bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B11: The early autophagy inhibitor verteporfin moderately enhances the antitumor activity of gemcitabine in a pancreatic ductal adenocarcinoma model
Authors: Donohue Elizabeth , Thomas Anitha , Maurer Norbert , Manisali Irina , Zeisser-Labouebe Magali , Zisman Natalia , Anderson Hilary J. , Webb Murray , Bally Marcel , Roberge Michel 
Published: August 2014

Abstract
Autophagy, a cellular self-eating process that is activated by several cancer drugs and appears to function as a protective mechanism, is a promising therapeutic target. Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to chemotherapy, and has been described as requiring elevated autophagy for growth. To date, all preclinical reports and clinical trials investigating pharmacological inhibition of autophagy have used chloroquine or hydroxychloroquine, which block autophagy at a late stage. Verteporfin is a newly discovered autophagy inhibitor that blocks autophagy at an early stage by inhibiting autophagosome formation. Here, we report that PDAC cell lines show variable sensitivity to verteporfin in vitro and that verteporfin inhibits autophagy stimulated by gemcitabine, the current standard treatment for PDAC. Pharmacokinetic and efficacy studies in a BxPC-3 xenograft mouse model demonstrate that verteporfin accumulated in tumors at autophagy-inhibiting levels but did not reduce tumor volume or increase survival as a single agent. However, in combination with gemcitabine, verteporfin moderately reduced tumor growth and enhanced survival compared to gemcitabine alone. Our results do not agree with the premise that autophagy inhibition is effective against PDAC as a single-modality treatment, but they support autophagy inhibition as an approach to sensitize PDAC to gemcitabine.
Citation Format: Elizabeth Donohue, Anitha Thomas, Norbert Maurer, Irina Manisali, Magali Zeisser-Labouebe, Natalia Zisman, Hilary J. Anderson, Murray Webb, Marcel Bally, and Michel Roberge. The early autophagy inhibitor verteporfin moderately enhances the antitumor activity of gemcitabine in a pancreatic ductal adenocarcinoma model. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B11.
Abstract B13: Occult progression by Apc-deficient intestinal crypts as a target for chemoprevention
Authors: Fischer Jared M. , Shibata Darryl , Liskay R Michael 
Published: August 2014

Abstract
Although Apc mutation is widely considered an initiating event in colorectal cancer, little is known about the earliest stages of tumorigenesis following sporadic Apc loss. Therefore, we have utilized a novel mouse model that facilitated the sporadic inactivation of Apc via frameshift reversion of Cre in single, isolated cells. Our system enables tracking the fates of Apc-deficient intestinal stem cells. Our results suggest that consistent with Apc being a “gatekeeper”, loss of Apc early in life during intestinal growth leads to adenomas or increased crypt fission, manifested by fields of mutant but otherwise normal-appearing crypts. By contrast, later-occurring in life Apc loss has minimal consequences with mutant crypts being less prone to either increased crypt fission or adenoma formation. Using the stem cell specific Lgr5-CreER mouse, in which Apc loss is induced at defined ages and in varying numbers of crypts, we find that Apc-deficient field size again correlates with progression to adenoma. To evaluate this early stage prior to adenoma formation as a therapeutic target, we examined the chemopreventive effects of sulindac on Apc-deficient crypt field formation. We found that sulindac reduces adenomas and inhibits the morphologically occult spread of Apc-deficient crypts. Taken together these results suggest that: 1) A field of Apc-deficient crypts is an important intermediate between loss of Apc and adenoma formation, 2) Earlier Apc loss promotes increased crypt fission and subsequent field formation, and 3) Normal-appearing Apc-deficient crypts are potential unappreciated targets for cancer screening and chemoprevention.
Citation Format: Jared M. Fischer, Darryl Shibata, R Michael Liskay. Occult progression by Apc-deficient intestinal crypts as a target for chemoprevention. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B13.
Abstract B18: Targeting rapamycin-induced autophagy in cancer
Authors: Alayev Anya , Snyder Rose B. , Holz Marina K. 
Published: August 2014

Abstract
Mechanistic target of rapamycin complex 1 (mTORC1) is an important regulator of cell cycle progression and proliferation, and is a target of the inhibitor rapamycin. The 40S ribosomal S6 Kinase 1 (S6K1) is one of the best characterized downstream targets of mTORC1. The mTORC1/S6K1 pathway is hyperactivated in many types of cancer, contributing to cancer pathogenesis and progression.
Autophagy is a cellular mechanism conserved in all eukaryotes, whose role is to maintain homeostasis of the cell under stress-induced conditions by recycling intracellular components. In cancer, autophagy may serve to protect cancer cells from cell death and may contribute to acquired drug resistance. The mTORC1/S6K1 signaling pathway is an important regulator of autophagy. One of the concerns that arise with the use of mTORC1 inhibitors, such as rapamycin analogs (or rapalogs), is that rapalogs promote autophagy and cause cell senescence, which protects cancer cells from undergoing apoptosis.
Recent evidence suggests that a possible mechanism by which mTORC1 regulates autophagy may involve the tumor suppressor programmed cell death protein 4 (PDCD4), which is a downstream target of S6K1. Inhibition of mTORC1/S6K1 signaling causes upregulation of PDCD4 expression, which correlates with increased autophagy induction. We observed that suppressing PDCD4 expression in combination with rapamycin reduces autophagy and causes cancer cells to undergo cell death via apoptosis. Our results indicate that such strategy prevents rapamycin-induced upregulation of autophagy, while maintaining inhibition of mTORC1/S6K1 signaling, and promotes progression to apoptosis.
Citation Format: Anya Alayev, Rose B. Snyder, Marina K. Holz. Targeting rapamycin-induced autophagy in cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B18.
Abstract B65: Immune cell priming and potentiation of anti-tumor effects by Imprime PGG®
Authors: Yokoyama Yumi , Nelson Mariana I. , Ottoson Nadine C. , Kirstein Mark N. , Walsh Richard , Michel Kyle S. , Danielson Michael E. , Antonysamy Mary A. 
Published: August 2014

Abstract
Biothera is developing Imprime PGG® (Imprime PGG) for cancer that is synergistic with multiple anti-tumor monoclonal antibodies, demonstrating the potential to improve patient outcomes in a wide range of cancer indications. Although, the antitumor potential of Imprime PGG has now been well documented in several preclinical models, its immunomodulatory potential has not been fully elucidated. Here, we studied the in vivo effects of Imprime PGG, a pharmaceutical grade soluble yeast-derived β-1,3/1,6 glucan, on immune cell binding and function, using both tumor bearing and non-tumor bearing mice. Immunodeficient nude mice, with or without tumor (i.e. MiaPaCa-2 human pancreatic tumor), were administered a single dose of Imprime PGG (i.v.) and 3 days later, immune cells in peripheral blood, spleen, and/or tumor were isolated and evaluated for Imprime PGG binding and function. Using flow cytometric methods, Imprime PGG was found to bind B cells, macrophages, and neutrophils in whole blood and in addition, bound to NK cells in spleen. Notably, in mice bearing tumor, Imprime PGG administration lead to a relatively high percentage of Imprime PGG-bound macrophages and neutrophils in the tumor microenvironment. Furthermore, for the first time, we were able to demonstrate that Imprime PGG administered in vivo had the ability to “prime” immune cells and enhance their antitumor function. Administration of Imprime PGG increased the cytotoxic ability of immune cells, such as macrophages and NK cells, and lead to higher antibody mediated cytotoxicity and increased sensitivity to non-specific stimuli. Likewise, immune cells primed in vivo with Imprime PGG demonstrated increased cytokine responses (such as KC; a mouse isoform of human IL-8, IL-6, G-CSF, and MIP-1α and preliminary cytokine data on tumor infiltrating effector cells support an antitumor profile. Collectively, these results indicate that Imprime PGG when administered in vivo “primes” immune effector cells for enhanced antitumor activity. These observations further validate the potential benefit of combining this unique immunomodulatory drug with antitumor monoclonal antibodies as a positive treatment strategy in cancer.
Citation Format: Yumi Yokoyama, Mariana I. Nelson, Nadine C. Ottoson, Mark N. Kirstein, Richard Walsh, Kyle S. Michel, Michael E. Danielson, Mary A. Antonysamy. Immune cell priming and potentiation of anti-tumor effects by Imprime PGG®. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B65.
Abstract C02: Transient metabolic complex, the purinosome, for metabolic adaptation in cancer cells
Authors: An Songon , Kyoung Minjoung 
Published: August 2014

Abstract
Sequential metabolic enzymes have long been hypothesized to form transient multienzyme complexes to regulate metabolic pathways in cells. Human de novo purine biosynthetic complex, the “purinosome,” stands as first examples of this cellular phenomenon. The purinosome formation indeed increased desired metabolic flux in cells. The purinosome assembly/disassembly was also dynamically regulated by multiple cellular factors; including microtubule networks, protein kinase CK2, and Gi-protein coupled receptors. However, we barely understand the structural organization of the purinosome. We will discuss our recent progress providing unprecedented insights into the mechanism of purinosome assembly/disassembly upon environmental changes. Taken together with our knowledge of purinosome regulatory systems, we propose that the purinosome dynamics could be part of metabolic alterations and adaptations of cancer cells. Given that purine biosynthesis has been a validated target for anticancer chemotherapy, this new level of understanding purine biosynthesis will open new opportunities of therapeutic intervention in human cancers.
Citation Format: Songon An, Minjoung Kyoung. Transient metabolic complex, the purinosome, for metabolic adaptation in cancer cells. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C02.
Abstract C33: Integrated analysis of sequence variations and copy number in TCGA colon adenocarcinoma data
Authors: O'Hara Andrea , Keshavan Raja , Culot Louis , Shams Soheil 
Published: August 2014

Abstract
The Cancer Genome Atlas (TCGA) data is available via the TCGA portal and includes copy number data and whole exome sequencing data. Nexus Copy Number 7 was used to evaluate level-1 approved SNP array data from the colon adenocarcinoma (COAD) data set. All samples were subjected to match-paired analysis to evaluate somatic copy number variation. Samples were subjected to extensive pre-processing, including systematic G/C wave correction, ploidy correction, gender correction and quality control. Corresponding level-3 somatic mutation data was used for an integrated analysis of copy number and sequence variation with the COAD data set. Comprehensive copy number analysis identified frequent (&gt;35%) copy number gains of chr7, chr8q, chr13 and chr20, and losses of chr8p, chr17p, and chr18. GISTIC analysis further identified statistically significant focal changes which included loss of FHIT on chr3. Genes KRAS and BRAF were among the most frequently mutated genes. Integrated analysis identified several regions of copy number change that significantly co-occurred with BRAF mutation. Copy number profiles varied significantly between hypermutable and non-hypermutable samples. Potential chromothriptic events were also observed within the COAD dataset. An approach that can integrate structural and sequence variation among samples will be presented.
Citation Format: Andrea O'Hara, Raja Keshavan, Louis Culot, Soheil Shams. Integrated analysis of sequence variations and copy number in TCGA colon adenocarcinoma data. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C33.
Abstract C51: Interleukin-4 receptor α chain regulates the growth of primary and metastatic mammary tumors
Authors: Venmar Katherine T. , Hwang Daniel , Dozier Ashley , Carter Kathy , Gillani Sareena , Fingleton Barbara 
Published: August 2014

Abstract
This abstract is being presented as a short talk. A full abstract is printed in the Proffered Abstracts section (PR13) of the Conference Proceedings.
Citation Format: Katherine T. Venmar, Daniel Hwang, Ashley Dozier, Kathy Carter, Sareena Gillani, Barbara Fingleton. Interleukin-4 receptor α chain regulates the growth of primary and metastatic mammary tumors. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C51.
Abstract IA25: Metastasis pathways
Authors: Massagué Joan 
Published: August 2014

Abstract
The mechanisms that turn disseminated tumour cells (DTCs) into metastasis-initiating seeds are largely unknown. We recently identified molecular sensors and stromal factors that amplify cell survival and stem cell pathways in DTCs from breast, lung, and renal cancers. These mechanisms prime tumor cells for metastasis in animal models and are associated with relapse in patients. For example, SRC primes triple-negative (TN) breast cancer DTCs for a robust response of the PI3K-Akt pathway to CXCL12 and IGF1 in the bone marrow. The leukocyte-tethering receptor VCAM-1 primes TN DTCs for PI3K-Akt activation in the lungs. For stem cell fitness, the extracellular matrix protein tenascin-C (TNC) forms micrometastatic niches that amplify WNT and NOTCH signaling in TN breast cancer cells. A CXCL1-S100A8 paracrine loop protects DTCs from the stresses of metastasis and chemotherapy, suggesting a link for the clinically coupled phenomena of relapse and chemoresistance. Though encouraging, this progress has only accentuated an old puzzle: How do organ-specific metastatic traits emerge in primary tumors? We identified a role of the breast tumor stroma in selecting cancer cells in TN breast cancers that are primed for metastasis to bone. Cancer-associated fibroblasts (CAFs) in TN breast tumors skew heterogeneous cancer cell populations towards a predominance of clones that thrive on the CAF-derived factors CXCL12 and IGF1. Carcinoma clones selected in this manner are primed for metastasis in the CXCL12-rich microenvironment of the bone marrow. Coupled with processes of tumour self-seeding, whereby DTCs may recirculate, reseed and expand in their tumors of origin, the process of metastatic seed pre-selection may further sway the organotropic metastatic traits of tumors. We conclude that stromal signals resembling those of a distant organ select for cancer cells that are primed for metastasis in that organ, thus illuminating the evolution of metastatic traits in a primary tumour and its distant metastases.
In related studies we identified mediators of brain metastasis of lung adenocarcinoma and breast cancer.
Citation Format: Joan Massagué. Metastasis pathways. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA25.
Abstract IA29: Functional genomics, experimental models and cancer
Authors: Hahn William C. 
Published: August 2014

Abstract
Large scale characterization of cancer genomes has led to information regarding the identify, number, and types of alterations found in human tumors. However, the large number of mutations identified to date require complementary approaches to understand the function of these mutated genes and to elucidate pathways involved in cancer initiation and progression. Over the past several years, we have developed genome scale RNAi libraries and open reading frame expression libraries that permit a systematic evaluation of genes involved in cancer initiation and maintenance. We have used these tools to dissect known and novel pathways involved in malignant transformation. In particular, we have dissected the signaling pathways related to beta catenin and KRAS, two well-known cancer drivers that have proven difficult to target therapeutically. These approaches have identified new components of these pathways, which may provide a foundation for therapeutic strategies.
Citation Format: William C. Hahn. Functional genomics, experimental models and cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA29.
Abstract IA32: Targeting cancer cell dependencies on developmental signal transduction pathways
Authors: Lum Lawrence 
Published: August 2014

Abstract
Developmentally important signal transduction pathways such as those controlled by the secreted Wnt and Hedgehog (Hh) ligands are frequently exploited in cancerous cells to promote unfettered growth. We describe functional and chemical genomics-based efforts to recover actionable mechanisms sustaining cancer-associated Wnt and Hh signaling. We discuss chemically tractable strategies for disrupting the fatty acylation of Wnt proteins and unanticipated vulnerabilities in Hh signaling to inhibitors of the Bcl-2 antiapoptotic proteins. Our findings extend the portfolio of druggable enzymes with anti-cancer relevance and reveal novel compensatory prosurvival mechanisms in cancerous cells that incorporate developmental pathway components.
Citation Format: Lawrence Lum. Targeting cancer cell dependencies on developmental signal transduction pathways. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr IA32.
Abstract PR14: Lineage labeling elucidates the natural history of metastatic colonization
Authors: Aiello Nicole M. , Bajor David L. , Vonderheide Robert H. , Stanger Ben Z. 
Published: August 2014

Abstract
Compared to primary tumor formation and invasion, relatively little is known about later stages of the metastatic cascade, including the seeding and colonization of distal tissues. To visualize these late steps in metastasis, we have generated an autochthonous mouse model of pancreatic ductal adenocarcinoma in which all pancreatic epithelial cells are genetically labeled with yellow fluorescent protein (the KPCY model). This system allows for the detection of single seeded tumor cells in distant organs, as well as micrometastasis and larger lesions. We have assessed the size distribution of metastatic lesions in two frequently colonized organs, the liver and lung, and found that single cells and clusters consisting of less than ten cells represent the majority of lesions in both tissues; however these small lesions only progress to gross metastasis in the liver, not the lung. We have previously used the KPCY model to study the dynamic process of epithelial-mesenchymal transition (EMT) and its involvement in invasion and dissemination from the primary tumor. We have extended these studies to assess the role of EMT and the reverse phenomenon, mesenchymal-epithelial transition (MET), in seeding and colonization at metastatic sites. Our results suggest that while EMT is favored for entry into the circulation, there may be selection for epithelial tumor cells or MET at the metastatic site. Additionally this model allows us to investigate the parallel evolution of metastatic lesions, from single cells to macrometastasis, and the associated metastatic microenvironment.
Citation Format: Nicole M. Aiello, David L. Bajor, Robert H. Vonderheide, Ben Z. Stanger. Lineage labeling elucidates the natural history of metastatic colonization. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr PR14.
Abstract B40: Mitochondrial superoxide dismutase (Sod2) confers a survival advantage to ovarian cancer cells under stress conditions by enhancing mitochondrial respiratory reserve capacity
Authors: Dier Usawadee , Uusitalo Larissa , Giroux Corinne , Hempel Nadine 
Published: August 2014

Abstract
The formation of cellular spheroids is considered to be an important step in the metastatic progression of ovarian cancer. These clusters of tumor cells are characterized by an enhanced survival within the peritoneal cavity, the ability to attach at secondary metastatic sites within the cavity and associated with increased chemoresistance. High expression of mitochondrial superoxide dismutase (Sod2), which regulates mitochondrial redox balance, has been observed in metastatic ovarian cancer, specifically ovarian clear cell carcinomas (CCC), and in vitro, following spheroid formation. To assess the role of Sod2 in spheroid formation and ovarian cancer metastasis we utilized siRNA knock-down to decrease Sod2 expression in Ovcar3 and the CCC cell line ES-2. Surprisingly, under normal culture conditions, decreasing Sod2 levels had little effect on proliferation and spheroid formation. To elucidate the role of Sod2 on ovarian cancer mitochondrial function an extracellular flux metabolic analyzer (Seahorse Bioscience) was utilized to measure rates of cellular respiration. While the basal oxygen consumption rate remained unchanged, a decrease in Sod2 expression resulted in a concomitant decrease in respiratory reserve capacity. This reserve capacity is an important determinant of a cell's ability to increase metabolic rate under stress conditions. Given that ovarian cancer spheroids are exposed to the hypoxic environment of the peritoneal cavity, the role of Sod2 on ovarian cancer spheroid formation was assessed under low oxygen (1%) conditions. Hypoxia increased the clonogenicity and spheroid size of control cells, which was significantly abrogated following Sod2 knock-down. These data suggest that Sod2 confers a survival advantage to ovarian cancer spheroids under stress conditions by maintaining an adequate mitochondrial respiratory reserve. Manipulating mitochondrial function and redox balance by effectively targeting mitochondrial antioxidant enzymes may enhance chemosensitivity and allow for novel therapeutic strategies against ovarian cancer.
Citation Format: Usawadee Dier, Larissa Uusitalo, Corinne Giroux, Nadine Hempel. Mitochondrial superoxide dismutase (Sod2) confers a survival advantage to ovarian cancer cells under stress conditions by enhancing mitochondrial respiratory reserve capacity. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr B40.