bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B65: The mitochondrial antioxidant Superoxide Dismutase 2 is necessary for ovarian cancer spheroid formation
Authors: Hemachandra LP Madhubhani , Dier Usawadee , Uusitalo Larissa M. , Hempel Nadine 
Published: August 2014

Abstract
The formation of cellular spheroid aggregates in the Intraperitoneal Cavity (IP) is considered to be an important step in the metastatic progression of ovarian cancer. Spheroids may represent a unique morphological adaptation that enhances long-term survival of tumor cells in the IP cavity, reminiscent of dormant cell populations. Like other dormant tumor cells, in vivo-isolated and in vitro-cultured spheroids exhibit enhanced chemoresistance and display markers of quiescence. We show that expression of mitochondrial superoxide dismutase (Sod2), which regulates mitochondrial redox balance, is significantly increased during formation of dense spheroids from a number of ovarian cancer cell lines. This is accompanied by increases in the quiescence marker p27(kip1). Importantly, siRNA and shRNA knock-down of Sod2 compromise spheroid formation and integrity, and abrogate increases in p27(kip1) expression in anchorage-independent 3D cultures. Mechanistically, it is likely that increases in Sod2 expression protect cells from build-up of mitochondrial and IP cavity-derived ROS, enhancing their survival as dormant spheroid populations. In addition, bioenergetic data suggest that Sod2 is directly involved in enhancing the mitochondrial integrity of tumor cells within spheroid aggregates. This leads to a metabolic profile that is associated with a slowing in ATP demand and an enhanced respiratory reserve capacity, with Sod2 being intricately involved in manipulating these changes. Enhanced Sod2 expression, a concomitant decrease in mitochondrial ROS and changes in mitochondrial function are likely indicators of a quiescence adaptation of tumor spheroids, necessary for survival in the IP cavity. Manipulating mitochondrial function and redox balance by effectively targeting mitochondrial antioxidant enzymes may provide novel therapeutic strategies to combat recurrence and metastatic spread of ovarian cancer.
Citation Format: LP Madhubhani Hemachandra, Usawadee Dier, Larissa M. Uusitalo, Nadine Hempel. The mitochondrial antioxidant Superoxide Dismutase 2 is necessary for ovarian cancer spheroid formation. [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 B65.
Abstract B77: Targeting ovarian cancer promoting effects of adipocytes by metformin
Authors: Rattan Ramandeep , Tebbe Calvin , Chhina Jasdeep , Sarigiannis Kalli , Giri Shailendra , Munkarah Adnan 
Published: August 2014

Abstract
At the time of surgery, 80% of the ovarian cancers are found to be metastasized to the omentum, a large fat pad covering the abdominal organs. Omental metastasis is thought to be due to the promotion of homing, growth and migration of ovarian cancer cells by factors secreted by adipocytes, which include cytokines, adipokines and growth factors. These adipocytes also act as fuel depot providing for the energy needs of fast growing ovarian tumor cells. The objective of our study was to investigate if metformin can modulate or limit the adipocyte mediated tumor-promoting and migrating effects. For this, mouse preadipocyte cells were differentiated in the presence or absence of metformin and various parameters including lipid accumulation, AMPK activation and adipogenesis transcription factors were examined. Conditioned media from undifferentiated and differentiated adipocytes was used to evaluate ID-8 mouse ovarian cancer cell proliferation and migration. Conditioned media from differentiated but not from undifferentiated preadipocytes, increased ID-8 cell proliferation (p&lt;0.05) and migration (p&lt;0.050), which were attenuated in presence of metformin (p&lt;0.05). Metformin treatment inhibited adipogenesis as evident by the reduction of neutral lipid accumulation. Metformin treatment increased AMP-activated protein kinase (AMPK) activity as evident from higher level of phosphorylation of AMPK and its immediate downstream target ACC (Acetyl Co Carboxylase). It also inhibited the key adipogenesis transcription factors (CEBPαa; CEBPβb, SREBP1) during the process of adipocyte diffrenetiation. A targeted Cancer Pathway Finder RT-PCR based gene array (Qiagen) revealed 21 genes that were upreguated and 2 were downregulated more than 2-fold in ID-8 cells in presence of adipocyte conditioned media, which were modulated by metformin.
Together, metformin treatment inhibited the adipocyte mediated ovarian cancer cell proliferation and migration. It also blunted the expression of cancer associated genes that were induced by adipocyte influence in cancer cells. This study suggests that metformin could be a therapeutic option for ovarian cancer as it not only targets ovarian cancer but alternatively, also modulates the environmental milieu around it.
Citation Format: Ramandeep Rattan, Calvin Tebbe, Jasdeep Chhina, Kalli Sarigiannis, Shailendra Giri, Adnan Munkarah. Targeting ovarian cancer promoting effects of adipocytes by metformin. [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 B77.
Abstract IA12: Ovarian cancer: Time for a new paradigm
Authors: Ozols Robert F. 
Published: August 2014

Abstract
The majority of patients with ovarian cancer are still diagnosed with advanced stage disease as screening and early detection have not been successful. The cornerstones of therapy have been surgical cytoreduction followed by combination chemotherapy. Numerous clinical trials in the past 4 decades have evaluated various chemotherapeutic approaches and different treatment modalities. Despite this intensive research effort, standard therapy remains surgery and chemotherapy with paclitaxel plus carboplatin. Most patients will achieve a clinical complete remission but over 75% will relapse and recurrent ovarian cancer is not curable. While 5-year survival rates have improved, there has been no significant improvement in overall survival. It is not likely that significant improvements in either surgery or cytotoxic chemotherapy are forthcoming. Molecular targeted therapy is under intensive investigation. However, antiangiogenesis treatment, and PARP inhibiors ( in BRCA patients) have, as yet, only improved progression free survival without an improvement in survival. More specific molecular targets must be identified. Functional genomics, improved pre-clinical models, and a better understanding of the molecular pathogenesis of ovarian cancer perhaps hold the key to novel therapies which will increase the cure rate.
Citation Format: Robert F. Ozols. Ovarian cancer: Time for a new paradigm. [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 IA12.
Abstract IA18: Evolutionary dynamics of high-grade serous ovarian cancer genomes across anatomic space and time
Authors: Shah Sohrab 
Published: August 2014

Abstract
High-grade serous ovarian cancer (HGSC) is characterized by poor outcome, often attributed to emergence of treatment-resistant sub-clones. We sought to measure the degree of genomic diversity within primary, untreated HGSC to examine the natural state of tumor evolution prior to therapy. We performed exome sequencing, copy number analysis, targeted amplicon deep sequencing and gene expression profiling on thirty-one spatially and temporally separated HGSC tumor specimens (six patients) including ovarian masses, distant metastases, and fallopian tube lesions. We found widespread intra-tumoral variation in mutation, copy number, and gene expression profiles, with key driver alterations in genes present in only a subset of samples (e.g. PIK3CA, CTNNB1, NF1). On average, only 51.5% of mutations were present in every sample of a given case (range: 10.2%-91.4%), with TP53 as the only somatic mutation consistently present in all samples. Complex segmental aneuploidies, such as whole genome doubling, were present in a subset of samples from the same individual, with divergent copy number changes segregating independently of point mutation acquisition. Reconstruction of evolutionary histories showed one patient with mixed HGSC and endometrioid histology with common etiologic origin in the fallopian tube and subsequent selection of different driver mutations in the histologically distinct samples. In this patient, we observed mixed cell populations in the early fallopian tube lesion, indicating diversity arises at early stages of tumorigenesis. Our results reveal that HGSC exhibit highly individual evolutionary trajectories and diverse genomic tapestries prior to therapy, exposing an essential biological characteristic to inform future design of personalized therapeutic solutions and investigation of drug resistance mechanisms.
Citation Format: Sohrab Shah. Evolutionary dynamics of high-grade serous ovarian cancer genomes across anatomic space and time. [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 IA18.
Abstract IA19: Intratumoral heterogeneity and drug response in high-grade serous carcinoma
Authors: Brenton James D. 
Published: August 2014

Abstract
Our understanding of the molecular basis of epithelial ovarian cancer has changed dramatically over the past 10 years. We now recognise that different histological subtypes are fundamentally different diseases, based on recent discoveries identifying the cell-of-origin and key driver mutations for high-grade serous (HGSOC) and clear cell ovarian cancers. The major challenge for the development of personalized treatment for HGSOC is the extreme genomic heterogeneity between cases and additional intratumoural heterogeneity (ITH). We have previously shown that HGSOC is characterised by ubiquitous TP53 mutation and we have proposed that early loss of TP53 may be permissive for the development of a wide range of mutator phenotypes, which may contribute to platinum resistance and ITH.
I will discuss our recent findings showing profound ITH in HGSOC and how tandem mutator phenotype may alter evolution in HGSOC. We have developed new methods to identify and quantify circulating tumour DNA in plasma samples from women with HGSOC. These methods provide highly specific biomarkers of response to treatment and can be used to track the emergence of resistant clonal populations. Application of these methods in a national study of relapsed ovarian cancer and in new clinical trials will provide critical clinical data to develop personalized treatment strategies for women with HGSOC.
Citation Format: James D. Brenton. Intratumoral heterogeneity and drug response in high-grade serous carcinoma. [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 IA19.
Abstract IA20: Analyzing the cellular basis for heterogeneity in serous ovarian carcinoma
Authors: Neel Benjamin G. 
Published: August 2014

Abstract
Serous ovarian cancer (SOC) is the leading cause of morbidity/mortality from gynecologic cancer. Current therapies increase survival, yet the majority of SOC patients die of their disease. The cancer stem cell (CSC) hypothesis holds that only a subset of tumor cells can initiate/maintain the tumor and might be more resistant to chemotherapy. In the CSC model, it should be possible to purify a stable population with the ability to generate transplantable tumors that recreate the heterogeneity of the initial malignancy. We previously reported that CD133 marks all TIC from several primary SOC, but in some cases, TIC activity is also found in the CD133– fraction. Also, the TIC phenotype is unstable in xenografts.
To address whether the expression of an unidentified protein marks all TIC in SOC, we performed high-throughput flow cytometry (profiling 365 cell surface markers) and combined these analyses with mass cytometry, a transformative technology allowing examination of 35 cell surface/intracellular markers on a single cell. Analysis of 40 primary SOC samples provided further evidence for inter- and intra-patient heterogeneity. Current analyses focus on functional validation of subpopulations marked by combinations of cell surface/stem cell genes.
In the course of these studies, we have generated a large cohort of SOC xenografts. Xenografts recapitulate the inter- and intra-patient heterogeneity of SOC when their gene expression and copy number profiles are compared. Indeed, they also recapitulate the patient's sensitivity to standard of care chemotherapy. These xenografts might provide a useful model l for more efficient and personalized testing of investigational drugs for SOC.
Citation Format: Benjamin G. Neel. Analyzing the cellular basis for heterogeneity in serous ovarian carcinoma. [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 IA20.
Abstract IA27: Combinatorial immunotherapy using whole tumor antigen: Evidence from phase I trials
Authors: Kandalaft Lana E. , Tanyi Janos , Chiang Cheryl , Coukos George 
Published: August 2014

Abstract
Novel therapeutic strategies are warranted in recurrent ovarian cancer. We report two independent consecutive studies of combinatorial immunotherapy comprising dendritic cell (DC)-based autologous whole tumor antigen vaccination in combination with antiangiogenesis therapy. Thirty one patients with recurrent progressive stage III and IV ovarian cancer with available tumor lysate from debulking surgery enrolled in two different vaccination studies. First six underwent priming with intravenous bevacizumab and oral metronomic cyclophosphamide followed by vaccination with an autologous DC preparation pulsed with freeze-thaw autologous tumor lysate while the other 25 underwent vaccination with an enhanced vaccine of autologous DCs loaded with HOCl-oxidized autologous tumor lysate administered intranodally in combination with antiangiogenesis therapy. Both studies were followed by lymphodepletion and transfer of autologous vaccine-primed, ex vivo CD3/CD28-costimulated peripheral blood T-cells, in combination with antiangiogenesis therapy and vaccination. Feasibility, safety, biological and clinical efficacy were evaluated.
Eleven patients have completed vaccination and T cell transfer to date, while twenty-three additional patients completed vaccination only. Vaccination was well tolerated and elicited tumor-specific T cell responses against various ovarian tumor antigens. Preliminary results demonstrate that patients' DCs loaded with HOCl-oxidized lysate elicited strong tumor-specific IFN-gamma; secretions and produced high levels of Th1-priming cytokines and chemokines, including IL-12. A clinical benefit of 65% correlated with the immune response with some patients experiencing prolonged progression free survival. Following lymphodepletion, adoptive transfer of vaccine-primed T-cells was well tolerated and resulted in durable reduction of T-regulatory cells and restoration of vaccine-induced antitumor immunity in patients who experienced clinical benefit. One patient exhibited a complete response at end of study and stable disease was observed in 7 out of the 11 patients who completed vaccination and T cell transfer. Data on additional patients will be presented at the meeting.
Our results suggest the use of combinatorial cellular immunotherapy comprising DC vaccination with whole tumor antigen and adoptive lymphocyte transfer using tumor antigen-specific T cells for the treatment of patients with recurrent ovarian cancer is promising yet warrants further investigation.
Citation Format: Lana E. Kandalaft, Janos Tanyi, Cheryl Chiang, George Coukos. Combinatorial immunotherapy using whole tumor antigen: Evidence from phase I trials. [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 IA27.
Abstract IA7: Determinants of clinical outcome in ovarian cancer
Authors: Bowtell David D.L. 
Published: August 2014

Abstract
Clinical outcome for ovarian cancer has seen little improvement over the last two decades despite intensive research and clinical trial activity. Why has ovarian cancer been so intractable? Patient cohort studies that seek to unravel the determinants of clinical outcome allow a focus on molecular changes that are important to patient health, as well as providing experiments of nature that help researchers identify drivers of disease. The presentation will provide examples of somatic and germline determinants of patient outcome that must be considered when seeking biomarkers of tumor behavior. Intratumoral heterogeneity and tumor evolution during therapy will also be discussed.
Ovarian cancer has been fragmented into distinct molecular subtypes and the origins of the different histotypes revised. However, fragmentation has also resulted in unexpected convergence, involving the discovery of molecular similarities of ovarian cancer subtypes with other solid cancers. Ovarian cancer provides an excellent example of a reclassification of solid cancer that is currently underway, based on molecular properties of a tumor rather than anatomy.
Citation Format: David D.L. Bowtell. Determinants of clinical outcome 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 IA7.
Abstract PR04: DNA-PK inhibition resensitizes ovarian cancer cells to cisplatin in vivo and is associated with modulation of AKT pathway signaling
Authors: Cheraghchi-Bashi-Astaneh Azadeh , Sousa Camila H. De , Maginn Elaina , Dai Yan , Wasan Harpreet , Mills Gordon B. , Gabra Hani , Stronach Euan A. 
Published: August 2014

Abstract
Sustained proliferative signaling and resisting cell death are two fundamental hallmarks of cancer. The AKT pathway is a frequently aberrant, highly interconnected, intracellular signaling network that connects a wide variety of cell stimuli to proliferative and apoptotic cellular control. We have shown that inappropriate control of the AKT pathway underlies failure of chemotherapy in ovarian cancer and furthermore have shown that DNA-PKcs, a component of the non-homologous-end-joining DNA repair pathway, phosphorylates AKT on serine residue 473 in the nucleus of platinum resistant ovarian tumor cells, but not sensitive cells from the same patient. DNA-PK mediated AKT activation in chemoresistant cells results in inhibitory phosphorylation of the pro-apoptotic protein BAD and stabilization of the anti-apoptotic Bcl-2 protein. We report that inhibition of DNA-PK restores response to cisplatin in chemoresistant ovarian cancer cells in vivo. SKOV3 tumor xenografts were implanted subcutaneously into the flanks of Balb/c nu/nu mice and treated with 7.5mg/kg or 10mg/kg DNA-PKcs inhibitor, NU7441 daily (5days on/2 days off) for 2 weeks alone or in combination with 1mg/kg cisplatin twice weekly. DNA-PK inhibition or cisplatin alone were ineffective however in combination decreased tumor growth at 14 days by 89% (7.5mg/kg NU7441) and 90% (10mg/kg NU7441), relative to platinum only treatment. Tumor xenografts were recovered and analyzed by reverse phase protein array (RPPA). Analysis has revealed AKT pathway signaling alterations that underlie the enhanced response to cisplatin on addition of NU7441. DNA-PK inhibition is an attractive therapeutic strategy for resensitizing resistant tumors to platinum based therapy, directly linking the DNA damage caused by platinum to the pro-survival AKT pathway.
This abstract is also presented as Poster A50.
Citation Format: Azadeh Cheraghchi-Bashi-Astaneh, Camila H. De Sousa, Elaina Maginn, Yan Dai, Harpreet Wasan, Gordon B. Mills, Hani Gabra, Euan A. Stronach. DNA-PK inhibition resensitizes ovarian cancer cells to cisplatin in vivo and is associated with modulation of AKT pathway signaling. [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 PR04.
Integrated Analysis of Transcriptomes of Cancer Cell Lines and Patient Samples Reveals STK11/LKB1–Driven Regulation of cAMP Phosphodiesterase-4D
Authors: He Ningning , Kim Nayoung , Song Mee , Park Choa , Kim Somin , Park Eun Young , Yim Hwa Young , Kim Kyunga , Park Jong Hoon , Kim Keun Il , Zhang Fan , Mills Gordon B. , Yoon Sukjoon 
Published: August 2014

AbstractThe recent proliferation of data on large collections of well-characterized cancer cell lines linked to therapeutic drug responses has made it possible to identify lineage- and mutation-specific transcriptional markers that can help optimize implementation of anticancer agents. Here, we leverage these resources to systematically investigate the presence of mutation-specific transcription markers in a wide variety of cancer lineages and genotypes. Sensitivity and specificity of potential transcriptional biomarkers were simultaneously analyzed in 19 cell lineages grouped into 228 categories based on the mutational genotypes of 12 cancer-related genes. Among a total of 1,455 category-specific expression patterns, the expression of cAMP phosphodiesterase-4D (PDE4D) with 11 isoforms, one of the PDE4(A-D) subfamilies, was predicted to be regulated by a mutant form of serine/threonine kinase 11 (STK11)/liver kinase B1 (LKB1) present in lung cancer. STK11/LKB1 is the primary upstream kinase of adenine monophosphate–activated protein kinase (AMPK). Subsequently, we found that the knockdown of PDE4D gene expression inhibited proliferation of STK11-mutated lung cancer lines. Furthermore, challenge with a panel of PDE4-specific inhibitors was shown to selectively reduce the growth of STK11-mutated lung cancer lines. Thus, we show that multidimensional analysis of a well-characterized large-scale panel of cancer cell lines provides unprecedented opportunities for the identification of unexpected oncogenic mechanisms and mutation-specific drug targets. Mol Cancer Ther; 13(10); 2463–73. ©2014 AACR.