bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 39: Discovery of PEN-221, an SSTR2-targeting maytansinoid conjugate with potent activity in vitro and in vivo
Authors: White Brian H. , Bazinet Patrick , Whalen Kerry , DuPont Michelle , Quinn James M. , Alargova Rossitza , Yeung Tsun Au , Brockman Adam , Gifford James , Oller Haley , Kriksciukaite Kristina , Lemelin Charles-Andre , Soo Patrick Lim , Moreau Benoit , Perino Samantha , Sharma Gitanjali , Shinde Rajesh , Sweryda-Krawiec Beata , Simcox Mary , Wooster Richard , Bilodeau Mark T. 
Published: July 2017

Abstract
Here we describe the discovery and the structure of PEN-221, a somatostatin receptor 2 (SSTR2) targeting peptide conjugated to DM1. PEN-221 is the first clinical compound from Tarveda’s Pentarin platform, which utilizes miniaturized drug conjugates that diffuse rapidly and deeply into solid tumors. Antibody drug conjugates (ADCs) have garnered a significant amount of attention in their ability to direct cytotoxic drugs to cancer cells; however, the efficacy of ADCs in solid tumors is limited by the slow diffusion of such large molecules through solid tumor tissue. Pentarins are designed to improve the efficacy of targeted therapies through effective tumor cell targeting and enhanced tumor penetration.
SSTR2, a GPCR overexpressed in multiple types of neuroendocrine tumors, including small cell lung cancers, internalizes rapidly upon agonist stimulation, making it an ideal vector for delivering cytotoxic payloads. Examination of a variety of SSTR2 targeting ligands, as well as several potential conjugation sites, led to the identification of the C-terminal side chain of [Tyr3]-octreotate amide as the best conjugation site for a lipophilic payload. The use of DM1 as a payload afforded superior receptor affinity and receptor internalization when compared to other similarly potent microtubule-targeting agents. In vitro studies show that PEN-221 has receptor-dependent cytotoxic effects, and preclinical studies demonstrate PEN-221 induces tumor regression in several SSTR2 expressing xenograft models.
Citation Format: Brian H. White, Patrick Bazinet, Kerry Whalen, Michelle DuPont, James M. Quinn, Rossitza Alargova, Tsun Au Yeung, Adam Brockman, James Gifford, Haley Oller, Kristina Kriksciukaite, Charles-Andre Lemelin, Patrick Lim Soo, Benoit Moreau, Samantha Perino, Gitanjali Sharma, Rajesh Shinde, Beata Sweryda-Krawiec, Mary Simcox, Richard Wooster, Mark T. Bilodeau. Discovery of PEN-221, an SSTR2-targeting maytansinoid conjugate with potent activity in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 39. doi:10.1158/1538-7445.AM2017-39
Abstract 390: Identification and characterization of survival-associated genomic features across tumor types
Authors: Smith Joan , Lin Ann , Giuliano Chris , Sheltzer Jason M. 
Published: July 2017

Abstract
The basic biology that differentiates a primary cell from a transformed cell has been elucidated over the past several decades. Mutations in a limited number of oncogenes and tumor suppressors free the cell from growth-inhibitory checkpoints and allow proliferation in the absence of external stimuli, leading to tumor formation. Yet, primary tumors themselves are rarely deadly: greater than 90% of cancer mortality results from metastasis. What drives metastasis, and, more broadly, what distinguishes a lethal cancer from one with a favorable prognosis, is poorly understood.
To address this question, we have performed a comprehensive meta-analysis on genomic data from primary tumors that are linked to patients’ clinical outcomes. Utiliizing data from &gt;20,000 patients, we have identified protein-coding genes, lncRNAs, miRNAs, methylation sites, and CNVs in primary tumors that are significantly associated with patient prognosis across cancer types. Multivariate analysis reveals a hierarchy of survival determinants: the strongest mortality-associated factors are enriched for components of the mitotic cell cycle, while secondary clusters of genes are involved in extracellular matrix remodeling, cell motility, and angiogenesis. Survival-associated genomic features are indicative of immune infiltration into primary tumors and oxidative phosphorylation activity.
In vitro and in vivo analyses reveal that mortality-associated genes rarely promote the direct transformation of primary cells. Instead, CRISPR mutagenesis reveals that these genes largely represent tumor dependencies, and in their absence cancer cells fail to proliferate. Through this analysis, we have identified new genetic dependencies common across cancer cells, including C16ORF59 and C5ORF46. In total, our results represent the largest assessment of genomic features linked to cancer prognosis completed to date, and offer several lines of insight into the biological differences between fatal and benign cancers.
Note: This abstract was not presented at the meeting.
Citation Format: Joan Smith, Ann Lin, Chris Giuliano, Jason M. Sheltzer. Identification and characterization of survival-associated genomic features across tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 390. doi:10.1158/1538-7445.AM2017-390
Abstract 3904: Inhibition of the ERK5 pathway as a novel approach to target human chronic myeloid leukemia stem cells
Authors: Tusa Ignazia , Cheloni Giulia , Gray Nathanael , Gozzini Antonella , Sbarba Persio Dello , Rovida Elisabetta 
Published: July 2017

Abstract
Tyrosine kinase inhibitors (TKi) targeting BCR/ABL are very effective for the treatment of Chronic Myeloid Leukaemia (CML). However, resistance mechanisms or their inefficacy on CML leukaemia stem cells (LSC) may lead to relapse. Therefore, there is urgent need to identify new molecular targets. The Extracellular signal-Regulated Kinase 5 (ERK5) is a Mitogen-Activated Protein Kinase involved in cancer. Our aim was to study a possible role of the ERK5 pathway in CML LSC.
Cells used were: human CML cell lines K562 and KCL22 that express constitutively active ERK5; CML patient-derived cells and CD34+ cells from heathy donors (after informed consent had been obtained). Cells were incubated in normoxic (routine) or hypoxic (0.2% O2) primary cultures (LC1) in the presence or the absence of drugs. Day-7 LC1 cells were transferred to drug-free, non-selective normoxic secondary cultures (LC2), to measure LC2 repopulation as a read-out of progenitor/stem cell potential (CRA assay). Compounds: XMD8-92 (ERK5 inhibitor) and BIX02189 (MEK5 inhibitor); imatinib (BCR/ABL inhibitor, IM).
We previously showed that stem cell potential of CML LSC is maintained in severe hypoxia. In K562 and KCL22 cells and in primary cells derived from 9 CML patients, the treatment in hypoxic LC1 with XMD8-92 or BIX02189, but not with IM, impaired progenitor/stem cell potential. The same results were obtained by combined treatment of XMD892 with IM. Importantly, XMD8-92 did not affect progenitor/stem cell potential of CD34+ cells from heathy donors. In colony formation ability assays ERK5 inhibition decreased colony formation by human primary CML cells to a higher extent than that by normal human CD34+ hematopoietic cells. Interestingly, in hypoxia, combined treatment XMD8-92/IM decreased the expression of genes relevant for stem cell maintenance such as p21, nanog and c-myc and the expression of CD26, a CML LSC marker. Moreover, combined XMD8-
92/IM maintained low the expression of p27, another gene involved in stem cell maintenance, that is increased by either drug when administered alone.
This indicate that the ERK5 pathway inhibitors impaired LSC maintenance of CML cell lines and primary CML cells.
Citation Format: Ignazia Tusa, Giulia Cheloni, Nathanael Gray, Antonella Gozzini, Persio Dello Sbarba, Elisabetta Rovida. Inhibition of the ERK5 pathway as a novel approach to target human chronic myeloid leukemia stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3904. doi:10.1158/1538-7445.AM2017-3904
Abstract 391: A comparative genomics approach to understanding the control of cell context dependent P53 binding
Authors: Sundaresan Varsha , Li Ying , DiCiaccio Benedetto , Lin Victor T. , Zhou Lei 
Published: July 2017

Abstract
Cancer is considered to be a genetic disease characterized by sequential accumulation of mutations. Recent studies have provided evidence that epigenetic changes and regulatory sequence mutations could also dysregulate oncogenes and tumor suppressors. As a transcription factor, P53 is activated in response to oncogenic stress and exerts distinct anti-proliferative functions based on the stressor and cell type. Though a number of ChIP-Seq studies have identified thousands of P53 binding sites in mammalian genomes, the functionality of these binding sites remains to be established. In addition, we know little about what controls stress and cell context specific binding profile of P53.
Traditionally, mutations in the coding regions of p53 have been extensively studied to gain insights on its role in cancer and to identify strategies to restore the functions of p53 in cancer cells. We hypothesize that mutations in or epigenetic silencing of functionally important P53 binding sites play an important role in tumorigenesis as well. Since functional regulatory regions tend to be more evolutionarily conserved, in this project we propose using a comparative genomics approach to identify functional P53 binding sites and determine if these regions are involved in tumorigenesis.
In order to study how P53 binding following DNA damage differs between cell types, we aim to perform comparison between P53 ChIP-Seq data generated in our lab from Drosophila embryos at different developmental stages and a cell line (Kc167) as well as published datasets from mammalian stem cells and differentiated cells. Differential expression analysis using RNA-Seq exhibited that at an early stem cell-like stage there is P53-dependent induction of pro-apoptotic genes in response to DNA damage but not in the differentiated stages. We are seeking to establish functionally significant P53 binding sites by combining ChIP-Seq data and gene expression data obtained using RNA-Seq. The importance of these binding sites will be verified by CRISPR-Cas9 -mediated genome editing. We will also perform comparison studies of DNA damage-induced P53 binding in human, mouse and Drosophila to identify analogous patterns.
Knowledge gained from this study will help us to understand the role of non-coding regulatory regions in tumorigenesis, and predict patient response to apoptosis inducing therapeutic agents. It may also lead to novel strategies to restore cellular sensitivity to chemotherapy or radiation.
Citation Format: Varsha Sundaresan, Ying Li, Benedetto DiCiaccio, Victor T. Lin, Lei Zhou. A comparative genomics approach to understanding the control of cell context dependent P53 binding [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 391. doi:10.1158/1538-7445.AM2017-391
Abstract 392: Application of somatic mutation-based expression profiles for high-throughput phenotyping in cancer
Authors: Varn Frederick S. , Wang Yue , Cheng Chao 
Published: July 2017

Abstract
Somatic mutations have been heavily implicated in initiating and driving cancer growth and metastasis. These alterations serve as upstream events that have broad transcriptional effects by altering protein structure and function and interfering with signaling pathways. Here, we apply an iterative approach that utilizes patient gene expression profiles to define mutation-associated transcriptomic signatures. We use these signatures to quantify the level at which a given somatic mutation affects its gene’s downstream activities. Using TP53 in breast cancer as an example, we show that while TP53 mutations are the primary predictor of altered p53 activity, events such as copy number alterations and methylation changes may represent alternative routes to high p53 disruption. Conversely, we identify a class of TP53 mutations that have minimal downstream transcriptomic effects. By expanding this approach to other genes and tumor types, we show that mutation signatures derived from different tissue types exhibit varying levels of conservation, suggesting a degree of tissue-specificity in the downstream effects of somatic mutations. To provide functional context to our results, we examine the associations between different mutation signatures and various cancer-related features, including patient survival, immune infiltration, and pathway activity. Together, our results indicate the utility of using patient gene expression profiles to study mutation function. Going forward, these results may be useful in functionally annotating variants of unknown significance and broadening the potential of precision medicine-based therapeutic approaches.
Citation Format: Frederick S. Varn, Yue Wang, Chao Cheng. Application of somatic mutation-based expression profiles for high-throughput phenotyping in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 392. doi:10.1158/1538-7445.AM2017-392
Abstract 3920: Tumor volume as a predictor of lymph node metastases in prostate cancer
Authors: Molokwu Chidi N. , Yuen Keith , Addla Sanjay , Singh Rajindra , Chahal Rohit 
Published: July 2017

Abstract
Introduction: Pelvic lymph node dissection (PLND) is recommended during radical prostatectomy (RP) in patients with high risk prostate cancer (PCa). Guidelines recommend extended PLND in patients who have &gt;5% probability of lymph node involvement, calculated from pre-operative parameters. PLND increases procedure time and potential morbidity to patients. Tumour size has been reported to be predictive of biochemical recurrence after RP. We analysed the utility of several parameters including tumour size in predicting lymph node metastases in order to further refine the population who require PLND during RP.
Materials & Methods: We maintained a prospective database of Robotic Assisted Radical Prostatectomy (RARP) from July 2012 to August 2016 consisting of a cohort of 531 patients. Patients with &gt;5% calculated probability of lymph node metastasis had PLND during RARP. We performed multiple linear regression using age, PSA, D’Amico risk score, ISUP prognostic group, clinical T-stage, radiological T-stage, tumour volume, tumour volume relative to prostate size (relative tumour volume), and number of nodes excised during PLND to determine if any of these parameters could predict the presence of lymph node metastases.
Results: Of the cohort of 531 patients, 154 had PLND during RARP. Of the PLND cohort, 15 (10%) had pN1 disease. Tumour volume (r2 0.044, p= 0.0098), relative tumour volume (r2 0.033, p=0.026) and number of lymph nodes excised (r2 0.046, p=0.0075) were independent predictors of pN1 disease. D’Amico risk score (r2 0.019, p=0.089) approached but did not reach statistical significance. Patients with pN1 disease all had primary tumours ≥6cc.
Conclusions: In our cohort of PLND patients, tumour volume was an independent risk factor for pN1 disease. With the increasing availability of multi-parametric MRI, tumour volume can be measured pre-operatively as an adjunct to PIRADS scoring. The role of tumour volume and relative tumour volume in predicting lymph node metastasis in conjunction with other pre-operative parameters requires further investigation. The use of tumour volume in determining the need for PLND in patients undergoing RP may help to further refine the population at highest risk for pN1 disease and avoid the additional morbidity of PLND in those at low risk. In addition, our findings support the recommendation of performing an extended PLND to maximise regional lymph node clearance.
Citation Format: Chidi N. Molokwu, Keith Yuen, Sanjay Addla, Rajindra Singh, Rohit Chahal. Tumor volume as a predictor of lymph node metastases in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3920. doi:10.1158/1538-7445.AM2017-3920
Abstract 3926: Is FGD3 a potentially prognostic marker for breast cancer
Authors: Sun Yuliang , Willis Scooter , Lin Xiaoqian , Achua Justin , Williams Casey , Leyland-Jones Brian 
Published: July 2017

Abstract
Background: Prognostic factors are capable of providing information on clinical outcomes at the time of diagnosis; they are usually indicators of growth, invasion, and metastatic potential (Gasparini G. et al. 1993; Hayes DF. et al. 1998). Tissue marker is one of the prognostic factors; to date, only a small proportion of markers are ultimately clinically useful, including Ki-67 and HER2. Faciogenital dysplasia 3 protein (FGD3), a putative regulator of cell morphology and motility, has been shown to regulate cell migration. In a study of 3,256 tumors, low expression of FGD3 mRNA indicates poor outcome (Hayakawa M. et al. 2008; Scooter W. et al. 2014). However, an immunohistochemistry (IHC) study to evaluate FGD3 protein expression has not been done. We hypothesize that the expression levels of FGD3 protein by IHC might improve the prediction of patient outcomes, and FGD3 might be a potentially prognostic marker of breast cancer.
Materials and Methods: 322 cases of breast cancer Tissue Microarrays (TMA) (BR1504a, BR1505b, HBre-Duc068Bch-01, and BR20837) were purchased from US Biomax, Inc (Rockville, MD). Rabbit polyclonal antibody against FGD3 was purchased from Novus Biologicals, LLC (Littleton, CO). Tissue cores were stained for FGD3 with Dako’s EnVision + Dual Link System. Image acquisition was performed using an Olympus camera and software. FGD3 protein expression by IHC was quantitatively determined in the range of 0-4. Unpaired t-test was used for data analyses.
Results: 1) Benign tumor and breast adenocarcinomas in lower stages showed strong expression of FGD3, whereas the breast adenocarcinomas in higher stages showed mild ~ weak expression. 2) Invasive breast cancer in stage IIA showed strong FGD3 expression compared to matched metastatic carcinoma which showed mild expression of FGD3. 3) FGD3 protein levels for tumors (n=135) with N0 indicating no regional lymph node metastasis were compared with tumors with lymph node metastasis (N1-3; n=98) and corresponding matched metastatic tissue (n=103). An unpaired t-test comparing N0 vs. N1-3 showed lymph node metastasis is associated with lower FGD3 protein levels (p&lt;0.0001).
Conclusion: FGD3 protein expression levels within breast tumors were different according to metastatic status. Our IHC results suggest the possibility of FGD3 to be a prognostic marker in patients with breast cancer.
Citation Format: Yuliang Sun, Scooter Willis, Xiaoqian Lin, Justin Achua, Casey Williams, Brian Leyland-Jones. Is FGD3 a potentially prognostic marker for breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3926. doi:10.1158/1538-7445.AM2017-3926
Abstract 3927: Programmed cell death ligand 1 expression in resected colorectal adenocarcinomas: association with micrometastasis
Authors: Hwang Ilseon , Park Keon Uk , Kim Jin Young , Ryoo Hun-Mo , Lee Yun-Han 
Published: July 2017

Abstract
Background: Programmed cell death 1 (PD-1) and its ligand (PD-L1) are key suppressors of the cytotoxic immune response. PD-L1 expression on tumor cells may be induced by the immune microenvironment, resulting in immune escape, and an adverse prognosis in many malignancies. In colorectal carcinoma the response to PD-1/PD-L1 inhibition is correlated with microsatellite instability. However, little is known about the clinicopathologic, molecular, and prognostic characteristics of colorectal carcinoma with PD-L1 expression.
In surgically resected colorectal adenocarcinoma, micrometastasis should be crucial for recurrence, and micrometastasis may be related to PD-L1. The aim of this study is to assess the PD-L1 expression and its association with clinicopathologic manifestations.
Methods: PD-L1 expression was evaluated in 176 resected colorectal adenocarcinomas using tissue microarrays. Immunohistochemical staining was performed to evaluate the expression of PD-L1. The relationship of clinicopathologic manifestations and PD-L1 expression in colorectal cancer were evaluated by chi-squared test, Kaplan-Meier survival and Cox regression test.
Results: High PD-L1 expression was present in 52.8% colorectal adenocarcinoma and was not related pathologic T or N stage. High PD-L1 expression was associated with decreased recurrence rate (p &lt; 0.001), better disease-free survival (p &lt; 0.001). Cox regression analysis revealed that pathologic N stage and High PD-L1 expression was an independent prognostic factors of disease-free survival (p &lt; 0.001).
Conclusion: High PD-L1 expression is an independent prognostic factor, such as pathologic stage in colorectal adenocarcinoma. PD-L1 expression is independent prognostic factor, relating immune response to micrometastasis and immune suppression by PD-L1 may not be effective in micrometastasis of colorectal adenocarcinoma.
Key words: PD-L1, colon, cancer, immunology, micrometastasis
Citation Format: Ilseon Hwang, Keon Uk Park, Jin Young Kim, Hun-Mo Ryoo, Yun-Han Lee. Programmed cell death ligand 1 expression in resected colorectal adenocarcinomas: association with micrometastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3927. doi:10.1158/1538-7445.AM2017-3927