bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-263: Novel tumor suppressors and mutationally affected signaling pathways in small-cell lung cancer identified by whole exome sequencing
Authors: Peifer Martin , Thomas Roman K. 
Published: June 2012

Abstract
Small-cell lung cancer (SCLC) is an aggressive lung cancer subtype characterized by early metastasis and a peculiar neuroendocrine phenotype. Unfortunately, SCLC is difficult to sample because these patients are not routinely undergoing surgery. In order to shed light on the biology of this tumor type and to discover novel therapeutic targets, we have conducted whole-exome sequencing of 24 SCLC tumors as well as high-density gene copy number analyses of 64 SCLC specimens. On average we observe a high mutation rate of 7.9±1.0 protein changing mutations per million basepairs and an unusually high C:G&gt;A:T transversion rate that has been associated with excessive smoking. In addition to frequent mutations in TP53 (80%) and RB1(63%), we identified mutations in LRP1B (13/24 samples), a gene that is known to be frequently mutated in lung adenocarcinoma. To our surprise, we found a significant enrichment of neuronal genes (FDR q-value: &lt; 10e-10) suggesting that the neuroendocrine differentiation of SCLC might be primarily driven by mutational events. Other frequently mutated genes encode proteins involved in cell-cell and cell-matrix interactions. This observation might explain the aggressiveness and metastatic capability of SCLC. A systematic analysis of copy number losses and loss of heterozygosity revealed a distinct pattern for novel candidate tumor suppressor genes when integrated with somatic mutations. Performing the pathway analysis on each individual sample clearly showed that SCLC tumors segregate by mutational landscape. Furthermore, the analysis of autopsy-derived tumor specimens revealed that surgically resected tumors are not dissimilar to late-stage SCLC. In summary, we have defined the mutational and genomic landscape of SCLC that may help explaining some of the phenotypic and clinical properties of this fatal tumor type. Our data provides a rich source for future functional analyses of putative tumor suppressor genes and oncogenes as well as for potential novel drug targets.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-263. doi:10.1158/1538-7445.AM2011-LB-263
Abstract SY18-01: Alterations in metabolic pathways to support cancer cell proliferation
Authors: Vander Heiden Matthew G. 
Published: June 2012

Abstract
Unlike the majority of differentiated cells, many cancer cells metabolize glucose by aerobic glycolysis even in the presence of sufficient oxygen to support mitochondrial respiration. This phenomenon, also known as the Warburg effect, is characterized by increased glycolysis with lactate production and decreased oxidative phosphorylation. We have argued that aerobic glycolysis may be selected for by cancer cells to meet the distinct metabolic needs of proliferation. Unlike metabolism in differentiated cells, which is geared toward efficient ATP generation, the aerobic glycolysis observed in cancer cells appears to be adapted to facilitate the accumulation of biomass.
Our understanding of how cancer cells meet their metabolic needs is based primarily on studies of cultured cells, and nutrient conditions in vitro differ significantly from those seen by tumor cells in vivo. Our long-term objective is to develop a comprehensive understanding on how cell metabolism is altered to accommodate anabolic synthesis and support the growth of tumors in vivo. The M2 isoform of pyruvate kinase (PK-M2) promotes the metabolism of glucose by aerobic glycolysis, contributes to anabolic metabolism, and appears necessary for optimal tumor growth in vivo. Paradoxically, these consequences of PK-M2 isoform selection are associated with decreased pyruvate kinase enzyme activity. Experiments to test the hypothesis that decreased pyruvate kinase activity promotes anabolic metabolism and cell proliferation in vivo will be presented. This includes data generated using genetically engineered mouse cancer models and small molecule activators of PK-M2. Additionally, efforts to understand pyruvate kinase-mediated regulation of glycolysis in cancer cells will be discussed. Decreased pyruvate kinase activity in cancer cells is accompanied by an alternate regulation of glycolysis. This creates a branch point in glycolysis to divert 3-phosphoglycerate into the serine biosynthesis pathway, and this reorganization of metabolic flux appears to be is important for proliferation. In fact, in some cancers a substantial portion of the total glucose flux is directed to serine synthesis and additional genetic evidence will be presented to suggest that glucose flux into this pathway can promote cell transformation. Finally, the role of the tumor environment, and how this contributes to the reorganization of metabolic pathways to support anabolic metabolism will be discussed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY18-01. doi:10.1158/1538-7445.AM2011-SY18-01
Abstract SY19-01: Identifying and overcoming immune barriers at the level of the tumor microenvironment
Authors: Gajewski Thomas Frank 
Published: June 2012

Abstract
Immunotherapeutic approaches for the treatment of melanoma, such as tumor antigen-based vaccines, can frequently boost immune responses as measured in the peripheral blood. However, clinical responses as measured by tumor shrinkage have been observed in only a minority of patients. This observation has prompted careful analysis of the tumor microenvironment to probe for biologic correlates to clinical response and also to identify mechanisms of tumor resistance. Patients with advanced melanoma treated on two different vaccine platforms had pretreatment tumor biopsies analyzed by Affymetrix gene expression profiling. Supervised hierarchical clustering was performed based on favorable or unfavorable clinical outcome. An expanded bank of tumors was also analyzed to increase the sample size and better understand gene patterns that segregate into subtypes. Two major categories of melanoma metastases have been observed. One subgroup of patients has an inflamed phenotype that includes expression of chemokines, T cell markers, and other immunoregulatory factors. Clinical responders to melanoma vaccines appear to fall within this subset. This group also contains the highest expression of negative regulatory factors, including PD-L1, IDO, and FoxP3, suggesting that these immune suppressive mechanisms may dominantly inhibit antitumor T cell function in those patients. In addition, absence of B7 expression suggests that classical T cell anergy also may be operational. Preclinical experiments have confirmed a critical role for all 4 of these mechanisms in limiting antitumor T cell efficacy in vivo, giving candidate treatment strategies for translation back into the clinic. These include IDO inhibitors, anti-PD-1 mAbs, and approaches to deplete CD25+ Tregs. A second subset of patients is represented by tumors which are noninflamed and lack chemokines for T cell recruitment. Therefore, a major barrier in these cases appears to be failed T cell migration into tumor sites. Experimental strategies to augment T cell migration can have important antitumor effects in preclinical models. Finally, the presence of inflammatory factors was associated with a type I IFN transcriptional signature, and murine experimental models have confirmed a critical role for type I IFN signaling in mediating innate immune “sensing” of a growing tumor in vivo. Our results confirm that molecular profiling of melanoma metastases may be useful as a predictive biomarker for response to melanoma vaccines. In addition, specific features identified in defined subsets of patients offer new therapeutic strategies based on overcoming resistance to immune destruction at the level of the tumor microenvironment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY19-01. doi:10.1158/1538-7445.AM2011-SY19-01
Abstract SY24-01: Pluripotency genes as targets for cancer prevention
Authors: Dhodapkar Kavita 
Published: June 2012

Abstract
Recent studies have suggested an overlap between the core pathways that maintain pluripotency in embryonal stem (ES) or induced pluripotency stem (iPS) cells and those implicated in oncogenesis. The presence of ES/iPS signature genes can be demonstrated in diverse cancers and correlates with a poorer outcome. The ES pathways have been shown to be particularly expressed in the putative cancer stem cell (CSC) population within the tumor bulk. Therefore pathways that regulate stemness are being actively targeted in human cancer. Here, I will discuss evidence for immune-mediated targeting of the core ES genes, such as OCT4 and SOX2 in humans. Initial studies suggested that humoral and cellular responses against SOX2 can be detected in patients with preneoplastic monoclonal gammopathy of undetermined significance (MGUS). Presence of anti-SOX2 T cell responses correlated with reduced risk of progression to clinical myeloma. Surprisingly, T cell responses against OCT4, a common marker of ES cells, can be readily detected in healthy human donors. OCT4-specific T cell response resides predominantly in the CD4+ T cell compartment and comprises of CD45RO+ memory T cells. These T cells can be readily expanded in culture using autologous dendritic cells loaded with OCT4-expressing germ cell tumors. In contrast to the finding with healthy donors, T cell immunity to OCT4 is deficient in freshly isolated circulating T cells from patients with germ cell tumors (GCTs). However, these T cells can be observed after chemotherapy-induced cell death of tumor cells in vivo. The capacity of the human immune system to target both of the core pluripotency genes (SOX2 and OCT4) may facilitate harnessing the immune system against GCTs and putative CSCs in diverse tumor types. ES-associated genes such as OCT4 seem to be dispensable for the function of adult stem cells in mice, suggesting that targeting these genes in the setting of cancer might not carry adverse effects against normal adult stem cells. As these immune responses seem to be engaged during early stages of carcinogenesis, including in preneoplastic states, we suggest that they may also be particularly attractive targets for immune-mediated cancer prevention in diverse high-risk settings.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY24-01. doi:10.1158/1538-7445.AM2011-SY24-01
Abstract SY26-02: Targeting lipogenesis in EGFR-activated glioblastomas
Authors: Mischel Paul S. 
Published: June 2012

Abstract
Cancer is a disease characterized by mutational activation and enhanced dependence on oncogenic signal transduction cascades. Cancer is also characterized by major shifts in cellular metabolism, including glucose utilization and uptake, energy metabolism and lipogenesis. The molecularly circuitry linking oncogenic signal transduction cascades and therapeutically targetable metabolic circuits is only beginning to be understood. This talk will focus on glioblastoma, the most common malignant primary brain tumor of adults and one of the most lethal of all cancers. Glioblastoma is characterized by nearly universal PI3K pathway hyperactivation, including EGFR amplification and mutation. Studies leading to molecular dissection of the signaling networks linking mutated EGFR with enhanced lipogenesis will be discussed, including integration of studies performed in cell lines, in vivo models and tumor tissue from patients treated with targeted inhibitors. The talk will describe the identification of a therapeutically targetable, novel EGFR/PI3K/SREBP-1 dependent prosurvival metabolic signaling pathway, as well as recent studies linking this pathway to altered fatty acid synthesis and cholesterol homeostasis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY26-02. doi:10.1158/1538-7445.AM2011-SY26-02
Abstract A24: Germline deletion at 3p12.3 in patients with hereditary breast and colorectal carcinoma
Authors: Abreu Francine B. , Santos Erika MM , Rossi Benedito M. , Krepischi Ana C. , Achatz Maria I. , Carraro Dirce M. , Brentani Ricardo R. , Kowalski Luiz P. , Rogatto Silvia R. 
Published: June 2012

Abstract
Lynch syndrome (LS) is a common hereditary syndrome that predisposes to colorectal cancer (CRC). Breast carcinoma has been described as the most common extracolonic tumors among Brazilian patients with LS. In this study, it was investigated members of two families with breast and colorectal carcinomas. The patient 1 (SM56) had breast carcinoma at age of 50. The patient 2 (SM37) had CRC at 52 years old, presented bilateral breast carcinoma (73 and 76 years old) and reported a reproductive history of four abortions. The daughter of patient 2 (SM37-2) had breast cancer at 55 years old. In both families, their relatives had history of CCR, breast cancer, endometrium carcinoma and prostate cancer. The patients were screened for BRCA1, BRCA2, CHEK2, TP53, MLH1 and MSH2 mutations by Sanger's sequencing method. All of them were negative for pathogenic mutations. Copy number alterations (CNAs) were investigated by array comparative genomic hybridization (aCGH) using a platform of 4×180K (Agilent). Genomic data were extracted with Feature Extraction software and analyzed using Genomic Workbench Standard 5.0.14, statistical algorithm ADM2 and sensitivity threshold of 6.7. The data were compared with the Database of Genomic Variations (DGV) and with a reference dataset obtained from 82 healthy Brazilian individuals. Alterations identified in more than 5% of the reference dataset were excluded from both patients. All three cases presented the same microdeletion on 3p12.3 (79.951 pb) where is mapped the ROBO1 gene. Quantitative Real Time PCR (qPCR) using primers flanking the region confirmed the ROBO1 microdeletion. CNAs mapped on ROBO1 or involving the same region microdeleted are not previously described in DGV or in our dataset from Brazilian health individuals. ROBO1 is involved in the regulation of cell migration, cell death and angiogenesis. The 5′ region contains a CpG island and was found to be hypermethylated and showing allelic losses in 3p12 in sporadic primary invasive breast carcinomas (Dallol et al, Oncogene 21:3020, 2002). At first time, ROBO1 was associated with Hereditary Breast and Colorectal Carcinomas in two different families suggesting to be a highly penetrant mutation associated with elevated risk to develop cancer among the relatives. Further studies in tumor samples from these patients could demonstrate the Knudson's two hit hypothesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A24.
Abstract A37: A dominantly acting allele of murine Mcm4 causes chromosome instability and promotes leukemiogenesis
Authors: Bagley Bruce N. , Maklakova Vilena , Kendziorski Christina , Adams David J. , Collier Lara S. , Marshall Jonathon G. , Lester Rachael A. , Cancel Michelle M. , Bendzick Laura G. , Keane Thomas , Kogan Scott C. , Sullivan Ruth , Cormier Robert 
Published: June 2012

Abstract
Mouse models have been invaluable tools for studying human cancer. Given the contribution of mouse models to understanding tumorigenesis, when a spontaneous mouse mutant that developed heritable T cell lymphoblastic leukemia/lymphoma (T-ALL) arose in our colony, we pursued studies to both characterize the disease in these mice and to identify the mutant gene responsible for the phenotype. Because the mutation was spontaneous and the phenotype was dominant, we named the mutant Spontaneous dominant leukemia (Sdl). Sdl heterozygous mice develop disease with short latency and high penetrance; while mice homozygous for the mutation die early during embryonic development. We have discovered a spontaneously acquired mutation in Mcm4 in Sdl mice by whole exome sequencing. MCM4 is part of the heterohexameric complex of MCM2–7 that is important for licensing of DNA origins prior to S phase and also serves as the core of the replicative helicase that unwinds DNA at the replication fork. Previous studies in murine models have discovered that reduced levels of MCM complexes resulting from hypomorphic Mcm alleles promote tumor formation by causing genomic instability. However, Sdl mice possess normal levels of MCMs and there is no evidence for loss-of-heterozygosity at the Mcm4 locus in Sdl leukemias; indicating that the Sdl Mcm4 allele is not a hypomorphic or loss-of-function allele. Sdl mice harbor increased numbers of spontaneous micronuclei and Sdl T-ALLs are characterized by intragenic deletions at the Notch1 locus. Therefore, our studies indicate that dominantly acting alleles of MCMs can be compatible with viability but have dramatic oncogenic consequences caused by chromosome instability.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A37.
Abstract A7: Participation of atopic condition in melanoma B16-BL6 development
Authors: Jimenez-Andrade G. Yanek , Lamas Monica , Gonzalez-Espinosa Claudia 
Published: June 2012

Abstract
Atopy is a condition characterized by the increase of total serum immunoglobulin E (IgE) levels and a tendency to develop allergic reactions. Allergy in general and specifically atopic dermatitis seems to be associated with an increased risk of melanoma development, but those findings are not conclusive. Mast cells play a central role in allergic reactions because they can be activated by IgE-antigen-dependent crosslinking of the Fc Rl receptor. Since mast cells have been found in the periphery of solid tumors and their presence correlates with tumor angiogenesis and growth, it has been proposed that activation of mast cells may facilitate blood vessel formation and tumor development.
We evaluated the melanoma growth in atopic states and the role of mast cells in this process. Since hyper-responsiveness is a critical condition in atopic states, we developed a murine model of atopic condition that allowed us to quantify the increase in the inflammatory state in mice. C57BL/6J mice were sensitized with intravenous (i.v) injection of different concentrations of a monoclonal anti-DNP IgE (SPE-7 clone). Twenty-four hours after IgE administration, atopic condition was evaluated by cutaneous passive anaphylaxis (PCA) assays. A specific antigen for the SPE-7 IgE (DNP-HSA) was i.v. injected together with in Evans blue colorant and extravasation of the colorant was quantified by standard methods.
C57BL/6J control and atopic mice were inoculated subcutaneously with 0.5×106B16-BL6 melanoma cells in serum-free Tyrode's buffer 24 hours after vehicle or IgE (750 ng i.v.) administration. Tumor weight was assessed during 4 weeks after inoculation of tumor cells in the ear. Results shown that tumor growth was faster in atopic than non-atopic mice.
To investigate the role of mast cells in melanoma growth in atopic condition, we evaluated the tumor weight gain in mast cell deficient Kit (Wsh/Wsh) (W-sh) and mast cell reconstituted (W-sh-rec) mice in normal and atopic conditions. Melanoma tumor growth was impaired in non-atopic and atopic W-sh mice and restored in non-atopic W-sh rec. Interestingly, melanoma growth was greater in W-sh rec atopic mice than in all the groups tested.
Our results suggest that atopic condition facilitates melanoma tumor growth and that mast cells participate in this effect.
This work was supported by CONACyT Grants 83079 and 79162. Scholarship 210067.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A7.
Abstract B17: Synergism between p53 and Mcl-1 in hepatocyte maturation and survival
Authors: Weng Shih-Yen , Hsiao Michael , Huang Pei-Hsin , Tao Mi-Hua , Yang-Yen Hsin-Fang , Yang Chia-Yu , Li Chao-Chin , Sun Te-Ping , Tung Shu-Yun , Yen Jeffrey Jong-Young , Tsai Ting-Fen , Chen Chun-Ming , Chen Sung Ho 
Published: June 2012

Abstract
Mcl-1 plays an apical role in many cell survival programs. Mice without Mcl-1 die at early embryonic stage. A conditional knockout approach has thus been employed to study Mcl-1 functions in the liver. Mice without Mcl-1 in hepatocytes (Alb-Mcl-1 −/−) were viable but manifested some defects in the mature liver, including enlarged cell size, enhanced apoptosis and proliferation of liver cells. An increased level of p53 was also observed in adult Alb-Mcl-1 −/− mouse livers. We thus generated Alb-Mcl-1 −/− mice in p53-deficient background to examine whether p53 was involved in Mcl-1 deficiency-induced hepatocyte apoptosis. Loss of p53 in Alb-Mcl-1 −/− mice (DKO mice) resulted in a very high frequency of neonatal death. Further analysis revealed that such early lethality was likely due to hepatic failure caused by a marked reduction of fully-differentiated hepatocytes at the perinatal/neonatal stage. On the other hand, those DKO mice that did survive to adulthood manifested much more severe liver cell damage than Alb-Mcl-1 −/−mice of the same age, suggesting that p53 is activated in Alb-Mcl-1 −/− livers to help resolve Mcl-1 deficiency-induced hepatocyte damage. Last, we demonstrated that p53 enhanced-hepatocyte survival is a cell-autonomous effect, and that such effect is mediated in part through transcriptional up-regulation of p21 Waf1/Cip1 in Alb-Mcl-1 −/− livers.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B17.