bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA05: Intratumor genetic heterogeneity as a predictive biomarker in head and neck squamous cell carcinoma
Authors: Mroz Edmund A. , Rocco James W. 
Published: September 2020

Abstract
The presence of heritable genetic differences among cancer cells within a tumor, called intratumor genetic heterogeneity, has long been suspected of playing a role in the poor responses of some tumors to traditional therapies. Research over the past decade has now documented the existence of genetic heterogeneity within tumors of individual patients and acknowledged its potential clinical significance. The research methods for identifying intratumor genetic heterogeneity were not readily adaptable to widespread clinical application until the development of a quantitative measure (MATH—mutant allele tumor heterogeneity) based on whole-exome sequencing of individual tumor samples. MATH values could be readily derived from biopsy or surgical specimens prior to the decision to utilize adjuvant radiation or chemotherapy. MATH analysis has now been used in HNSCC genomic data sets, along with clinical outcome data, to document a relation of high intratumor genetic heterogeneity to shorter overall survival (OS) in a large, multi-institutional study. Recent analysis examining the impact of high and low heterogeneity as measured by MATH suggests that the relation of intratumor heterogeneity to OS likely depends on the specific type of adjuvant therapy used. Our results demonstrate that patients with high intratumor heterogeneity (high MATH scores) would benefit from adjuvant radiation even when NCCN clinical treatment guidelines suggest that it could be omitted. In contrast, patients with low MATH tumors should likely adhere to these guidelines. Our results also support that patients with high MATH tumors will likely not benefit from the addition of adjuvant chemotherapy to radiotherapy, and thus could be spared the additional morbidity of complications from combination therapy. Current HNSCC NCCN treatment guidelines are based on either clinical or pathologic tumor stage and in the postoperative setting the presence or absence of high-risk pathologic features such as positive or close margins and tumor extra nodal extension. Intratumor genetic heterogeneity as measured by MATH analysis has the potential to further inform stage- and pathology-based treatment decisions and consequently should be evaluated in controlled prospective trials that compare adjuvant radiation against chemoradiation following surgery for HNSCC.
Citation Format: Edmund A. Mroz, James W. Rocco. Intratumor genetic heterogeneity as a predictive biomarker in head and neck squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr IA05.
Abstract A36: Developing a novel treatment for advanced ovarian cancer by targeting the c-Met pathway
Authors: Chaparala Anusha , Swetzig Wendy M. , Strohl Anna E. , Wei Jian-Jun , Matei Daniela , Shahabi Shohreh 
Published: September 2020

Abstract
Approximately one-third of epithelial ovarian tumors exhibit higher levels of c-Met, a receptor tyrosine kinase, activated by Hepatocyte Growth Factor (HGF). c-Met plays an important role in the growth and metastasis of tumor cells. Increased c-Met expression is associated with decreased survival and resistance to chemotherapy in various tumors. More recently, our team identified c-Met overexpression as a mechanism of resistance to neoadjuvant chemotherapy (NACT) in ovarian cancer (OC). The c-Met pathway has been explored as a therapeutic target in various solid tumors, and antibodies targeting c-Met have been proposed as novel anticancer agents. This project aims to investigate the effectiveness of a c-Met monoclonal antibody-drug conjugate (c-Met ADC) in OC models. Here we show that the anti-c-Met antibody alone effectively diminishes c-Met signaling (phosphorylation of c-Met and downstream Akt) but does not inhibit OC cell proliferation. In contrast, the c-Met ADC significantly decreases viability and induces apoptosis in c-Met-expressing OC cells. To validate c-Met expression as a predictor of resistance to NACT in OC, we analyzed c-Met expression in matched pre- and post-treatment samples collected from OC patients undergoing treatment with NACT and in a tissue microarray containing 20 ovarian tumors post-NACT. Detectable c-Met was recorded in ~50% of post-NACT specimens. We evaluated the in vitro antitumor activity of c-Met-ADC on the primary cells isolated from patients, before and after NACT, to assess tumor cell sensitivity to c-Met ADC. The results from these studies support the development of c-Met-ADC as a novel treatment for OC.
Citation Format: Anusha Chaparala, Wendy M. Swetzig, Anna E. Strohl, Jian-Jun Wei, Daniela Matei, Shohreh Shahabi. Developing a novel treatment for advanced ovarian cancer by targeting the c-Met pathway [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 A36.
Abstract A43: Centrosome amplification favors survival and impairs ovarian cancer progression
Authors: Morretton Jean-Philippe , Herbette Aurelie , Cosson Camille , Mboup Bassirou , Latouche Aurelien , Gestraud Pierre , Popova Tatiana , Stern Marc-Henri , Nemati Fariba , Decaudin Didier , Bataillon Guillaume , Becette Veronique , Meseure Didier , Nicolas Andre , Mariani Odette , Bonneau Claire , Barbazan Jorge , Vincent-Salomon Anne , Mechta-Grigoriou Fatima , Roman-Roman Sergio , Rouzier Roman , Sastre-Garau Xavier , Goundiam Oumou , Basto Renata 
Published: September 2020

Abstract
Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The most common subtype of EOC is high-grade serous (HGSOC), which responds at least initially to chemotherapy but has a worse overall prognosis. Genomic, transcriptomic, and proteogenomic profiling of HGSOC suggested a whole spectrum of molecular diversity, including homologous recombination pathway deficiencies (HRD). The centrosome is the main microtubule (MT)-organizing center of animal cells. It facilitates the accuracy of chromosome segregation during mitosis and influences cell polarity and migration. The presence of more than two centrosomes in a cell, centrosome amplification, has long been associated with tumorigenesis. However, little is known about the real status of centrosome numbers in human cancers and whether numerical alterations are solely associated with poor prognosis. We screened 100 samples of primary EOCs including 88 HGSOC, using immunofluorescence and state-of-the-art microscopy, to determine the centrosome-nucleus index (CNI). We integrated these data with genomic alterations, HRD status, and patient outcome. We found that EOCs are highly heterogeneous, with infrequent but strong centrosome amplifications leading to higher CNI than in healthy tissues. Strikingly, while a correlation between CNI and genomic alterations, such as aneuploidy or chromosome rearrangements, could not be established, we found that high CNI correlates with increased patient survival and sensitivity to chemotherapy, independently of HRD status. Using ovarian cancer cellular models to manipulate centrosome numbers and patient-derived xenografts (PDXs), we found that higher CNIs can positively impact the response to chemotherapy and inhibit peritoneal cell dissemination.
Citation Format: Jean-Philippe Morretton, Aurelie Herbette, Camille Cosson, Bassirou Mboup, Aurelien Latouche, Pierre Gestraud, Tatiana Popova, Marc-Henri Stern, Fariba Nemati, Didier Decaudin, Guillaume Bataillon, Veronique Becette, Didier Meseure, Andre Nicolas, Odette Mariani, Claire Bonneau, Jorge Barbazan, Anne Vincent-Salomon, Fatima Mechta-Grigoriou, Sergio Roman-Roman, Roman Rouzier, Xavier Sastre-Garau, Oumou Goundiam, Renata Basto. Centrosome amplification favors survival and impairs 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 A43.
Abstract A45: Quinacrine induces necrosis of ovarian high-grade serous carcinoma cells by breaking the mitochondria ROS balance
Authors: Huang Ching-I , Chu Tang-Yuan , Huang Hsuan-Shun 
Published: September 2020

Abstract
Ovarian high-grade serous ovarian carcinoma (HGSC) was found to be initiated and promoted by repeated exposure of fimbrial epithelium to ovulatory ROS with resultant intolerable stress of oxidative damages and DNA repair load. Consequential cell apoptosis is overcome on the one hand by quenching excessive ROS by hemoglobin contributed by retrograde menstruation and on the other by upregulation of antioxidant machinery. A dangerous balance is achieved between the oxidative stress and antioxidation and between DNA damage stress and repair. Breaking of this balance on the stress side such as by DNA chelating agent such as cisplatin or inhibitors targeting on DNA repair enzyme such as PARP leads to therapeutic cell killing. In this report, we show ROS enhancing drug such as quinacrine effectively kill HGSC cells and its tubal precursor cells with p53 and Rb defect. Quinacrine is a traditional antimalarial drug with wide antitumor effect in either a single agent or combined with chemotherapy drugs. We show here that quinacrine has a cytotoxic effect in two HGSC cell lines (KURAMOCHI, OVSAHO) and in an HPV E6/E7-immortalized human fimbrial epithelial cells, which are readily fully transformed by ovulatory follicular fluid. Cytotoxicity was observed dose-dependently at concentrations ranging from 2.5μM to 25μM. Flow cytometry analysis indicated a cell necrosis (PI +, annexin V-) 48hr post-treatment. We further found a significant induction of the mitochondrial ROS upon quinacrine treatment, and ROS inhibitor N-acetyl-l-cysteine considerably reversed this cytotoxic effect. The study proves the concept of breaking the balance of mitochondria-ROS is a feasible strategy for the development of a new drug for ovarian HGSC.
Note: This abstract was not presented at the conference.
Citation Format: Ching-I Huang, Tang-Yuan Chu, Hsuan-Shun Huang. Quinacrine induces necrosis of ovarian high-grade serous carcinoma cells by breaking the mitochondria ROS balance [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 A45.
Abstract A57: Identification of novel targets for ovarian cancer treatment
Authors: Noriega Ricardo , Reyes Jeyshka , Quiñones Blanca , Serrano Joseline , Vivas Pablo , Pérez Josué 
Published: September 2020

Abstract
Ovarian cancer remains one of the most lethal diseases for the female reproductive system with 22,530 new cases and more than 13,980 deaths predicted for 2019 in the United States alone, according to the American Cancer Society. Currently, there is no effective therapy for ovarian cancer patients, in particular for those who become resistant to chemotherapy (cisplatin). We need to identify novel targets for ovarian cancer therapy. We performed RNA deep-sequencing studies in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. Several RNA (messengers and long noncoding) were differentially abundant in cisplatin-resistant versus cisplatin-sensitive cells. Many of these RNAs have not been previously studied in ovarian cancer. Therefore, we performed rigorous bioinformatic studies that included data filtering and survival rates (using Kaplan-Meier plot analysis) and IPA (Ingenuity Pathway Analysis) to select key candidate genes that can be used as potential targets for ovarian cancer therapy. Additional data filtering was used to select a list of candidate genes whose expression correlates with the overall survival and progression-free survival of ovarian cancer patients. Future experiments will investigate the biologic consequence of targeting each of these candidate genes in ovarian cancer cells and ovarian cancer mouse models.
Citation Format: Ricardo Noriega, Jeyshka Reyes, Blanca Quiñones, Joseline Serrano, Pablo Vivas, Josué Pérez. Identification of novel targets for ovarian cancer treatment [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 A57.
Abstract A58: HR-ESI-MS identification of novel triterpenoid antitumor substances in securidaca 1, using activity-guided SRB assay
Authors: Obasi Titus Chukwuemeka , Oprean Radu 
Published: September 2020

Abstract
Background: Securidaca 1 is a triterpenoid saponin fraction obtained from African medicinal plant S. longipedunculata, whose action activated apoptosis via inhibition of PI3K-AKT downstream. Preliminary studies show an IC50 of 7.03 (μg/mL), with RT-qPCR gene expression revealing a fold-change reduction of MCL-1 and BCL2L1 antiapoptotic proteins, as well as the inhibition of AKT-3, VEGFA, and CDH-1. Therefore, considering the role of PI3K-AKT pathway in tumoral resistance of ovarian cancer and epithelial-mesenchymal transition during development, our major aim was to isolate and identify the components of securidaca 1 responsible for the activity.
Experimental Procedure: Freeze-dried sample of securidaca 1 was fractionated by FLASH chromatography (RP-C18) and the resultant fractions screened by SRB cytotoxicity assay (96-well format) using HeLa cell line. The most promising subfraction was further purified by semipreparative HPLC (reversed-phase). Isolated substances were identified by HR-ESI-MS and IC50s determined and compared with 5-fluorouracil (5-FU) reference standard.
Results: The HR-ESI-MS spectrum under negative ion mode revealed the parent molecular ion peaks of the semipreparative fractions (FR15-6 and FR15-7), whose IC50s were confirmed at 3.84 and 4.83 μg/mL, respectively, on HeLa cell line, more sensitive than 5-FU. MS/MS fragmentation spectra (negative ion mode) show putative fragments of molecular ions 455 and 425 (m/z), respectively, typically indicating oleanine triterpenoid aglycone. Post-TLC derivatization tested positive to Liebermann Burckhard and Carr Price reactions, and sugars.
Conclusion: FR15-6 and FR15-7 are potential candidates for anticancer development whose actions may be responsible for antitumor activities previously seen in securidaca 1. Work is ongoing to evaluate their capacities in blocking tumor development via antiapoptotic effectors of PI3K-AKT downstream pathway.
Note: This abstract was not presented at the conference.
Citation Format: Titus Chukwuemeka Obasi, Radu Oprean. HR-ESI-MS identification of novel triterpenoid antitumor substances in securidaca 1, using activity-guided SRB assay [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 A58.
Abstract A63: Whole-genome CRISPR/CAS9 screen using patient samples reveals JunB as a unique genetic liability
Authors: Takahashi Nobuhiro , Keys Heather , Mohan Raghav , Zhang Lihua , Li Yi , Saatcioglu Hatice D. , Nagykery Nicholas , Donahoe Patricia K. , Sabatini David , Pépin David 
Published: September 2020

Abstract
Background: Epithelial ovarian cancers are the fifth leading cause of cancer-related deaths in American women, with a five-year overall survival rate for patients diagnosed at advanced stages of less than 30%. High-grade serous ovarian cancers (HGSOCs), the most common histologic subtype, often initially responds to platinum-based chemotherapy. However, over 80% of patients experience chemoresistant recurrence in advanced-stage disease.
Methods: We have established over 40 patient-derived HGSOC cell lines from ascites of patients with recurrences and hypothesized that these refractory HGSOC cell lines may each possess genetic liabilities and be dependent on unique pathways for survival that can be identified using an unbiased screening approach for the development of personalized therapies. In one such example, we identified candidate genes that are uniquely essential to a single HGSOC patient (ptD), as proof of concept, using a genome-wide lentiviral sgRNA library, containing 187,536 sgRNAs targeting 18,543 protein-coding human genes and 1,504 nontargeting control sgRNAs in a Cas9-containing vector.
Results: The unbiased CRISPR screen identified BRAF (p=2E-6) as a specific susceptibility of ptD, confirming the known oncogene addiction of this primary cell line carrying a V600E mutation, as well as a significant sensitivity to JUNB deletion (p=6E-6). Knockout of the JUNB gene, using lentiviruses expressing guide RNAs and Cas9 protein targeted to JUNB, repressed cell proliferation in vitro in ptD cells but not other primary cell lines. Moreover, in a xenograft mouse model, JUNB KO ptD cells displayed slower tumor growth than control JUNB WT cells.
Conclusion: We have confirmed in a single patient cell line our ability to identify and validate unique genetic liabilities, suggesting the approach can be scaled to rapidly screen primary HGSOC samples for personalized therapy.
Citation Format: Nobuhiro Takahashi, Heather Keys, Raghav Mohan, Lihua Zhang, Yi Li, Hatice D. Saatcioglu, Nicholas Nagykery, Patricia K. Donahoe, David Sabatini, David Pépin. Whole-genome CRISPR/CAS9 screen using patient samples reveals JunB as a unique genetic liability [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 A63.
Abstract B14: Atovaquone targets STAT3 in ovarian cancer spheroids
Authors: Neil Kayli E. , Lacroix Sarah J. , Walker David F. , Liu Suhu , Frank David A. , Walker Sarah R. 
Published: September 2020

Abstract
Ovarian cancer remains a deadly disease for countless women. Recent evidence demonstrates that ovarian cancer cell clusters, spheroids, are important in promoting ovarian recurrence and metastasis. Often these spheroids are resistant to therapy. Therefore, we were interested in identifying drugs that could target ovarian cancer spheroids. To do this, we wanted to identify pathways that were activated in cells growing in three-dimensional (3D) clusters. Analysis of gene expression from 2D and 3D growing cells identified STAT3 as a pathway enriched in 3D growing cells. STAT3 is a transcription factor that is activated by tyrosine phosphorylation. In ovarian cancer cells, activation usually occurs from interleukin 6 (IL-6) binding to the IL-6 receptor and recruiting the signal transducer molecule (GP130, IL6ST). This activates Jak kinases that then tyrosine phosphorylates STAT3. Once activated, STAT3 dimerizes, translocates into the nucleus, and regulates the expression of target genes. Using shRNA targeting STAT3 and the upstream signaling molecule, GP130, we found that reduction of both STAT3 and its upstream signaling molecule GP130 reduced the growth of spheroids. This suggested that targeting STAT3 or an upstream signaling molecule might be a viable treatment option. Atovaquone, used normally for the treatment of malaria or the prevention of pneumocystis pneumonia, inhibits STAT3 activation by inhibiting the expression of GP130 on the cell surface. Therefore, we hypothesized that atovaquone would have efficacy in ovarian cancer spheroids. Treatment of ovarian spheroids with atovaquone reduced their growth and viability. Importantly, atovaquone inhibited STAT3 tyrosine phosphorylation and target gene expression, demonstrating that atovaquone is inhibiting STAT3 in ovarian spheroids. Preliminary data suggest that overexpression of STAT3 partially rescues the effects of atovaquone on spheroid growth. As spheroids are also involved in ovarian cancer metastasis, we are currently assessing the effects of atovaquone on spheroid-mediated ovarian cancer metastasis. Taken together, our data suggest that atovaquone may be a beneficial treatment for ovarian cancer patients.
Citation Format: Kayli E. Neil, Sarah J. Lacroix, David F. Walker, Suhu Liu, David A. Frank, Sarah R. Walker. Atovaquone targets STAT3 in ovarian cancer spheroids [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 B14.
Abstract B21: Oncogenic BRAF and KRAS mutations in endosalpingiosis
Authors: Chui M. Herman , Shih Ie-Ming 
Published: September 2020

Abstract
Endosalpingiosis, or ectopic fallopian tube epithelium, frequently involves the peritoneum and lymph nodes in patients with ovarian low-grade serous borderline tumor or carcinoma, but the pathogenic significance of these microscopic lesions remains unclear. Using laser-capture microdissection and digital droplet PCR, we investigated whether endosalpingiosis harbors the driver mutations in BRAF and KRAS, commonly seen in low-grade serous tumors. Of 21 women with endosalpingiosis associated with a synchronous or metachronous ovarian low-grade serous tumor, mutations were identified in 11 (52%) cases and the identical mutation was shared between the tumor and endosalpingiosis in 10/11 cases. In contrast, of 12 cases of endosalpingiosis not associated with an ovarian tumor, only 1 harbored a KRAS mutation. Across mutation-positive cases, the median mutant allelic frequency was 37% (range: 12 – 67%). Ki-67 immunohistochemical staining revealed significantly decreased proliferative index in endosalpingiosis relative to low-grade serous tumors, but no difference with eutopic tubal epithelium. BRAF or KRAS-mutated endosalpingiosis had significantly lower Ki-67 index compared to lesions lacking mutations in both genes. Functional studies using fallopian tube epithelial cell cultures demonstrate that enforced expression of KRAS-G12V causes phosphorylation of downstream ERK, with associated growth impairment and induction of p21, suggesting oncogene-induced senescence. We demonstrate that endosalpingiosis represents a striking example of cancer driver mutations in deceptively normal-appearing cells, signifying this innocuous-appearing lesion as a monoclonal proliferation with neoplastic potential.
Citation Format: M. Herman Chui, Ie-Ming Shih. Oncogenic BRAF and KRAS mutations in endosalpingiosis [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 B21.