine and was associated with a decrease in phosphorylation of Ser-15 of p53. Finally, in cells not expressing p53, citral inhibited proliferation, but not through apoptosis. Instead in the p53-negative SKOV-3 cells, citral treatment caused endoplasmic reticulum stress indicated by increase in phosphorylation of eIF2α and the expression of CHOP, GADD45, EDEM, ATF4 and Hsp90 and increased ATG5 and LC3-II suggesting the cells were undergoing autophagy. The study identifies the mechanism that allows citral to produce its cytotoxic effects. Combined with our recent results that nanoparticle-encapsulated citral decreases in vivo growth of 4T1 murine breast tumors, the results from the current study suggest that citral and its analogs be considered as chemotherapeutic agents. Since citral mediates its cytotoxic effects primarily by inducing oxidative stress, it is likely that this monoterpenes and its derivatives can be used for the treatment of a variety of solid tumors including ovarian cancer.
Citation Format: Arvinder Kapur, Mildred Felder, Lucas Fass, Justanjyot kaur, Austin Czarnecki, Kavya Rathi, Manish Patankar. The monoterpene, citral, increases intracellular oxygen radicals and inhibits cancer cell proliferation by inducing apoptosis and endoplasmic reticulum stress . [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B73.
Abstract B82: Application of modulated electro-hyperthermia for the cellular target therapy in ovarian cancer cells.
Authors: Yang Wookyeom , Chay Doo Byung , Cho Hanbyoul , Kim Sunghoon , Kong Jinkyoung , Son Geumseon , Choi Jihui , Jae-hoon. Kim 
Published: May 2016

Abstract
Background: Oncothermia as modulated electro-hyperthermia is an anti-cancer therapy that was approved by TUV-SUD in Germany, Health Canada in Canada, and Therapeutic Goods Administration in Australian. Oncothermia induces apoptosis via destroying the plasma membrane of cancer cells and leads to accumulation of heat-induced damages mostly in cells located in the tumor tissue while providing minimal damages to the surrounding normal tissue. Thus, oncothermia has recently become a potentially effective therapeutic tool for cancer.
Methods: LabEHY-100, an oncothermia device from Oncotherm (Germany & Hungary), was used for all in vitro studies. Ovarian cells were exposed to thermal damage induced by LabEHY-100, and subsequently, the cancer cells were analyzed in terms of viability, levels of apoptosis, autophagic markers and cell cycle status. In addition, xenograft tumors which generated by OVCAR-3 and patients derived tumor, were exposed to thermal damage induced by LabEHY-100 after which the tumor progression was monitored. The efficacy of combination therapy using both oncothermia and 3-methyladenine (3-MA), an autophagy inhibitor, was assessed using crystal violet assay.
Results: Our studies showed that oncothermia resulted in growth inhibition in ovarian cancer cell tested. Apoptotic markers such as cleaved caspase-3 and PARP were upregulated in cells exposed to oncothermia compared to the control cells exposed to hyperthermia. Oncothermia also led to reduction in the mass and the volume of the tumors in the mouse transplanted with xenografts derived from cancer cells and ovarian cancer patient tumors. FACS analysis showed that cell cycles of these cells were not disrupted by oncothermia. Still there was a significant increase in the number of sub-G1 population, which consisted of dying cells including apoptotic cells. However, the xenograft cells recovered from cellular damage even after inducing autophagy via oncothermia. Combined treatment with oncothermia and 3-MA, a autophagy inhibitor, was more effective in inhibiting cancer cell growth than treatment with each alone.
Conclusion: Oncothermia can potentially be an effective therapy for ovarian cancer cells.
Conflict of interest : We obtained funding and in vitro device for electro-hyperthermia from HOSPICARE. Co., Ltd. (Seoul, Republic of Korea).
Citation Format: Wookyeom Yang, Doo Byung Chay, Hanbyoul Cho, Sunghoon Kim, Jinkyoung Kong, Geumseon Son, Jihui Choi, Kim Jae-hoon. Application of modulated electro-hyperthermia for the cellular target therapy in ovarian cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B82.
Abstract IA02: Genomic classification of ovarian cancer.
Authors: Bowtell David D. L. 
Published: May 2016

Abstract
Human cancers have been classified for hundreds of years primarily by their anatomical location, and more recently by morphological criteria and the extent of local and distant spread. As cancer is quintessentially a genetic disease, genomics has allowed a reclassification of human cancers, including ovarian cancer, based on gene expression, epigenetic modification, mutational and copy number profiles. The presentation will describe how genomic analyses have helped highlight important molecular distinctions between and within histological subtypes of ovarian cancer, improved the diagnosis of rare subtypes, identified molecular subtypes with different biological properties and clinical outcomes, elucidated driver mutations in primary and recurrent disease, and suggested new approaches to the clinical management of ovarian cancer.
Citation Format: David D. L. Bowtell. Genomic classification of ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA02.
Abstract IA04: Targeting DNA repair in ovarian cancer therapy.
Authors: D'Andrea. Alan D. 
Published: May 2016

Abstract
Large-scale genomic studies have shown that half of epithelial ovarian cancers (EOCs) have alterations in genes regulating homologous recombination (HR) repair. Loss of HR accounts for the genomic instability and replicative stress of EOCs and for their cellular hyperdependence on alternative poly-ADP ribose polymerase (PARP)-mediated DNA repair mechanisms. On the basis of this hyperdependence, in 2014, the FA approved the PARP inhibitor, olaparib, for patients with advanced ovarian cancer associated with BRCA1 and BRCA2 germline mutations, whose tumors are HR deficient. Previous studies have implicated the DNA polymerase POLQ in an error-prone pathway required for the repair of DNA double-strand breaks, referred to as alternative endjoining (alt-EJ). In Drosophila melanogaster and Caenorhabditis elegans, POLQ functions in alt-EJ and in the maintenance of genome stability at sites of G-quadruplex structures. Whether POLQ interacts with canonical DNA repair pathways to prevent genomic instability at stalled replication forks has remained unknown. We have recently demonstrated an inverse correlation between HR activity and POLQ expression in EOCs (Ceccaldi R. et al, Nature, 518: 258-262, 2015). While knockdown of POLQ in HR-proficient cells upregulates HR activity and RAD51 nucleofilament assembly, knockdown of POLQ in HR-deficient EOCs results in enhanced cell death. Consistent with these results, genetic inactivation of an HR gene (Fancd2) and Polq in mice results in embryonic lethality. Moreover, POLQ contains a repeat of RAD51 binding motifs, and it blocks D-loop formation and recombination. Importantly, PARP1 activity is required for the recruitment of POLQ to sites of DNA repair, accounting, in part, for the PARP1 hyperdependence of HR-deficient ovarian tumor cells. Taken together, these results reveal a synthetic lethal relationship between the HR pathway and PARP1/POLQ-mediated alternative end-joining in EOCs, and identify POLQ as a novel druggable target for ovarian cancer therapy. Such inhibitors may be useful in the treatment of PARP inhibitor-resistant ovarian cancers.
Citation Format: Alan D. D'Andrea. Targeting DNA repair in ovarian cancer therapy. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA04.
Abstract IA08: PI3K- and PARP-inhibitors for the treatment of women cancers.
Authors: Wulf Gerburg M. , Juvekar Ashish , Cantley Lewis C. , Matulonis Ursula A. 
Published: May 2016

Abstract
Amplification of PIK3CA is highly prevalent in ovarian cancer and isoform-specific and pan-PI3K inhibitors have entered clinical trials. However, identifying tumor subtypes and biological mechanisms that predict for response to PI3K inhibitors as single agents or in combination has been a challenge.
We previously reported that combining a phophoinositide 3-kinase (PI3K) inhibitor with a poly ADP ribose polymerase (PARP)-inhibitor enhanced DNA damage and cell death in breast cancers that have genetic aberrations in BRCA1 and TP53. We now show that the enhanced DNA damage induced by PI3K inhibitors in this mutational background is a consequence of impaired production of deoxynucleotides needed for DNA synthesis and DNA repair. Inhibition of PI3K causes a reduction in all four deoxynucleotide triphosphates (dATP, dTTP, dGTP and dCTP), while inhibition of AKT is less effective than inhibition of PI3K in suppressing nucleotide synthesis and inducing DNA damage. Carbon flux studies reveal that PI3K-inhibition disproportionately affects the non-oxidative pentose phosphate pathway (non-ox PPP) that delivers ribose-5-posphate required for base ribosylation. In vivo in a mouse model of BRCA1-linked triple-negative breast cancer combined PI3K- and PARP-inhibition was superior to either agent alone to induce durable remissions of established tumors. Our data indicate that PI3K inhibitors induce DNA damage in tumors that have defects in DNA damage repair pathways and that they do so by impairing the production of Ribose-5-phosphate and amino acids needed for deoxynucleotide synthesis. An ongoing phase I/II study (NCT01623349, PI: Matulonis) examines the safety and toxicity of a PI3K/Parp-inhibitor combination in ovarian and breast cancer.
Citation Format: Gerburg M. Wulf, Ashish Juvekar, Lewis C. Cantley, Ursula A. Matulonis. PI3K- and PARP-inhibitors for the treatment of women cancers. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA08.
Abstract IA11: Deciphering the immunobiology of ovarian cancer to create effective immunotherapy.
Authors: Powell Daniel J. 
Published: May 2016

Abstract
Deep interrogations of the immunological landscape of human ovarian cancer has revealed the importance of the immune system in tumor control. In particular, the finding that intratumoral accumulation of tumor-infiltrating lymphocytes (TILs) is associated with improved survival in ovarian and various other cancer types supports the notions that spontaneously-arising T-cells with antitumor activity reside in cancer and control tumor outgrowth, and that this prognostic biomarker can be reinforced though administration of immunotherapy. Since this association was first described more than a decade ago, more sophisticated analyses have refined our understanding of the complex interplay between ovarian cancer cells and the host immune system. This includes the recent elucidation of a phenotypically-defined subset of ovarian cancer associated TILs that exhibit specific reactivity against autologous tumor cells, which represent a potential source for tumor-reactive T cell for use in the adoptive immunotherapy of ovarian cancer. Additionally, the discovery that the antigenic repertoire recognized by TILs is comprised of both shared tumor associated antigens and patient specific neo-antigens derived from mutated self-proteins uniquely expressed by the ovarian cancer cell has rationalized the clinical testing of highly personalized vaccines. While induction of patient-specific T cell responses holds significant promise, further analysis has revealed that the ovarian cancer microenvironment harbors a myriad of immunosuppressive factors that have the potential to thwart otherwise effective T cell responses. Ovarian cancer cells downregulate the expression of molecules associated with immune recognition and preferentially recruit inhibitory cells such as regulatory T cells to the tumor site. Ovarian cancer cells also express multiple negative immunoregulatory ligands that interact with reciprocal receptors expressed preferentially by the subset of tumor-reactive T cells and thereby limit their activity, however, with a new cadre of antibodies that effective block these axes of immunosuppression, clinical trials are underway to determine the efficacy of this form of passive immunomodulation and encouraging results are emerging. Taken together, detailed exploration of the immunobiology of the ovarian cancer microenvironment has increased our understanding of the roles of the cellular and molecular elements that influence tumor outgrowth. This knowledge serves as a roadmap for the rational development of effective immunotherapeutic approaches in ovarian cancer.
Citation Format: Daniel J. Powell, Jr. Deciphering the immunobiology of ovarian cancer to create effective immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA11.