bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B70: Targeted activation of macrophages to limit ovarian cancer progression.
Authors: Barham Whitney , Wilson Andrew , Ortega Ryan , Saskowski Jeanette , Tikhomirov Oleg , Giorgio Todd , Khabele Dineo , Yull Fiona E. 
Published: May 2016

Abstract
Macrophages are a major population in the ovarian tumor microenvironment and are capable of exhibiting either pro- or anti-tumor effects. The overall outcome of macrophage interactions with tumor cells is a balance between anti-tumor immune responses and the pro-tumor effects of re-educated tumor associated macrophages (TAMs). Our goal is to develop a treatment that will shift the balance of responses from pro- to anti-tumor resulting in significant clinical benefit. Using macrophage-specific doxycycline-inducible transgenics, IkappaBalpha -/- and wild type bone marrow derived macrophages (BMDMs), and tumor-associated macrophages (TAMs) we have generated convincing evidence both in vitro and in vivo that activating nuclear factor-kappaB (NF-κB) signaling specifically in macrophages induces anti-tumor effects by direct and indirect mechanisms. We are testing two strategies to translate this important finding into clinical usage. The first is delivery of MTP-PE via liposomes that are taken up by macrophages resulting in increased NF-κB activity. This strategy has the advantage that a similar approach is in current clinical usage for osteosarcoma therapy. However, it may prove to have some limitations based on the relatively non-specific activation of macrophages that would be induced. Therefore, our second strategy, designed to increase the specificity of response, is the development of mannosylated nanoparticles that mediate delivery of siRNA specifically to a subset of macrophages, namely the mannose receptor expressing TAMs. We have investigated multiple siRNAs capable of modulating the NF-κB signaling pathways and have evidence that delivery of IκBα siRNA results in beneficial changes in the expression of target genes in macrophages to generate antitumor outcomes. We have promising data using a model of ovarian cancer progression in which ID8 tumor cells are introduced into the peritoneal cavity that supports our therapeutic concept. While further optimization will be necessary, we believe that these treatments have the potential to be used alone or, due to the induction of both direct tumor cytotoxic and immune stimulatory effects, could be used in combination with standard chemotherapy to improve responses of treatment resistant tumors or with T cell mediated therapy to improve outcomes via increased recruitment of T cells.
Citation Format: Whitney Barham, Andrew Wilson, Ryan Ortega, Jeanette Saskowski, Oleg Tikhomirov, Todd Giorgio, Dineo Khabele, Fiona E. Yull. Targeted activation of macrophages to limit ovarian cancer progression. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B70.
Abstract B76: Involuntary weight loss is an independent prognostic factor for overall survival and predicts better response to chemotherapy in high-grade serous ovarian cancer patients.
Authors: Sznurkowski J. Jan , Pawlowski Maciej , Kabata Pawel 
Published: May 2016

Abstract
High-grade serous ovarian cancer (HGSOC) is the most common and very aggressive histological type of this neoplasm. Most of the patients require platinum-based chemotherapy following primary surgical treatment.
Aim: to assess the prognostic value of involuntary weight loss between surgery and first cycle of chemotherapy.
Material and methods: Out of 73 patients surgically treated for HGSOC, 64 received adjuvant chemotherapy. Prognostic value of several clinico-pathological features was assessed, including change of body weight between the day of primary debulking surgery and 1st cycle of chemotherapy. Survival analyses included the Kaplan–Meier method, log-rank test and Cox proportional hazards model.
Results: The median follow-up was 47.25 months (range 17–79 months). Median change of body weight in the group of 64 patients who received chemotherapy was -3.5 kg (range from -33kg to +5kg). Higher weight loss values (median -5 kg, range: -1 to -33 kg) were observed in platinum-resistant patients (n=21) compared to platinum-sensitive ones (n=43) (median -3.5 kg, range: -5 to -14 kg) (p= 0.03). Weight loss between primary surgery and first cycle of chemotherapy was found to be independent prognostic factor for decreased OS (HR=3.8, CI 95%= 1.15-12.53, p=0.0285) and PFS (HR= 3.07; CI 95%= 1.28-7.38; p= 0.0123).
Conclusions: Prevention of weight loss and nutritional wasting in HGSOC patients planned for adjuvant chemotherapy might improve results of treatment. Further prospective trials on nutrition of this group of patients are needed.
Citation Format: J. Jan Sznurkowski, Maciej Pawlowski, Pawel Kabata. Involuntary weight loss is an independent prognostic factor for overall survival and predicts better response to chemotherapy in high-grade serous ovarian cancer patients. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr B76.
Abstract IA06: Regulation of BRCA1- and BRCA2-dependent DNA repair.
Authors: Durocher Daniel 
Published: May 2016

Abstract
High-grade serous epithelial ovarian cancers are strongly associated with defective homologous recombination (HR), a DNA repair pathway involved in the mending of DNA double-strand breaks (DSB) and in which the BRCA1, PALB2 and BRCA2 tumor suppressors play key roles. In late December last year, the first poly(ADP-ribose) polymerase (PARP) inhibitor, lynparza or olaparib as it is widely known was approved in Europe and in the US for the treatment of ovarian cancer in tumors with deleterious mutations in the BRCA1 and BRCA2 genes. The approval of olaparib marks a milestone in the development of targeted cancer therapies, as it is the first approved drug that is based on the concept of synthetic lethality. In my presentation, I will report the identification of a system that licenses the assembly of a BRCA1-PALB2-BRCA2 complex in the S and G2 phases of the cell cycle. This system plays a major role in restricting the activation of DNA repair by HR to these cell cycle phases and I will discuss the implication of this newly discovered regulatory pathway to our understanding of genome maintenance and PARP inhibitor therapy.
Citation Format: Daniel Durocher. Regulation of BRCA1- and BRCA2-dependent DNA repair. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA06.
Abstract IA12: Determinants of resistance and response in high-grade serous ovarian cancer.
Authors: Bowtell David D. L. 
Published: May 2016

Abstract
In contrast to other solid cancers, overall survival for patients with high-grade serous ovarian cancer (HGSC) is little changed over the last 30 years and it has been difficult to advance beyond platinum-based combination chemotherapy. As HGSC are driven by genomic copy number change rather than recurrent point mutation, we undertook whole genome sequence (WGS) analysis of a large HGSC cohort in order to survey structural variation at high resolution. Utilizing 114 tumors from 92 patients, we performed transcriptome, methylation, and miRNA expression analyses to support the WGS data, and compared resistant, refractory, and sensitive primary disease. We evaluated tumor and normal DNA samples from patients with primary refractory, primary resistant or primary sensitive disease to better understand the drivers of these clinical phenotypes. We also characterized paired pre-treatment chemosensitive and post-resistance samples, and end-stage HGSC obtained from patients who underwent a research autopsy. We found that gene breakage involving tumor suppressors such as NF1 and RB1 is a common form of inactivation in HGSC and in other circumstances contributes to acquired chemotherapy resistance in some patients. We found evidence of a chemotherapy footprint in the genome of recurrent tumor samples. We observed a striking degree of diversity of other mechanisms of acquired resistance, including multiple independent germline BRCA1 or BRCA2 reversion events in individual patients, loss of BRCA1 promoter methylation, a shift in molecular subtype to a desmoplastic phenotype, and a recurrent promoter fusion associated with overexpression of a driver of drug resistance, validated in an independent dataset. Collectively these findings underscore the plasticity of the HGSC genome and indicate that pre-empting resistance by modifying current first line therapy or countering it when it emerges will require a diversity of approaches.
Citation Format: David D. L. Bowtell. Determinants of resistance and response in high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA12.
Abstract IA21: Mutant p53 activities in tumor development.
Authors: Lozano Guillermina 
Published: May 2016

Abstract
Alterations in the p53 tumor suppressor gene stand out as the most common alteration in many cancers including 96% of ovarian serous carcinoma. The fact that most p53 alterations in tumors are missense mutations suggests that cells expressing mutant p53 have an inherent biologic advantage (often termed gain of function (GOF)) over tumors lacking p53. Mouse models directly examined the role of p53 mutants in tumorigenesis and show an increased invasiveness and aggressive nature of mutant p53 tumors as opposed to those lacking p53. An additional prerequisite for GOF is the stabilization of mutant p53 proteins by various signaling pathways. The emerging themes by which mutant p53 exhibits its gain of function are 1) through formation of mutant p53 complexes with other proteins that modify their activities (p63 and p73, for example), and 2) by interaction of mutant p53 with other transcription factors (SREBP and Ets2, for example) that bring a potent transcriptional activation domain to promoters not normally regulated by wild type p53. An understanding of the mechanisms that drive mutant p53 activities in ovarian serous carcinoma is needed.
Citation Format: Guillermina Lozano. Mutant p53 activities in tumor development. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr IA21.
Abstract PR07: Synchronous ovarian and endometrial carcinomas: The case for pseudo-metastasis.
Authors: Anglesio Michael S. , Wang Yi Kan , Maassen Madlen , Horlings Hugo M. , Bashashati Ali , Gilks Blake , Kommoss Stefan , Huntsman David G. 
Published: May 2016

Abstract
Background: Almost half of ovarian endometrioid histotype carcinomas present with concurrent endometrial carcinoma or pre-cancerous lesions. These “synchronous” ovarian and endometrial (SEO) tumors, when organ-confined and low-grade, consistently behave as two independent primary tumors, rather than a tumor-metastasis pair typical of advanced-stage carcinoma. Our study aims to investigate the ancestral relationship between ovarian and endometrial components of SEOs.
Methods: We identified a cohort of SEOs and performed targeted, with the Illumina Truseq Custom Amplicon assay, and exome-level, with Nugen Ovation Library System and Agilent SureSelect XT2 capture, library construction followed by massively parallel sequencing on illumina MiSeq or HiSeq.
Results: Despite complexities introduced as a result of sampling formalin fixed and paraffin embedded archival specimens we were able to confirm shared identical mutations, and thus a clonal relationship, between ovarian and endometrial tumors in all but one case.
Discussion: In simultaneous presentation of cancer of the endometrium and ovary from our series we observed strong evidence of a primary tumor and metastasis relationship. However, the clinical behavior of this series, and SEOs in general, defies the basic tenant of cancer metastasis as a dire prognosis. Curiously similar anomalies, where there is advanced stage yet favorable outcome, occur in other organ systems. We therefore suggest a generalizable process “pseudo-metastasis” through which cells can spread to microenvironment-compatible and physically accessible sites. This restricted metastatic process can occur in cells that lack the full complement of cancer-associated transformation hallmarks required for tissue invasion and hematogenous or lymphatic metastasis. This phenomenon may be an important early step in dissemination of apparent multi-focal benign lesions, pre-malignant lesions, and low-grade carcinomas.
This abstract is also presented as Poster B07.
Citation Format: Michael S. Anglesio, Yi Kan Wang, Madlen Maassen, Hugo M. Horlings, Ali Bashashati, Blake Gilks, Stefan Kommoss, David G. Huntsman. Synchronous ovarian and endometrial carcinomas: The case for pseudo-metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr PR07.
Abstract 07: Using copy number alterations to identify targeted therapies in a preclinical model of osteosarcoma
Authors: Breese Marcus R. , Sayles Leanne C. , Sweet-Cordero Alejandro 
Published: May 2016

Abstract
Osteosarcoma (OS) is an aggressive bone malignancy affecting approximately 400 pediatric patients in the United States annually. Compared with other pediatric cancers, OS has a low 5-year overall survival rate. There are few treatment options for patients that progress on standard therapy, making it important to identify new therapeutic targets for these high-risk patients. At the genomic level, OS is characterized by significant genomic instability, resulting in numerous copy number alterations (CNA) and structural variations (SV). Unfortunately, many of the CNAs and SV events are non-recurrent, making each disease highly patient-specific. We hypothesized that CNAs may be drivers of OS and that we could use patient-specific CNA profiles to identify actionable targets in OS. In order to test this in a preclinical setting, we have developed a robust program for generating and maintaining patient-derived xenografts (PDX) from patients with OS. In a pilot study of 3 patients, we used a combination of tumor/normal whole-genome sequencing (WGS) and commercial gene panel testing to identify potentially druggable targets using CNA. For samples tested with WGS, gene-level CNA was assessed for a number of clinically actionable genes. For each gene, CNA was determined using the normalized ratio of sequencing reads mapped to the gene in the tumor versus the normal sample. The degree of CNA was used to help prioritize potential targets. For the commercially tested samples, genes were either reported as amplified or not. Using these results to inform target selection, we treated each PDX with a drug matched to its corresponding CNA predicted target. In each sample, we saw a significant reduction in the growth rate of the PDX compared to vehicle or a non-matched drug. This suggests that using the patient-specific CNAs to identify drug targets may be an effective strategy in the treatment of OS.
Citation Format: Marcus R. Breese, Leanne C. Sayles, Alejandro Sweet-Cordero. Using copy number alterations to identify targeted therapies in a preclinical model of osteosarcoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 07.
Abstract 29: Concordance of somatic mutations found in primary tumors and plasma circulating-free DNA from early and late-stage colorectal cancer patients
Authors: Bray Steven M. , Ebert Philip J. , Calley John N. , Higgs Richard E. , Wulur Isabella H. , Wong Swee Seong , Horn Candice L. , Martinez Ricardo , Reinhard Christoph 
Published: May 2016

Abstract
Circulating-free DNA (cfDNA) holds great potential for non-invasive somatic mutation detection in cancer patients as a so-called “liquid biopsy”. A liquid biopsy is especially valuable when tumor tissue is not available and for longitudinal monitoring of tumor burden or emerging resistance. In such cases, tumor-specific mutations are not known a priori and in order to detect tumor-derived somatic mutations it is best to interrogate a broad panel of cancer genes. The primary obstacle to sequencing cfDNA with broad mutation panels is achieving the necessary limit of detection to identify small amounts of tumor-derived cfDNA relative to the predominant wild-type cfDNA in the plasma of cancer patients. Tumor-derived cfDNA levels correlate with tumor stage, also making it an important consideration when investigating the sensitivity of this approach. We demonstrate the detection of somatic variants in several cancer genes in the plasma of early and late-stage colorectal cancer (CRC) patients by deep sequencing (&gt; 8,000X) the cfDNA and matched normal DNA of N=33 CRC patients using the AmpliSeq cancer panel. The AmpliSeq panel requires less than 10ng of input DNA and amplifies hotspot loci of 50 known cancer genes for next-generation sequencing (NGS). We observe at least one somatic mutation with greater than 0.1% variant allele frequency in the cfDNA of all 33 CRC patients. We also show the sensitivity of detecting tumor-derived somatic mutations in cfDNA by exome sequencing of the primary tumor tissue. We find higher sensitivity for tumor mutations in cfDNA of late-stage patients compared to early-stage patients. Overall, we demonstrate the feasibility of using NGS on a small sized cancer panel for identifying somatic mutations, including those with low variant allele frequency, in cfDNA of early and late-stage CRC patients. Although a cfDNA approach holds promise as a tool to aid in pre-clinical and clinical research, more work is needed to understand its performance under different assay and disease conditions.
Citation Format: Steven M. Bray, Philip J. Ebert, John N. Calley, Richard E. Higgs, Isabella H. Wulur, Swee Seong Wong, Candice L. Horn, Ricardo Martinez, Christoph Reinhard. Concordance of somatic mutations found in primary tumors and plasma circulating-free DNA from early and late-stage colorectal cancer patients. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 29.
Abstract 37: AKT1 activation promotes brain metastasis in a mouse model of melanoma
Authors: Kircher David , Cho Joseph , Robinson James , Arave Rowan , Green Russell , Chen Guo , Davies Michael , Grossmann Allie , VanBrocklin Matthew , McMahon Martin , Holmen Sheri 
Published: May 2016

Abstract
Brain metastases are a major cause of melanoma-related mortality and morbidity. The molecular mechanisms driving melanoma to the brain remain largely unclear, adding to the difficulties in both treating and prognosticating risk for this disease complication. One of the great barriers impeding the study of melanoma brain metastasis is the lack of an in vivo model that faithfully mimics the human disease. Based on previous studies implicating aberrant AKT signaling in human melanoma brain metastases, we evaluated the effect of activated AKT1 expression in non-metastatic BRAFV600E/INK4A-ARFNull mouse melanomas in vivo. Expression of activated AKT1 in this context resulted in highly metastatic melanomas with lung and brain metastases in 67% and 17% of our mice, respectively. Surprisingly, silencing of PTEN in BRAFV600E/INK4A-ARFNull melanomas did not yield a statistically significant metastatic phenotype but in combination with activated AKT1 resulted in decreased tumor latency and development of brain metastases in nearly 80% of tumor-bearing mice. Furthermore, we found evidence of increased mTOR signaling in BRAFV600E/INK4A-ARFNull mouse melanomas expressing activated AKT1 relative to PTEN-null counterparts. This study advances the field of melanoma brain metastasis by (1) providing the first in vivo, autochthonous model of melanoma with spontaneous metastasis to the lungs and brain, (2) demonstrating that expression of activated AKT1 is sufficient to elicit brain metastasis in BRAFV600E/INK4A-ARFNull mouse melanomas and (3) revealing distinct differences and cooperation between AKT1 activation and PTEN silencing in metastatic melanoma progression. In summary, this work advances our knowledge of the mechanisms driving melanoma brain metastasis and may provide valuable insights for the clinical management of this disease.
Citation Format: David Kircher, Joseph Cho, James Robinson, Rowan Arave, Russell Green, Guo Chen, Michael Davies, Allie Grossmann, Matthew VanBrocklin, Martin McMahon, Sheri Holmen. AKT1 activation promotes brain metastasis in a mouse model of melanoma. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 37.
Abstract 39: Association of single nucleotide polymorphisms (SNPs) in STS and SULT2B1 and response to androgen deprivation therapy (ADT) in men with advanced hormone sensitive prostate cancer (aHSPC)
Authors: Agarwal Neeraj , Buckley Tyler , Farnham James , Patel Shiven B. , Agarwal Archana , Tantravahi Srinivas , Teerlink Craig , Albright Frederick S. , Stephenson Robert A. , Alex Anitha , Cannon-Albright Lisa 
Published: May 2016

Abstract
Background: Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict time to response to androgen deprivation therapy (ADT) in aHSPC, serve as prognostic and predictive biomarkers, and guide towards more individualized upfront therapy.
Methods: 795 single nucleotide polymorphisms (SNPs) from the Illumina OmniExpress genotyping platform within the boundaries of 60 genes reported to be involved in the androgen metabolic pathway were investigated for association with time to onset of castration resistance prostate cancer (CRPC) in 118 Caucasian men with aHSPC, i.e. those progressing after definitive treatment, undergoing treatment with ADT. Cox proportional hazard analysis was employed using Gleason score as a covariate and assessing each SNP under an additive genetic model in which the number of minor alleles contributes increasing risk (or protection).
Results: Three SNPs in STS (steroid sulfatase gene), and three SNPs in SULT2B1 (sulfotransferase 2B1 gene) were significantly associated with time to CRPC on ADT while controlling for Gleason Score (p &lt; .005).
Conclusions: SNPs in STS and SULT2B1 significantly associated with time to CRPC on ADT in aHSPC, and may serve as predictive markers to ADT in this setting. Data are being validated in a larger cohort.
Citation Format: Neeraj Agarwal, Tyler Buckley, James Farnham, Shiven B. Patel, Archana Agarwal, Srinivas Tantravahi, Craig Teerlink, Frederick S. Albright, Robert A. Stephenson, Anitha Alex, Lisa Cannon-Albright. Association of single nucleotide polymorphisms (SNPs) in STS and SULT2B1 and response to androgen deprivation therapy (ADT) in men with advanced hormone sensitive prostate cancer (aHSPC). [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 39.