bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A30: Claudin-4-dependent mechanisms of high-grade serous ovarian cancer progression
Authors: Webb Patricia , Neville Margaret C. , Baumgartner-Wilson Heidi , Post Miriam D. , Goodspeed Andrew , Bitler Benjamin G.
Published: September 2020

In The Cancer Genome Atlas, Claudins-3, -4, and -7 are highly expressed in high-grade serous ovarian cancer (HGSOC). While claudins-3 and -7 are often expressed at tight junctions, claudin-4 (CLDN4) appears to be cytoplasmic, both in normal cells where it is expressed rarely and in a model of HGSOC, often used to study cellular interactions in this disease, OVCAR3 cells. CLDN4 expression reduces response to paclitaxel and conveys worse overall survival. We, therefore, wanted to further elucidate CLDN4-dependent mechanisms of cancer progression and therapeutic response. To address CLDN4 biology, we utilized immunohistochemical (IHC) analysis, loss-of-function studies, and several nonbiased approaches, including RNA-sequencing and proteomics. The IHC showed CLDN4 protein localized in the Golgi compartment with GM130 and around the cells at sites of cell-cell contact. Knocking down CLDN4 by 80% in OVCAR3 cells led them to undergo a transition from a more epithelial morphology to a mesenchymal phenotype (EMT). RNA-Seq analysis supports this morphologic interpretation by showing an increase in mRNA for genes coding for mesenchymal proteins such as fibronectin-1 (FN1), CD44, VIM, TNC, MMP2, and SNAI2 and a decrease in epithelial genes such as E-cadherin (CDH1), CD24, KRT18, and KRT19. RNA-Seq analysis of non-membrane protein kinases showed a 2-fold increase in PLAU, MSN, CAV1, CAV2, and EPHA2 and a 2-fold decrease in IGFBP2 and ERBB2, results that correlate well with the sensitivity of cancer cells to the BCR-ABL inhibitor, dasatinib. To determine the proteins that associate with CLDN4, we performed biotin ligase analysis (Bio-ID) fusing biotin protein ligase to CLDN4 and introducing the gene for the fusion protein into both OVCAR3 and OVCAR8 cells. Of the 36 proteins repeatedly more highly biotinylated in the presence of CLDN4-biotin ligase, 20 were identified as plasma membrane proteins and eight as Golgi localized by Gene Ontology analysis. Notably, we discovered a tyrosine protein kinase, YES1, to be biotinylated in both cell lines. YES1 is a poor prognostic indicator in HGSOC and promotes signal propagation following receptor tyrosine kinase activation, which contributes to a plethora of downstream outputs, including cell-cell adhesion and cell survival. These findings imply that CLDN4 expression is related to EMT and knockdown of CLDN4 could increase the sensitivity HGSOC to inhibitors such as dasatinib (BCR-ABL) or saracatinib (c-Yes).

Citation Format: Patricia Webb, Margaret C. Neville, Heidi Baumgartner-Wilson, Miriam D. Post, Andrew Goodspeed, Benjamin G. Bitler. Claudin-4-dependent mechanisms of high-grade serous ovarian cancer progression [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A30.
Abstract A44: A CRISPRi screen to identify combination therapies for improved treatment of ovarian cancer
Authors: Handly Erika D. , Kong Yi Wen , Braun Christian J. , Patterson Jesse C. , Yaffe Michael B.
Published: September 2020

Ovarian cancer is the fifth leading cause of cancer death for women in the United States, with only modest improvements in patient survival in the past few decades. Standard-of-care treatment is surgical debulking followed by a combination of platinum and taxane agents, but relapse and resistance frequently occur. In order to identify genes that cause sensitivity or resistance in tumor cells treated with platinum chemotherapeutics, I performed a CRISPRi-based screen that combined decreased gene expression of over 19,000 genes with the platinum drugs cisplatin and oxaliplatin. Genes whose knockdown caused sensitivity to the chemotherapeutics were identified through a multiobjective optimization approach to account for knockdown efficiencies and variances in sequencing depth. To filter the noise in the genome-wide screen and more confidently identify “hits,” a smaller pooled screen of one hundred targets was designed. Genes identified in this focused pooled screen as being important to platinum response in cells will be validated using approaches such as cell viability assays. The molecular mechanisms underlying the function of one or two of these genes in the chemotherapy response will be investigated in further detail. Thus, the project has the potential to define new molecular mechanisms by which tumors resist killing by chemotherapy and provide new therapeutic targets for front-line clinical standard-of-care combination chemotherapy regimes in the treatment of ovarian cancer.

Citation Format: Erika D. Handly, Yi Wen Kong, Christian J. Braun, Jesse C. Patterson, Michael B. Yaffe. A CRISPRi screen to identify combination therapies for improved treatment of ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A44.
Abstract A56: Novel L-sugar linked glycosylated antitumor ether lipids for killing platinum-resistant human epithelial ovarian cancer cells
Authors: Nachtigal Mark W. , Schweizer Frank , Arthur Gilbert
Published: September 2020

Glycosylated antitumor ether lipids (GAELs) are a promising class of investigational anticancer agents with potent antitumor activity against a range of cancers, including platinum-resistant high-grade serous ovarian cancer (HGSOC). We previously demonstrated that epithelial ovarian cancer (EOC) cell lines (HGSOC and endometrioid) and primary cells derived from patient ascites (HGSOC and clear cell) were sensitive to the cell-killing effects of D-glucosamine-derived GAELs via an apoptosis-independent mechanism. However, D-linked carbohydrates are metabolized by endogenous glucosidases in vivo, rendering the GAEL inactive. Thus, the aim of the current study was to synthesize a novel class of GAELs with L-linked carbohydrates and to evaluate their efficacy in EOC cell lines and patient samples. Out of seven novel compounds tested, L-rhamnose-GAEL was identified as the compound with the greatest efficacy for killing EOC cell lines and patient cells that were grown under adherent or nonadherent (3D) conditions. The drug-sensitive and drug-resistant syngeneic endometrioid EOC cell lines, A2780s and A2780cp, respectively, as well as the NIH:OVCAR-3 and COV362 HGSOC lines, were incubated with L-rhamnose-GAEL for 48 hours and the CC50 determined as 15 μM for A2780s, 22.5 μM for A2780cp, and 5 μM for NIH:OVCAR-3 and COV362 cells. Similar experiments were conducted with primary EOC cells, chemo-naïve EOC126 (clear-cell adenocarcinoma), and platinum-resistant EOC 183I (HGSOC). Cell viability decreased in a dose-dependent manner with CC50 of 12 μM for EOC126 and 22.5 μM for EOC183l. For comparison, when EOC126 and EOC183I were grown as 3D cultures the CC50for cisplatin was 20 μM and 40 μM, respectively. To evaluate the effect of using low-dose treatment of L-rhamnose-GAEL on primary EOC cells (chemo-naive and chemoresistant), cells were exposed to L-rhamnose-GAEL for 96 hours. These studies revealed that prolonged incubation led to low CC50 of 1-5 μM. These results showed that primary EOC cells derived from chemo-naïve and platinum-resistant patients were sensitive to the L-rhamnose-GAEL and offer a novel drug class capable of killing chemotherapy-resistant EOC cells.

Citation Format: Mark W. Nachtigal, Frank Schweizer, Gilbert Arthur. Novel L-sugar linked glycosylated antitumor ether lipids for killing platinum-resistant human epithelial ovarian cancer cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A56.
Abstract A61: FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy
Authors: Osterman Carlos J. Díaz , Ozmadenci Duygu , Kleinschmidt Elizabeth G. , Taylor Kristin N. , Barrie Allison M. , Jiang Shulin , Bean Lisa M. , Sulzmaier Florian J. , Li Jian , Chen Xiao Lei , Fu Guo , Ojalill Marjaana , Rappu Pekka , Heino Jyrki , Mark Adam A. , Xu Guorong , Fisch Kathleen M. , Weaver David T. , Pachter Jonathan A. , Győrffy Balázs , McHale Michael T. , Connolly Denise C. , Molinolo Alfredo , Stupack Dwayne G. , Schlaepfer David D.
Published: September 2020

Gene copy number alterations, tumor cell stemness, and development of platinum chemotherapy resistance contribute to high-grade serous ovarian cancer (HGSOC) recurrence. Stemness phenotypes involving Wnt-beta-catenin, aldehyde dehydrogenase activities, intrinsic platinum resistance, and tumorsphere formation are here associated with spontaneous genetic gains in KRAS, MYC, and FAK (KMF) genes, in a new aggressive murine model of ovarian cancer. Noncanonical signaling via FAK sustained KMF and human tumorsphere proliferation as well as resistance to cisplatin cytotoxicity. Platinum-resistant tumorspheres can acquire a dependence on FAK for growth. Accordingly, increased FAK tyrosine phosphorylation was observed within HGSOC patient tumors surviving neoadjuvant chemotherapy. Combining a FAK inhibitor with platinum overcame chemoresistance, triggering tumor cell apoptosis. FAK transcriptomic analyses across knockout and reconstituted cells identified 135 genes elevated by a FAK activity-dependent, beta-catenin, and Myc signaling axis including pluripotency and DNA repair genes. Identified target increases in HGSOC tumors may reflect oncogenic FAK signaling.

Citation Format: Carlos J. Díaz Osterman, Duygu Ozmadenci, Elizabeth G. Kleinschmidt, Kristin N. Taylor, Allison M. Barrie, Shulin Jiang, Lisa M. Bean, Florian J. Sulzmaier, Jian Li, Xiao Lei Chen, Guo Fu, Marjaana Ojalill, Pekka Rappu, Jyrki Heino, Adam A. Mark, Guorong Xu, Kathleen M. Fisch, David T. Weaver, Jonathan A. Pachter, Balázs Győrffy, Michael T. McHale, Denise C. Connolly, Alfredo Molinolo, Dwayne G. Stupack, David D. Schlaepfer. FAK activity sustains intrinsic and acquired ovarian cancer resistance to platinum chemotherapy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A61.
Abstract A74: The HIV protease inhibitor nelfinavir, alone or in combination with the proteasome inhibitor bortezomib, is cytotoxic to high-grade serous ovarian cancer cells regardless of platinum sensitivity
Authors: Subeha Mahbuba R. , Goyeneche Alicia A. , Lisio Michael A. , Telleria Carlos M.
Published: September 2020

High-grade serous ovarian cancer (HGSOC) is a deadly disease, affecting women worldwide. Major challenges in treating HGSOC patients involve overcoming resistance to platinum (Pt)-based therapy by developing novel treatment approaches. Nelfinavir (NFV), an anti-HIV drug, has shown to be effective against cancers of high secretory capacity—e.g., multiple myeloma—by aggravating the stress of the endoplasmic reticulum (ER). Its potential therapeutic role against HGSOC, however, remains unclear. We hypothesized that simultaneous ER stress aggravation by NFV and blockage of the proteolytic capacity of the proteasome with a proteasome inhibitor should cause sufficient ER stress to tilt cells to a death fate. In this study, we investigated the cytotoxicity of the ER aggravator NFV as monotherapy and in combination with the proteasome inhibitor bortezomib (BZ) against HGSOC cells having differential sensitivities to cisplatin (CDDP). NFV caused cell cycle arrest associated with increased expression of cyclin-dependent kinase inhibitor p27kip1, while triggering the unfolded protein response (UPR) in a dose-dependent manner and assessed by increased subrogate ER stress biomarkers GRP78 and CHOP. We also discovered that blocking the ubiquitin proteasome system (UPS) using cytostatic concentrations of BZ causes accumulation of poly-ubiquitinated proteins and further activation of the UPR. More importantly, when we combined BZ with NFV, we observed a potentiation of the action of BZ leading to HGSOC lethality regardless of Pt sensitivity. These results suggest that NFV could potentially be used following standard Pt-based treatment, either as monotherapy or in conjunction with proteasome inhibitors, to kill the remaining HGSOC cells that otherwise recur and recreate the disease. In addition, the data provide the rationale for rapid repurposing to treat HGSOC of two drugs clinically approved for other uses, as their systemic toxicities have already been assessed.

Citation Format: Mahbuba R. Subeha, Alicia A. Goyeneche, Michael A. Lisio, Carlos M. Telleria. The HIV protease inhibitor nelfinavir, alone or in combination with the proteasome inhibitor bortezomib, is cytotoxic to high-grade serous ovarian cancer cells regardless of platinum sensitivity [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A74.
Abstract A78: Pre-existing, poly-resistant cancer stem cells in high-grade serous ovarian cancer
Authors: Xie Jingzhong , Yamamoto Yusuke , Liew Audrey-Ann , Wang Bailiang , Mahalingam Rajasekaran , Duleba Marcin , Rao Wei , Niroula Suchan , Goller Kristina , Zhang Yanting , Wang Shan , Jazaeri Amir , Davies Peter , Torti Suzy , Draetta Giulio , Anderson Matthew , Brewer Molly , Crum Christopher , McKeon Frank , Xian Wa
Published: September 2020

High-grade serous ovarian carcinoma (HGSOC) is the most common and lethal form of epithelial ovarian cancer. While HGSOCs respond well to platinum and taxane chemotherapy, the majority of patients eventually relapse with treatment-resistant tumors. This new and ominous resistance property of recurrent tumors is generally thought to be acquired in a process aided by the mutagenic activities of the chemotherapy itself. However, using advanced and robust technology that enables the direct cloning of cancer stem cells (CSCs) from HGSOCs, our study challenges the notion that chemotherapy resistance is acquired. In particular, patient-specific “libraries” of CSCs generated from therapy-naive tumors show that, while the majority of the CSCs are rapidly killed by platinum-taxane treatment, a discrete subset is highly resistant to these drugs to which they had no prior exposure. More telling is that these pre-existing, platinum-taxane resistant CSCs also display a profound “polyresistance” to a wide range of unrelated chemotherapeutic drugs. Importantly, gene expression profiles of polyresistant CSCs are highly uniform within a particular patient and clearly distinct from those of sensitive clones. This finding suggests that resistant clones within a patient carry the same gene signature, suggesting that resistance is a singular and knowable event in each patient. Comparing the resistance gene expression signatures across patients is revealing a very limited set of common pathways involving nuclear receptors that likely hold the key to the polyresistance phenomena. Taken together, our study supports the concept that these poly-resistant variants exist and can be cloned from most if not all HGOC patients. Further, the cloning of these polyresistant cells sets in motion the possibility that such variants can be exploited to identify both key pathways of polyresistance and drugs that specifically and pre-emptively eliminate these clones to prevent onset of recurrent disease.

Citation Format: Jingzhong Xie, Yusuke Yamamoto, Audrey-Ann Liew, Bailiang Wang, Rajasekaran Mahalingam, Marcin Duleba, Wei Rao, Suchan Niroula, Kristina Goller, Yanting Zhang, Shan Wang, Amir Jazaeri, Peter Davies, Suzy Torti, Giulio Draetta, Matthew Anderson, Molly Brewer, Christopher Crum, Frank McKeon, Wa Xian. Pre-existing, poly-resistant cancer stem cells in high-grade serous ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A78.
Abstract B11: Collective extrusion initiates dissemination in organotypic model of high-grade serous carcinoma
Authors: Alshehri Sarah , Farsinejad Sadaf , Kung Douglas , Santi Estefan , Zhai Yali , Cattabiani Thomas , Wang Hongjun , Cho Kathleen , Iwanicki Marcin
Published: September 2020

Development of serous tubal intraepithelial carcinoma (STIC) from transformed fallopian tube secretory epithelial cells (FTSEC) is considered to be an initiating event for a significant proportion of high-grade serous carcinomas (HGSCs). Some regions of STIC lesions can form multicellular loosely cohesive outgrowths that apically extend out of the tubal epithelium. These outgrowths can detach and disseminate within the peritoneal cavity, causing organ obstruction. Immunohistochemical analysis of STICs suggests the possibility that molecular pathways associated with proliferation, DNA repair, cytoskeletal dynamics, and extracellular matrix adhesion contribute to outgrowth formation. Due to limited availability of transformed FTSEC in vitro culture models that faithfully capture outgrowth dynamics, the role of these pathways in STIC/HGSC outgrowth formation remains unknown. Here we present the development of an organotypic model of outgrowth formation. Long-term live-cell imaging of transformed human, and mouse FTSEC and STIC-like multicellular organotypic assemblies, have shown that outgrowths are initiated by collective apical extrusion of less-cohesive, loosely attached cell populations that can proliferate outside of the organotypic assembly. mRNA and immunofluorescence analysis of loosely attached cell populations revealed: (i) activation of Rho pathway, (ii) increased expression of several alpha integrin subunits that form heterodimers with beta 1 integrin, and (iii) nonpolarized apical and junctional localization of activated integrin beta 1. Pharmacologic or genetic inhibition of Rho-associated kinase (ROCK) blocked outgrowth formation without affecting cell proliferation. Conversely, activation of Rho significantly accelerated outgrowths, indicating that Rho-ROCK is a critical regulator of early steps of HGSC dissemination. Quantitative image-based evaluation of ROCK target phosphorylated myosin light chain expression in patient-derived xenograft cells revealed the presence of cell populations with high ROCK activation. Blocking integrin beta 1 activity resulted in the disintegration of already formed outgrowths. Our data indicate that cell populations with high Rho/ROCK activity remodel integrin beta 1-dependent adhesion to initiate apical extrusion and peritoneal dissemination.

Citation Format: Sarah Alshehri, Sadaf Farsinejad, Douglas Kung, Estefan Santi, Yali Zhai, Thomas Cattabiani, Hongjun Wang, Kathleen Cho, Marcin Iwanicki. Collective extrusion initiates dissemination in organotypic model of high-grade serous carcinoma [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B11.
Abstract B49: Effects of exercise on ovarian cancer initiation and progression
Authors: Bi Fangfang , Morrisson Madeline , Cady Sarah , Cerchia Alexandra , Yang Kevin , Ling Ivy , Yang-Hartwich Yang
Published: September 2020

Epidemiology studies support a strong association between physical activity and lower risk of cancer. Exercise is a promising nonpharmacologic strategy in preventing cancer and mitigating adverse effects of cancer and anticancer therapies. However, we have not been able to optimize the efficacy of exercise training as an anticancer intervention due to the lack of knowledge regarding the biologic mechanisms of action, the effective doses, and the biomarkers for predicting and monitoring responses of exercise-based intervention. Our objective is to utilize mouse models to determine the effects and underlying mechanisms of exercise on ovarian cancer initiation and progression. C57BL/6 mice ran on a treadmill for 45min daily to mimic human exercise activity. The control groups were placed on treadmill for 45min daily. After a month of this exercise regiment, both groups were injected with cancer cells derived from ovarian tumors of Dicer-/-; Pten-/-; Tp53R172H mice. Tumor progression was monitored through IVIS imaging system. Blood and peritoneal fluid samples were tested for cytokine levels. Tissue samples were collected and gene expression levels were quantified via qPCR. Peritoneal macrophages were isolated after acute exercise and were used in flow cytometry analysis or cocultured with cancer cells. Our model resembled the biologic changes of exercise in human. Eight-week treadmill-running exercise suppressed early tumor formation and tumor spreading. Exercise altered visceral fat tissue gene expression profile, which may inhibit cancer-induced cachexia and metabolic imbalance. In addition, one-hour exercise induced the acute proinflammatory activation of peritoneal macrophages. Coculture of peritoneal macrophages and PBMC (peripheral blood mononuclear cells) or NK (natural killer) cells from the exercise group and cancer cells reduced survival of cancer cells. Chronic and acute exercise can both suppress ovarian cancer tumorigenesis in mouse models. The underlying mechanisms involve enhancing anticancer immune system responses and adjusting metabolic balance. More research is needed to determine the specific mechanisms by which chronic and acute exercise affects ovarian cancer.

Citation Format: Fangfang Bi, Madeline Morrisson, Sarah Cady, Alexandra Cerchia, Kevin Yang, Ivy Ling, Yang Yang-Hartwich. Effects of exercise on ovarian cancer initiation and progression [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B49.
Abstract B52: Inhibition of ovarian cancer spheroid adhesion using graphene oxide nanomaterials
Authors: Lee Hak Rae , Geller Melissa A. , Azarin Samira M.
Published: September 2020

There is an urgent need for development of alternative treatment strategies for advanced-stage ovarian cancer. During metastatic spread, single cells or spheroids detach from the primary tumor and are carried by the peritoneal fluid until attaching to the mesothelial cells lining the abdominal cavity. While attachment of ovarian tumor cells and spheroids to the mesothelial layer is known to be mediated by β-integrins and CD44, efforts to block these receptors with antibodies have been insufficient to inhibit disease progression. As graphene oxide nanosheets have previously been shown bind to β-integrins on the surface of mesenchymal stem cells, we hypothesized that they would be able to attach to ovarian cancer spheroids, forming a physical barrier around the spheroids and thus inhibiting their adhesion to the mesothelium. SKOV-3 human ovarian cancer cells were used in this study, as this cell line was derived from ascites fluid. SKOV-3 cells were placed in poly(hydroxyethyl methacrylate) (polyHEMA)-coated plates for 24 hours to form spheroids, followed by 48-hour treatment with the nanosheets. The graphene oxide nanosheets were functionalized with 4-arm polyethylene glycol (PEG) to enhance biocompatibility and provide additional steric hindrance to prevent spheroid adhesion. Scanning electron microscopy confirmed that the nanosheets were able to bind to the tumor spheroids. Association of the nanosheets with the SKOV-3 spheroids reduced their adhesion to extracellular matrix proteins collagen and fibronectin as well as LP-9 human mesothelial cells over a 7-day time period, with the PEG-functionalized nanosheets showing the greatest reduction in adhesion. The nanomaterials did not exhibit cytotoxicity to LP-9 cells at the range of concentrations used to prevent adhesion. Receptor blocking studies confirmed that the nanosheets were predominantly engaging with the tumor spheroids via β-integrins. Finally, for tumor spheroids that did bind to the mesothelial cells, the presence of nanosheets on the surface of the spheroids decreased the rate of mesothelial layer clearance by the tumor cells. Taken together, these results demonstrate that graphene oxide nanomaterials can bind to ovarian tumor spheroids and inhibit their attachment to matrix proteins and mesothelial cells, while also reducing their ability to clear mesothelial cells once bound. Future efforts are focused on testing these materials with human ascites fluid and further modifying the nanosheets to enable ablation of tumor cells bound to the nanosheets to enhance their therapeutic potential.

Citation Format: Hak Rae Lee, Melissa A. Geller, Samira M. Azarin. Inhibition of ovarian cancer spheroid adhesion using graphene oxide nanomaterials [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B52.
Abstract B54: Adipogenic chemokines, body mass index, and ovarian cancer survival
Authors: Duque Sara , Anyanwu Nneka , Bukenya George , Karam Shriya , Son Deok-Soo , Wilson Andrew J. , Crispens Marta A. , Beeghly-Fadiel Alicia
Published: September 2020

Objectives: Obesity affects more than one-third of US adults and promotes the development and progression of many cancers. One mechanism by which obesity may influence ovarian cancer is via adipocyte-tumor cell communication, including the production of chemotactic cytokines, or chemokines, in the tumor microenvironment. Our goal was to measure adipogenic chemokine expression and examine associations with body mass index (BMI) and ovarian cancer survival.

Methods: We selected 25 chemokines from laboratory experiments that modeled adipogenesis, of which 22 had expression data available for 302 high-grade serous ovarian cancer cases from The Cancer Genome Atlas (TCGA). We measured mRNA expression using Taqman quantitative real-time polymerase chain reaction (QPCR) in 50 high-grade serous tumor samples and ascertained BMI from electronic medical records (EMR) from the Vanderbilt University Medical Center (VUMC). We also evaluated peri-diagnosis BMI (± 4 weeks) from EMR for 298 tumor registry-confirmed (165 serous and 133 nonserous) cases. Expression data were log transformed and dichotomized at median values; associations with disease-free survival (DFS) and overall survival (OS) were quantified using proportional hazards regression.

Results: In TCGA analyses, two ligands and one receptor had significant associations with better (CCL8 and CXCL13) and worse (CX3CR1) OS, respectively. Higher CXCL13 expression was also associated with better DFS in VUMC tumors, but significance was attenuated after adjustment for clinical covariates. CX3CR1 was not expressed in all tumors but was positively associated with BMI (Pearson’s r=0.69, P=0.019). Finally, among all 298 tumor registry-confirmed VUMC cases, BMI was not associated with OS, although higher BMI was associated with a 4% significantly increased risk of death among 133 nonserous cases.

Conclusions: Our findings suggest that obesity impacts chemokine expression in the tumor microenvironment and ovarian cancer survival. Further, differences between serous and nonserous subtypes may influence the relationship between obesity and ovarian cancer prognosis.

Citation Format: Sara Duque, Nneka Anyanwu, George Bukenya, Shriya Karam, Deok-Soo Son, Andrew J. Wilson, Marta A. Crispens, Alicia Beeghly-Fadiel. Adipogenic chemokines, body mass index, and ovarian cancer survival [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B54.
Abstract B70: Rac1 as a therapeutic target in ovarian cancer
Authors: Rivera Melanie , Grimes Martha M. , Dominguez Dayna , Kenney S. Ray , Guo Yuna , Romero Elsa , Brayer Kathryn J. , Guo Yan , Ness Scott A. , Adams Sarah F. , Muller Carolyn , Hudson Laurie G. , Wandinger-Ness Angela
Published: September 2020

Rac1 is a high-value therapeutic target for cancer based on its tumor-promoting activities, yet clinical applications targeting Rac1 are in their infancy. High expression and hyperactivation of Rac1 in ovarian cancer, along with our identification of R-ketorolac as a novel Rac1 and Cdc42 selective inhibitor with translational potential, prompt us to test the hypothesis that targeting Rac1 has therapeutic utility for ovarian cancer. Ascites tumor cell samples from ovarian cancer patients in a prospective study receiving racemic ketorolac for clinically indicated use in pain relief were previously reported to show time-dependent reduction of Rac1 and Cdc42 activities post-treatment. New RNA seq data of these patient samples reveals significant downregulation of genes involved in endocytosis, regulation of actin cytoskeleton, ER protein processing, TNF and NOD signaling. Conversely, the identified downregulated genes were overexpressed and associated with worse survival in ovarian cancer patients analyzed through The Cancer Genome Atlas (TCGA). Among the downregulated genes in the NOD pathway are chemokines and proinflammatory cytokines. Follow-up cytokine panels from patients confirm that racemic ketorolac treatment reduces the levels of immunosuppressive cytokines IL-6, IL-10, and RANTES in ascites fluids. Together, these data indicate there may be a benefit to the anti-inflammatory activity of the S- enantiomer, as well as the GTPase inhibitory activity of the R-enantiomer of ketorolac for ovarian cancer treatment.

Citation Format: Melanie Rivera, Martha M. Grimes, Dayna Dominguez, S. Ray Kenney, Yuna Guo, Elsa Romero, Kathryn J. Brayer, Yan Guo, Scott A. Ness, Sarah F. Adams, Carolyn Muller, Laurie G. Hudson, Angela Wandinger-Ness. Rac1 as a therapeutic target in ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B70.
Abstract IA11: Women at high risk for ovarian cancer: Novel strategies for identification and prevention
Authors: Lu Karen H.
Published: September 2020

Most women carry a lifetime risk of 1.4% of ovarian cancer. However, certain women with germline mutations in BRCA1, BRCA2, or other hereditary cancer genes have elevated lifetime risks, some as high as 50%. Identification of these unaffected, high-risk women, followed by patient-centered prevention strategies, is key to decreasing overall mortality from ovarian cancer. A number of barriers exist for identification—including cost, patient preference, and availability of genetics services. In an effort to decrease these barriers, novel delivery systems of genetic testing have been developed. We are currently testing an on-line genetic counseling and testing strategy in a study called Making Genetic Testing Accessible (MAGENTA). We hypothesize that online genetic education and testing with access to board-certified genetic counselors could improve access to genetic testing while maintaining test quality and clinical utility. In this prospective, randomized, national clinical trial, over 3,000 women with a family history of breast or ovarian cancer will undergo genetic testing. We will compare the effectiveness of online genetic education with optional telephone counseling with three other strategies: online genetic education with required pretest telephone genetic counseling, online genetic education with required post-test telephone genetic counseling, and online genetic education with required pre- and post-test telephone genetic counseling. The primary outcome is cancer risk distress at 3 months post disclosure of genetic test results. Additional endpoints include testing completion rate (defined as receiving results), genetics knowledge, cognitive outcomes (i.e., decisional satisfaction, decisional regret), and behavioral outcomes. We currently have women enrolled from all 50 states in the United States. Preliminary data from this study will be presented. In addition, we will discuss our prospective, multicenter surgical prevention study that has enrolled over 200 women nationwide who have undergone either a salpingectomy or risk-reducing salpingo-oophorectomy (RRSO). The concept of salpingectomy with delayed oophorectomy as a cancer-prevention strategy for high-risk women is based on multiple studies implicating the fallopian tube epithelia as the cell of origin for BRCA-associated high-grade serous ovarian cancer. This information, coupled with high-risk women’s desire to minimize side effects associated with surgical menopause from RRSO, forms the rationale for the study. Finally, we will discuss plans for a prospective, international trial of salpingectomy in high-risk women that will be powered for a cancer efficacy endpoint.

Citation Format: Karen H. Lu. Women at high risk for ovarian cancer: Novel strategies for identification and prevention [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA11.
Abstract IA16: ER stress responses shape the ovarian cancer immune-microenvironment
Authors: Cubillos-Ruiz Juan R.
Published: September 2020

Harnessing the intrinsic ability of our immune system to eliminate malignant cells represents the most promising new anticancer strategy since the development of chemotherapy. While cancer immunotherapy has been designated a scientific breakthrough, tumor-induced immunosuppression represents a major impediment to the success of this new approach in ovarian cancer. We uncovered that ovarian cancer inhibits the development of protective antitumor immunity by inducing a state of persistent “endoplasmic reticulum (ER) stress” in intratumoral dendritic cells (DCs) and T cells. First, we identified that sustained activation of the IRE1-XBP1 arm of the ER stress response in DCs was necessary for the aggressive and accelerated progression of primary and metastatic ovarian cancers in various preclinical models of disease. Mechanistically, intratumoral DCs exhibited constitutive IRE1-XBP1 activation, which was fueled by lipid peroxidation byproducts that caused ER stress by modifying ER-resident chaperones. Persistent XBP1 activation induced a comprehensive triglyceride biosynthetic program promoting accumulation of lipid droplets that subsequently impaired DC antigen presentation to T cells. Conditional deletion or therapeutic silencing of IRE1 or XBP1 in DCs restored their immunogenic function in the tumor and delayed ovarian cancer progression by eliciting protective antitumor T-cell responses. In addition, we recently demonstrated that ovarian cancer also triggers abnormal IRE1-XBP1 activation in T cells to control their mitochondrial function and antitumor activity. XBP1 upregulation in T cells isolated from human ovarian cancer specimens was associated with decreased intratumoral T-cell infiltration and reduced IFNG expression. Ascites fluid from ovarian cancer patients inhibited glucose uptake and caused N-linked protein glycosylation defects in T cells, leading to XBP1-driven mitochondrial dysfunction. Mechanistically, maladaptive XBP1 signaling limited the influx of glutamine necessary to sustain mitochondrial respiration under glucose-deprived conditions. Hence, ovarian cancer hosts lacking XBP1 selectively in T cells demonstrated superior antitumor immunity, delayed malignant progression, and increased overall survival. Taken together, our studies revealed that ovarian cancer provokes persistent IRE1-XBP1 signaling in immune cells to shape the tumor microenvironment and evade immune control. These findings provide a new mechanistic understanding of immunosuppression in ovarian cancer and offer novel avenues for immunotherapeutic intervention.

Citation Format: Juan R. Cubillos-Ruiz. ER stress responses shape the ovarian cancer immune-microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA16.
Abstract IA20: Personalized whole-tumor antigen vaccines in ovarian cancer: Using tumors for therapy
Authors: Kandalaft Lana E.
Published: September 2020

Disappointing results have been observed with the first-generation therapeutic cancer vaccines. However, the renaissance of immunotherapy with the checkpoint inhibitors and the demonstration, in preclinical models, that personalized vaccines can induce efficient antitumor T-cell responses have led to a renewed interest in cancer vaccination. Personalized whole-tumor lysate vaccines can encompass all putative antigens in a patient’s tumor and can potentially induce a broader, more efficient immune response. We report here a clinical study utilizing a personalized vaccine generated by autologous dendritic cells (DC) pulsed with autologous whole-tumor cell lysate (OCDC), in platinum-treated, immunotherapy-naïve, recurrent ovarian cancer patients in combination with bevacizumab or bevacizumab plus low-dose intravenous cyclophosphamide until disease progression or vaccine exhaustion. A total of 392 vaccine doses were administered without serious adverse events. Vaccine was shown to induce T-cell responses to autologous tumor antigen, which were associated with significantly prolonged survival (PFS). Vaccine was also shown to amplify T-cell responses against mutated neoepitopes derived from nonsynonymous somatic tumor mutations, and this included priming of T cells against previously unrecognized neoepitopes as well as novel T-cell clones of markedly higher avidity against previously recognized neoepitopes. Importantly, we demonstrate that the median PFS was 11.1 months in the population receiving the combination of vaccine plus bevacizumab and low-dose cyclophosphamide as compared to only 4.1 months in a historic population of patients from the same institution who received standard bevacizumab and low-dose cyclophosphamide without vaccine. We also demonstrate that survival at 2 years was 100% in the vaccine plus bevacizumab/cyclophosphamide group while it was only 40% in control patients receiving bevacizumab and cyclophosphamide alone. This proof-of-concept clinical study gives us a new horizon for the application of whole-tumor lysate personalized vaccines.

Citation Format: Lana E. Kandalaft. Personalized whole-tumor antigen vaccines in ovarian cancer: Using tumors for therapy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA20.
The Aged Microenvironment of Melanoma Feeds Escape from Targeted Therapy
Authors: Montal Emily D. , White Richard M.
Published: September 2020

Alicea and colleagues demonstrate that aged fibroblasts secrete lipids into the tumor microenvironment, allowing for nutrient exchange with melanoma cells. This supportive function of fibroblasts results in increased resistance to BRAF/MEKi therapy in the context of an aged microenvironment, providing crucial mechanistic insight into age-related drug resistance.

See related article by Alicea et al., p. 1282.
Jumping Translocation in a Patient with Acute Leukemia and Fatal Evolution
Authors: Sánchez Prieto Irene , López Rubio Montserrat , Arranz Eva , Ayala Rosa , Callejas Charavía Marta , Martín Guerrero Yolanda , Gil Fernández Juan José , Valenciano Martínez Susana , Castilla García Lucía , Argüello Marina María , Aspa Cilleruelo José María , Martínez Vázquez Celia , García Suárez Julio
Published: September 2020

Jumping translocations are uncommon cytogenetic abnormalities in which a segment of a donor chromosome, often 1q, is transferred to two or more receptor chromosomes. We describe the case of a 64-year-old man with a history of acute myeloid leukemia associated with myelodysplastic syndrome, who presented with a relapse of the leukemia and, concomitantly, with the appearance of a jumping translocation involving chromosome 1q. The patient had a poor clinical course without the possibility of performing targeted treatment, and he died 5 months after relapse. Jumping translocations are a reflection of chromosomal instability, and they could be related to epigenetic alterations such as pericentromeric chromatin hypomethylation, telomere shortening, or pathogenic variants of the TP53 gene. The existing data suggests a poor clinical outcome, a high risk of disease progression, and an unfavorable prognosis. More molecular studies are required to gain an in-depth understanding of the genetic mechanism underlying these alterations and their clinical significance and to be able to apply an optimal treatment to patients.
Reconsidering ECMO in Premature Neonates
Authors: Wild K. Taylor , Hedrick Holly L. , Rintoul Natalie E.
Published: September 2020

Extracorporeal membrane oxygenation (ECMO) is a life-saving intervention for neonates with respiratory failure or congenital cardiac disease refractory to maximal medical management. Early studies showed high rates of mortality and morbidities among preterm and low birthweight (BW) neonates, leading to widely accepted ECMO inclusion criteria of gestational age (GA) ≥34 weeks and BW >2 kg. In recent years, publications involving neonates of 32–34 weeks GA have reported improved survival and decreased intracranial hemorrhage. As such, ECMO should be considered on a case-by-case basis in premature neonates as long as the risks are understood.
“Nordestinidade”
Authors: Lima Pedro Ernesto Freitas
Published: September 2020

Atentos aos processos de legitimação de identidades, discutiremos o uso de narrativas sobre “nordestinidade” na produção, circulação e institucionalização das artes visuais de Pernambuco durante o século XX. Analisaremos como eventos e obras se organizaram em torno de narrativas e contranarrativas, aqui denominadas “nordestinidade”, tanto reverberando certo regionalismo freyreano, como também questionando a relação automática entre obras de artistas do Nordeste e o regionalismo, propostas por artistas como o grupo Camelo e por curadores como Moacir dos Anjos.
Cordialidade, malandragem e autoritarismo
Authors: Lima Gabriel Dos Santos
Published: September 2020

O presente artigo dedica-se a reler as noções de cordialidade, malandragem e autoritarismo – conforme estas se apresentam, respectivamente, nas obras de Sérgio Buarque de Holanda, Antonio Candido e Roberto Schwarz –, a fim de sugerir a validade de tais conceitos para a interpretação do momento brasileiro contemporâneo. Para tal, recorda e coloca em perspectiva tais noções, aproximando-as da situação presente.
Comparison Between Ticagrelor and Clopidogrel in Elderly Patients With an Acute Coronary Syndrome
Authors: Szummer Karolina , Montez-Rath Maria E. , Alfredsson Joakim , Erlinge David , Lindahl Bertil , Hofmann Robin , Ravn-Fischer Annica , Svensson Per , Jernberg Tomas
Published: September 2020

Background:

The comparative efficacy and safety of ticagrelor versus clopidogrel in older patients with myocardial infarction (MI) has received limited study.

Methods:

We performed an observational analysis of all patients ≥80 years (n=14 005) who were discharged alive with aspirin combined with either clopidogrel (60.2%) or ticagrelor (39.8%) after a MI between 2010 and 2017 registered in the national registry SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies). Inverse probability treatment weighting was used in Cox regression models to adjust for differences in demographics, in-hospital therapies, and medications. The primary ischemic outcome (death, MI, or stroke), and bleeding were obtained from national registries at 1 year. A sensitivity analysis in <80-year-old patients was performed.

Results:

In patients ≥80 years, the incidence of the primary ischemic outcome (hazard ratio [HR], 0.97 [95% CI, 0.88–1.06]) was similar for ticagrelor- and clopidogrel-treated patients. Ticagrelor was associated with a 17% and 48% higher risk of death (HR, 1.17 [95% CI, 1.03–1.32]) and bleeding (HR, 1.48 [95% CI, 1.25–1.76]), but a lower risk of MI (HR, 0.80 [95% CI, 0.70–0.92]) and stroke (HR, 0.72 [95% CI, 0.56–0.93]). In <80-year-old patients, the incidence of the primary ischemic outcome was 17% (HR, 0.83 [95% CI, 0.77–0.89]) lower with ticagrelor. Ticagrelor was associated with 15% (HR, 0.85 [95% CI, 0.76–0.96]) lower risk of death, 32% higher risk of bleeding (HR, 1.32 [95% CI, 1.18–1.47]), but lower risk of MI (HR, 0.82 [95% CI, 0.75–0.91]) and stroke (HR, 0.82 [95% CI, 0.69–0.98]).

Conclusions:

Ticagrelor use among elderly patients with MI was associated with higher risk of bleeding and death compared with clopidogrel. A randomized study of ticagrelor versus clopidogrel in the elderly is needed.
Seseli besserianum (Apiaceae), a restored species and a replacement name for Seseli peucedanifolium Besser

Authors: STOYANOV STOYAN , OSTROUMOVA TATIANA , DEGTJAREVA GALINA , SAMIGULLIN TAHIR
Published: September 2020

The taxonomic status of Seseli peucedanifolium Besser, a little-known and neglected species in the Bulgarian flora, has been revisited. The study of its morphology, fruit anatomy and sequence data (ITS and ETS) revealed that it should not be treated at infraspecific rank under S. rigidum or synonymized with S. tortuosum or S. arenarium. Seseli besserianum nom. nov. is herein proposed as a replacement name for S. peucedanifolium Besser, a later homonym of S. peucedanifolium Mérat.
Novelties and notes on Tradescantia (Commelinaceae) from Brazil

Authors: HASSEMER GUSTAVO , FUNEZ LUÍS A.
Published: September 2020

We present here novelties and notes on Tradescantia from Brazil. More specifically, we describe a narrowly endemic new species from southern Brazil (T. insularis), create a new name at the species rank (T. catharinensis) for T. crassula var. gaudichaudii, discuss the taxonomy of T. schwirkowskiana and T. serrana, and lectotypify T. tenella and present the first record of this species in the Southeast Region of Brazil. Finally, we provide an identification key to Tradescantia in Brazil.
The complete plastome sequence of Gordonia penangensis Ridl. supports the transfer of Asian Gordonia into Polyspora (Theaceae)

Authors: CHOO LE MIN , NIISSALO MATTI A. , LEONG PAUL K.F. , KHEW GILLIAN S.
Published: September 2020

Gordonia penangensis Ridl. is a rainforest tree native to Peninsular Malaysia and Singapore. Here we provide the complete plastome from a collection made in Singapore. The plastome sequence is 156,915 bp long with a large single copy, a small single copy and two inverted repeat regions of length 86,669, 18,200 and 26,023 bp, respectively. A total of 114 unique genes were identified, including 80 coding genes (seven in two copies), four ribosomal RNAs (all in two copies) and 30 transfer RNAs (seven in two copies). The plastome architecture and gene content are very similar to previously published plastomes from genus Polyspora, to which most Asian Gordonia species have been transferred. Phylogenetic analyses using maximum likelihood were carried out on CDS regions from complete plastomes of 88 taxa, including five out of the 43 species currently recognised to be from Polyspora. A nuclear DNA phylogeny based on ITS sequences was also generated. Our results support the view that all Asian species of Gordonia are best treated as Polyspora. Four new combinations, Polyspora penangensis (Ridl.) Niissalo & L.M.Choo, Polyspora singaporeana (Wall. ex Ridl.) Niissalo & L.M.Choo, Polyspora obtusa (Wall. ex Wight) Niissalo & L.M.Choo and Polyspora ovalis (Korth.) Niissalo & L.M.Choo are made. Three lectotypes are also designated here.