bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract IA13: Systems approach to drug development
Authors: Mills Gordon B. 
Published: August 2018

Abstract
One of the key lessons of the last century of cancer therapy is that combination therapy is, in most cases, necessary, particularly in advanced disease and complex epithelial tumors, to increase tumor control. However, as we have matured in the era of precision oncology which includes small-molecule targeted therapeutics and immuno-oncology agents, while response to targeted therapies are relatively frequent, durable responses are rare and in contrast responses to immuno-oncology agents are less frequent but are commonly durable and can approximate cures. It is thus clear that rational combination therapy approaches not only within a single modality but across different therapy approaches such as targeted and immunotherapy will be necessary to fulfill the promise of precision medicine.
Indeed, in terms of the emerging fields of target therapy and immuno-oncology, we are at the end of the beginning. A number of monotherapies have demonstrated remarkable activity. However, only a portion of patients with our best biomarkers respond and responses are in general short for monotherapy with targeted therapies. Responses to immuno-oncology monotherapy and even initial attempts at combination therapy are extremely exciting in that although only subpopulations of patients still benefit, responses can be remarkably durable, approximating cures. Given the intrinsic heterogeneity of tumors as well as the many mechanisms underlying resistance to targeted and immunotherapy, the limited benefit from monotherapy is to be expected.
The short term of response to therapy for most patients is due to a major degree to the almost inevitable emergence of resistance. We have used PARP inhibitors as an effective emerging therapy to explore genomic and adaptive mechanisms of resistance. Importantly, the tumor as well as the tumor ecosystem adapts to the stress induced by targeted or immunotherapy agents. These adaptive responses, which can be observed in tissue culture, animal models, and patient samples, offer therapeutic opportunities that can be targeted to increase the fraction of patients who will benefit as well as the depth and duration of responses. Based on this paradigm, we have identified a series of unexpected mechanisms of resistance to PARP inhibitors and have developed rational combination therapies to interdict emerging resistance. Based on these preclinical studies, we have promoted a number of therapies to clinical trials and have demonstrated exciting preliminary responses.
Citation Format: Gordon B. Mills. Systems approach to drug development. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA13.
Abstract IA17: Physical and in silico methods for improving sensitivity of detection of ctDNA for personalized medicine in high-grade serous ovarian cancer
Authors: Brenton James D. 
Published: August 2018

Abstract
Early detection of high-grade serous ovarian cancer (HGSOC) remains a major challenge owing to early metastasis from the fallopian tube and lack of specific symptoms or clinical signs. Noninvasive analysis of circulating tumor DNA (ctDNA) for common mutations has the potential to provide highly specific tests for detecting ovarian cancer. We have previously shown that TP53 ctDNA is highly correlated with total volume of disease using 3D volumetric reconstruction of CT images. However, detection of ctDNA requires ctDNA concentration to be greater than 0.5% for adequate sensitivity. Improved methods for detection of ctDNA are also required for reliable response monitoring during treatment and detection of minimal residual disease after surgery and systemic therapy.
I will discuss recent approaches in our lab that have investigated whether size selection of DNA fragments from plasma can increase the detection of ctDNA by enrichment away from cell free DNA of non-tumor origin. The majority of HGSOC ctDNA is in a size range of 90-150 bp based on whole-genome sequencing of cell free DNA from women with relapsed HGSOC and from HGSOC mouse xenografts. Using physical size selection in 35 patients with recurrent HGSOC and 16 additional patients with other cancer types yielded enrichment of mutated DNA fractions by a median of 4.3-fold allowing improved analysis by targeted, whole-exome, and whole-genome sequencing. This allowed identification of new mutations that otherwise were not observed.
Size selection allows detection of tumor alterations masked by non-tumor DNA in plasma, and could improve the sensitivity of liquid biopsy for applications in early diagnosis, detection of minimal residual disease and for establishing mutational signatures from ctDNA.
Citation Format: James D. Brenton. Physical and in silico methods for improving sensitivity of detection of ctDNA for personalized medicine in high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA17.
Abstract IA19: Granulosa cell and other rare ovarian cancers: Genomic-derived diagnostics and emergent management strategies
Authors: Huntsman David 
Published: August 2018

Abstract
Granulosa cell tumors, Sertoli-Leydig tumors, and small cell hypercalcemic ovarian cancers are clinically and biologically distinct. In the past few years the key mutations underpinning these mutations have been discovered. This has led to improved diagnostics for granulosa cell tumors and small cell hypercalcemic ovarian cancer. The discovery of pathognomonic mutations has led to the development of model systems and a better understanding of all three cancer types and for small cell ovarian cancer new treatment strategies.
Citation Format: David Huntsman. Granulosa cell and other rare ovarian cancers: Genomic-derived diagnostics and emergent management strategies. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA19.
Abstract IA20: Therapeutic targeting of ARID1A mutation in ovarian cancer
Authors: Zhang Rugang 
Published: August 2018

Abstract
SWI/SNF chromatin remodeling complexes regulate gene transcription by changing chromatin structure through hydrolyzing ATP. Cancer genome sequencing found that mutations in genes encoding for the subunits of the SWI/SNF complexes collectively occur in ~20% of all human cancers. For example, saturation analysis of The Cancer Genome Atlas (TCGA) cancer mutational profile reveals that the ARID1A subunit of the SWI/SNF complex shows one of the highest mutation rates among epigenetic regulators. Most notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas and 30% of ovarian endometrioid carcinomas. ARID1A mutation is a known genetic driver of ovarian cancer. Over 90% of the ARID1A mutations observed in ovarian cancer are frame-shift or nonsense mutations that result in loss of ARID1A protein expression. Loss of ARID1A correlates with late-stage disease and predicts early recurrence of ovarian clear cell carcinoma. Ovarian clear cell carcinoma ranks second as the cause of death from epithelial ovarian cancer and is associated with the worst prognosis among the major ovarian cancer subtypes when diagnosed at advanced stages. Additionally, for advanced-stage disease, there is currently no effective therapy. Here we will discuss emerging opportunities for therapeutic targeting of ARID1A mutation based on the genetic makeup of ARID1-mutated ovarian cancer with precision. They include synthetic lethality, the mutual exclusivity between ARID1A and TP53 mutations in ovarian cancer, and mechanism-guided combinatory approaches.
Citation Format: Rugang Zhang. Therapeutic targeting of ARID1A mutation in ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA20.
Abstract IA21: Small cell carcinomas of the ovary: Strengths and weaknesses
Authors: Levine Douglas A. 
Published: August 2018

Abstract
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and very aggressive malignancy that occurs mostly in young women. We and others previously described SCCOHT as a SMARCA4-mutated monogenic disease and unraveled other important molecular features, including apparent universal loss of SMARCA2 through epigenetic silencing. Typically, SMARCA4 and SMARCA2 are redundant catalytic subunits of the SWI/SNF complex and loss of either will result in the overexpression of the other. However, SCCOHT is unique in having concomitant loss of both subunits with restoration of either leading to tumor suppression. Nonetheless, despite these advances in understanding the biology of SCCOHT, there are few effective treatment options and survival rates remain poor.
In this presentation we will discuss the role of SMARCA4 and SMARCA2 on tumor growth. We will also present therapeutic options to manipulate SWI/SNF complex dependencies. We will present case histories of patients who have had positive responses to targeted therapies. We will also discuss responses to anti-PD1 immunotherapy and characterize the immune landscape of SCCOHT tumors using quantitative immunofluorescence and gene expression profiling. Unexpectedly for a low mutation burden cancer, the majority of the tumors demonstrated PD-L1 expression with strong associated T-cell infiltration. PD-L1 expression can be detected in both tumor and stromal cells, with macrophages being the most abundant PD-L1 positive cells in some tumors. These findings suggest that although SCCOHT are low-mutational-burden tumors, their immunogenic microenvironment that resembles the landscape of tumors that respond well to treatment with PD-1/PD-L1 blockade.
Citation Format: Douglas A. Levine. Small cell carcinomas of the ovary: Strengths and weaknesses. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA21.
Abstract PR04: Tumor-derived indoleamine 2,3-dioxygenase regulates density of tumor-infiltrating CD8+ T cells and myeloid-derived suppressor cells in a murine model of ovarian cancer
Authors: Amobi Adaobi E. , Tsuji Takemasa , McGray Robert , Odunsi Kunle 
Published: August 2018

Abstract
The catabolism of the essential amino-acid tryptophan by indoleamine 2,3-dioxygenase (IDO1) is a central pathway that contributes to an immunosuppressive microenvironment in many types of cancer. Our lab has previously shown that IDO1 expression in human ovarian tumor correlates with poor prognosis and poor tumor infiltration by CD8+ T cells, and that improved survival is associated with increased tumor-infiltrating lymphocytes. Thus, IDO1 inhibition represents an attractive target for cancer immunotherapy.
To establish the mechanism by which IDO1 inhibition augments immune responses in a murine model of metastatic ovarian cancer, we generated a stable IDO1-overexpressing cell line (IE9mp1-mIDO1) and confirmed functional IDO1 enzyme activity. C57BL/6 mice were challenged intraperitoneally with IE9mp1-mIDO1 or IE9mp1-Empty Vector as a control. IE9mp1-mIDO1 tumor-bearing mice displayed earlier onset of tumor burden and decreased overall survival.
To delineate the role of host- and tumor-derived IDO1 on immune cell infiltration in the tumor, IDO1 genetic knockout and C57BL/6 mice were challenged with IE9mp1-EV or -mIDO1 tumor cells. All mice challenged with IE9mp1-mIDO1 demonstrate decreased CD8+ T cells in the tumor compared to IDO1KO mice challenged with IE9mp1-EV tumor cells. Moreover, tumor-derived IDO1 mediates increased CD11b+Gr1+ myeloid derived suppressor cells (MDSC) in tumor ascites.
From these data, we conclude that abrogation of IDO1 enzyme function will promote antitumor immune responses by permitting increased effector T cells decrease MDSCs in the tumor microenvironment. Ongoing experiments will characterize the mechanism by which IDO1 inhibition may augment vaccine-induced immune responses in ovarian cancer.
This abstract is also being presented as Poster A19.
Citation Format: Adaobi E. Amobi, Takemasa Tsuji, Robert McGray, Kunle Odunsi. Tumor-derived indoleamine 2,3-dioxygenase regulates density of tumor-infiltrating CD8+ T cells and myeloid-derived suppressor cells in a murine model of ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr PR04.
Abstract A06: BRCA-like phenotype as a hallmark of osteosarcoma's converging evolution
Authors: Kovac Michal , Ribi Sebastian , Blattmann Claudia , Nathrath Michaela , Baumhoer Daniel 
Published: August 2018

Abstract
Background: Osteosarcomas are aggressive bone tumors with a high degree of genetic heterogeneity, which has historically limited treatment options in patients who do not respond to standard chemotherapy.
Methods: We sequenced exomes and genomes of 32 pretherapeutic osteosarcomas, 6 time-series consisting of chemotherapy-naïve biopsies, resection specimens, recurring tumors and/or metastases, and 15 unpaired metastases from (mainly) poor responders. We then interrogated signatures of mutation processes in cancer genomes and reconciled clonal maps with phylogenetic trees, thus building an evolutionary history of each tumor. Where possible, we searched for evidence of selection acting on the tumors and hallmarks that could be therapeutically exploited.
Results: We identified pathogenic mutations in at least 14 cancer drivers, some of which were formerly unknown in the context of osteosarcoma. However, there was no single cancer driver gene that could explain the majority of cases. Instead, &gt;80% of osteosarcomas exhibited a specific combination of single-base substitutions, LOH, or large-scale genome instability characteristic of BRCA1/2-deficient tumors. The BRCA-like phenotype developed through parallel evolution by deleterious mutations affecting the BRCA1/2 genes and their binding partners such as PALB2 or CHEK2. We therefore investigated the sensitivity of a panel of osteosarcoma cell lines to the poly(ADP)-ribose polymerase inhibitor talazoparib alone and in combination with chemotherapeutic drugs. We identified an association between homologous recombination repair deficiency and the response of osteosarcoma cell lines to talazoparib. In combination with temozolomide, talazoparib led to the activation of BAX and BAK, loss of mitochondrial membrane potential, DNA fragmentation, and caspase-dependent cell death.
Conclusion: The acquisition of a BRCA-like phenotype through converging evolution has important implications for the development of novel treatment strategies in osteosarcoma using PARP inhibitors alone or together with standard chemotherapy.
Citation Format: Michal Kovac, Sebastian Ribi, Claudia Blattmann, Michaela Nathrath, Daniel Baumhoer. BRCA-like phenotype as a hallmark of osteosarcoma's converging evolution [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A06.
Abstract A11: Arginine deprivation alters global lipid metabolism in ASS1-deficient sarcomas
Authors: Kremer Jeff , Prudner Bethany , Chang Samuel , Rogers Lenny , Tine Brian Van 
Published: August 2018

Abstract
Objective: Argininosuccinate Synthetase 1 (ASS1) is silenced in ~90% of sarcomas. This deficiency in the urea cycle causes sarcomas to become dependent on extracellular arginine for continued cell growth and survival, a condition named arginine auxotrophy. Arginine starvation induced by pegylated arginine deiminase (ADI-PEG20) induces dramatic alterations in global metabolism as well as an induction of autophagy. We investigated the specific changes in the lipidome of leiomyosarcoma cell lines induced by ADI-PEG20. By examining the alterations in esterified and nonesterified fatty acid metabolism we sought to understand the changes in the lipidome that are capable of being therapeutically exploited.
Methods: The cell lines SKLMS1 and SKUT1 were treated with ADI-PEG20. Cell pellets were collected and 33 esterified and nonesterified fatty acids were measured using GC/MS. Pathway analysis was then performed. Cell lines were then treated with a combination of ADI-PEG20 and TOFA (an acetyl CoA carboxylase inhibitor) or etoxomir/perhexiline (beta-oxidation inhibitors) to determine synthetic lethality.
Results: There were clear alterations in lipid metabolism induced by arginine deprivation. The fluctuations in lipid metabolism indicated pathways susceptible to inhibition by a variety of small-molecule inhibitors, namely that arginine deprivation sensitizes to inhibition of beta-oxidation. Cell culture experiments with ADI-PEG20 and a number of different small-molecule inhibitors demonstrated synthetic lethality upon cotreatment with ADI-PEG20 and beta-oxidation inhibitors.
Conclusion: Arginine deprivation causes global changes in lipid metabolism. The changes in metabolism are capable of being targeted by small-molecule inhibitors with the result being an induction of a synthetic lethality. By understanding the changes in the lipidome induced by arginine deprivation, we are building a multiagent synthetic lethal therapy for sarcoma based on metabolism that avoids chemotherapy.
Citation Format: Jeff Kremer, Bethany Prudner, Samuel Chang, Lenny Rogers, Brian Van Tine. Arginine deprivation alters global lipid metabolism in ASS1-deficient sarcomas [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A11.
Abstract A13: Genome-wide transcriptional analysis of HDAC inhibition-induced apoptosis in synovial sarcoma
Authors: Laporte Aimee N. , Poulin Neal M. , Lorzadeh Alireza , Wang Xiu Qing , werff Ryan Vander , Barrott Jared J. , Moska Michelle , Hughes Christopher , Morin Gregg , Jones Kevin B. , Hirst Martin , Underhill T. Michael , Nielsen Torsten O. 
Published: August 2018

Abstract
Introduction: Conventional cytotoxic therapies for synovial sarcoma provide limited benefit, and no drugs specifically targeting its driving SS18-SSX fusion oncoprotein are currently available. HDAC inhibition has been shown in previous studies to disrupt the driving complex implicated in synovial sarcoma, resulting in apoptosis induction.
Methods: Transcriptome analysis was undertaken in a panel of six human synovial sarcoma cell lines in order to uncover potential mechanisms of cell death following HDAC inhibition. By comparison studies with five additional publicly available related expression datasets, common class effects resulting from HDAC inhibition were investigated. Five human synovial sarcoma tumor samples were profiled by RNA-seq for comparison. A mouse model of synovial sarcoma was treated by HDAC inhibition and tumors were profiled for apoptotic markers.
Results: Cell cycle arrest, differentiation, and response to oxygen-containing species and cell death were common biologic responses among the panel of post-HDAC inhibitor expression studies. Specific to synovial sarcoma, reactivation of repressed tumor suppressor CDKN2A and induction of proapoptotic transcriptional patterns results in apoptosis and decreased tumor burden in vivo.
Conclusion: HDAC inhibition impedes SS18-SSX-mediated transcriptional deregulation, allowing for reactivation of normal cell cycle regulatory and apoptotic pathways. This study provides mechanistic support for a particular susceptibility of synovial sarcoma to HDAC inhibition as a means of potential clinical treatment.
Citation Format: Aimee N. Laporte, Neal M. Poulin, Alireza Lorzadeh, Xiu Qing Wang, Ryan Vander werff, Jared J. Barrott, Michelle Moska, Christopher Hughes, Gregg Morin, Kevin B. Jones, Martin Hirst, T. Michael Underhill, Torsten O. Nielsen. Genome-wide transcriptional analysis of HDAC inhibition-induced apoptosis in synovial sarcoma [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A13.
Abstract A15: Modeling sporadic gastrointestinal stromal tumor with BRAFV600E mutation
Authors: Ran Leili , Murphy Devan , Sher Jessica , Cao Zhen , Wang Shangqian , Walczak Edward , Guan Youxin , Xie Yuanyuan , Shukla Shipra , Zhan Yu , Antonescu Cristina R. , Chen Yu , Chi Ping 
Published: August 2018

Abstract
Gastrointestinal stromal tumor (GIST) is the most common subtype of sarcoma, characterized by activating mutations in KIT, PDGFRA, BRAF, N/H/KRAS, and loss of function genetic/epigenetic alterations in NF1, SDH-complex. Despite clinical advances for KIT/PDGFRA-mutant GIST, the scientific and clinical advances for KIT/PDGFRA-wild type GISTs have remained extremely limited due to the lack of model systems. Due to the lack of ICC-lineage specific cre system, modeling for sporadic GIST has not been feasible. ETV1 has recently been described as an ICC and GIST-lineage specific master regulator. Here, using the cre-activated Rosa26CAGGS-LSL-EYFP system, we demonstrate that Etv1CREERT2 preferentially activates cre in the Etv1-expressing ICC lineage by tamoxifen. Using the BrafCA conditional allele for cre-activated BrafV600E, we observed that BrafV600E alone, while leading to development of ICC hyperplasia, is not sufficient to drive GIST tumorigenesis. Combination of BrafV600E activation and Trp53 loss not only gives rise to ICC hyperplasia, but also leads to multifocal GIST-like tumors in mouse GI tract with 100% penetrance. We further demonstrate that the BrafV600E; Tp53-/- sporadic GIST mouse models are amenable for therapeutic intervention and recapitulate clinical responses to RAF inhibitors in human GIST. Our observations provide the first in vivo model for understanding the pathogenesis and therapeutic responses in BRAF-mutant GISTs. Importantly, these observations provide the proof of principle for modeling sporadic GIST in adult mice using the Etv1CREERT2 system and establish the feasibility and utility of establishing model systems for human GISTs that do not have any model systems available for mechanistic studies and therapeutic development.
Citation Format: Leili Ran, Devan Murphy, Jessica Sher, Zhen Cao, Shangqian Wang, Edward Walczak, Youxin Guan, Yuanyuan Xie, Shipra Shukla, Yu Zhan, Cristina R. Antonescu, Yu Chen, Ping Chi. Modeling sporadic gastrointestinal stromal tumor with BRAFV600E mutation [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr A15.