bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B8: Correlation of the expression of hepcidin mRNA and the serum iron, ferritin, and TIBC levels in hepatocellular carcinoma
Authors: Pawar Smita C. 
Published: June 2012

Abstract
Background: The present study correlated the expression of hepcidin mRNA and the levels of serum iron, ferritin, and TIBC in hepatocellular carcinoma (HCC).
Methods: Samples of cancerous and noncancerous liver tissue were taken from patients with HCC who underwent hepatectomy. Expression of hepcidin mRNA was evaluated by realtime PCR, and compared in tumors differing in their degree of differentiation and number of tumors. Correlations between hepcidin expression and the serum concentration of hepcidin were evaluated, together with the expression of the serum concentration of biochemical markers of iron metabolism.
Results: Hepcidin mRNA expression in non-cancerous and cancerous tissues was 1791.6 (34.3- 25187.4) and 58.7 (1.93235.8), respectively (P &lt; 0.0001). There were no significant differences in hepcidin expression among tumors differing in their degree of differentiation and number of tumors. The serum concentration of hepcidin did not correlate with hepcidin-mRNA expression. The serum iron level was found to be normal (125.4 ± 21.4 mg/dL). The serum ferritin level was also found to be normal 193.5(14.0-232.9 ng/mL). TIBC was (284.8 ±28.3 ng/mL). There were significant correlations between the serum levels of hepcidin and iron, hepcidin-25 and ferritin and hepcidin and TIBC.
Conclusion: The serum hepcidin concentration was correlated with the levels of serum iron and ferritin, but not with the level of hepcidin mRNA expression in either cancerous or non- cancerous liver tissue. Hepcidin is produced in patients with HCC, from non-cancerous liver tissue, even though production is inhibited in cancerous tissue. Expression of hepcidin mRNA is constitutively suppressed in cancerous, but not in non-cancerous liver tissue of patients with HCC.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):B8.
Abstract IA1-1: Systematic functional genomics and cancer target identification and validation
Authors: Hahn William C. 
Published: June 2012

Abstract
Recent advances in genomics now make it possible to consider enumerating all of the genetic lesions in specific cancers. While these approaches will yield critical information regarding the identify, number, and types of alterations found in human tumors, a complementary approach to decipher the molecular basis of malignant transformation depends upon the application of genome scale tools to annotate the function of genes 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. Using these libraries, we have now performed screens in a panel of human cancer cell lines to systematically identify cancer vulnerabilities. By combining these functional approaches with information derived from mapping the structural abnormalities present in cancer genomes, we have identified several new oncogenes that contribute to cancer development. In addition, many commonly occurring and well- validated oncogenes and tumor suppressor genes remain refractory to molecularly targeted therapies. For example, the proto-oncogene KRAS is mutated in a wide array of human cancers, most of which are aggressive and respond poorly to standard therapies. An alternative strategy for targeting KRAS is to identify gene products that, when suppressed or inhibited, result in cell death only in the presence of an oncogenic allele. Through the use of systematic RNAi screens, we have identified two kinases, TBK1 and STK33 that act in a synthetic lethal manner to selectively kill cancer cell lines that depend on mutant KRAS. Taken together, these studies suggest that combining forward and reverse genetic approaches with information derived from the cancer genome characterization projects will yield a comprehensive list of cancer vulnerabilities and establish a general approach for the rational identification of oncogenic and codependent pathways in cancer.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):IA1-1.
Abstract IA1-2: Drugging oncogenic transcription factors
Authors: Verdine Gregory L. 
Published: June 2012

Abstract
One of the most vexing problems in life science is that of “undruggability,” the difficulty of targeting certain biological macromolecules in vivo using existing drug or ligand discovery technologies. It has been estimated that as many as 80% to 90% of all potential targets, including many that have been extensively validated in humans and in animal models, are undruggable. Among the most biologically validated and yet chemically intractable of all targets are transcription factors, master regulatory proteins that are inappropriately activated in a large percentage of human tumors. The Verdine laboratory is developing powerful new chemistry-based platform technologies to address undruggable targets, including transcription factors. Specifically, the lab is developing “synthetic biologics,” molecules that, like biologics, possess the ability to target large flat surfaces, but that, like small molecules, are fully synthetic and hence can be modified at will. Progress on the development of one class of synthetic biologics—hydrocarbon-stapled alpha-helical peptides—for use in targeting transcription factors will be reviewed in this talk.
References:
1. Schafmeister CE, Po J, Verdine GL. An all-hydrocarbon cross-linking system for enhancing the helicity and metabolic stability of peptides. J Am Chem Soc. 2000;122:5891.
2. Walensky LD, Kung AL, Escher I, Malia TJ, Barbuto S, Wright R, Wagner G, Verdine GL, Korsmeyer SJ. Activation of apoptosis in vivo by a hydrocarbon-stapled BH3 helix. Science. 2004; 305:1466.
3. Bernal F, Tyler AF, Korsmeyer SJ, Walensky LD, Verdine GL. Reactivation of the p53 tumor suppressor pathway by a stapled p53 peptide. J Am Chem Soc. 2007;129: 2456.
4. Moellering RE, Cornejo M, Davis TN, Bianco CD, Aster J, Blacklow SC, Kung A, Gilliland DG, Verdine GL, Bradner JE. Direct inhibition of the NOTCH transcription factor complex. Nature. 2009;462:182.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):IA1-2.
Abstract IA2-1: Modeling drug sensitivity and resistance in human tumor-derived cell lines
Authors: Settleman Jeffrey 
Published: June 2012

Abstract
Agccumulating evidence points to the importance of genomic heterogeneity across human tumors as a critical determinant of the variable clinical response to molecularly targeted cancer therapies. We have used cancer cell lines as a model system for examining the relationship between underlying genotypes and sensitivity to candidate anticancer agents. These studies have revealed the utility of large panels of cancer cell lines to capture the genomic heterogeneity of human cancer and to identify clinically relevant genotype- phenotype relationships. These studies have begun to shed light on mechanisms underlying sensitivity as well as de novo and acquired resistance to a variety of small molecule inhibitors. Using this same platform, we have also identified a mechanism of reversible drug tolerance that involves a distinct chromatin state displayed transiently by small subpopulations of cancer cells. This drug-tolerant state can be disrupted by chromatin-modifying agents, potentially yielding a therapeutic opportunity to prevent or delay the development of more stable genetically conferred drug resistance mechanisms.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):IA2-1.
Abstract IA3-1: Variables for individualizing systemic therapy in patients with lung cancer
Authors: Bepler Gerold 
Published: June 2012

Abstract
Selecting the best therapy for a specific patient with non-small cell lung cancer (NSCLC) has always been the goal for physicians when advising patients and their families. Unequivocal tried-and-true parameters are disease stage, general health status, and the social environment. Other variables, such as age, gender, and histopathology are taken into consideration, but their role in therapeutic decision-making is not firmly established. More recently, tumoral molecular markers, either alone or in combination (referred to as molecular signatures), have emerged as variables for clinical decision making. When evaluating the utility of such markers, it is important to distinguish between the prognostic and predictive utility of a marker. A marker associated with patients’ survival independent of therapy is of prognostic value, while a marker associated with patients’ benefit from a specific therapy is of predictive value. This distinction is best illustrated by ERCC1 (excision repair cross-complementing group 1). In tumor specimens collected from participants in the International Adjuvant Lung Trial, ERCC1 was shown to be both prognostic and predictive. In patients randomized to the trial's control group; i.e., those that did not receive adjuvant chemotherapy, high levels of ERCC1 were associated with longer survival (the prognostic value). In contrast, when taking adjuvant chemotherapy into account, high levels of ERCC1 were associated with lack of benefit from adjuvant chemotherapy (the predictive value); i.e., only patients with low tumoral levels of ERCC1 derived benefit from adjuvant chemotherapy. In practice, predictive markers are of greatest value since they can guide clinical decision making, while a purely prognostic marker is of little or no value to clinical decision making. Many other molecular parameters have since emerged that can be used for decision making. These include EGF receptor mutations, eml4/alk rearrangements, Kras mutations, RRM1 expression levels, TS expression levels, and oncogenic pathway signatures. All of these variables have emerged from laboratory investigations and correlative clinical investigations. Prospective validation studies are required to solidify current knowledge, and many are in progress.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):IA3-1.
Abstract IA3-2: Utilization of genomic signatures to guide therapeutic decisions
Authors: Nevins Joseph R. 
Published: June 2012

Abstract
The heterogeneity of human cancers presents major challenges in understanding disease mechanisms as well as in developing an effective therapeutic strategy for the individual patient. The ability to tailor cancer therapy to characteristics of the individual patient, both with a focus on better utilization of existing standard-of-care regimens as well as new investigational drugs. Towards these goals, we have developed gene expression signatures that have the capacity to predict sensitivity to cytotoxic chemotherapeutics, and utilized these in prospective trials to determine their capacity to guide choice amongst multiple options. In addition, we have also made use of expression profiling to develop signatures of oncogenic pathway deregulation that can then be used to profile the state of these pathways within populations of tumors. These pathway signatures have been useful in dissecting disease heterogeneity, identifying subgroups of tumors with again distinct outcomes, and providing a link in pathway activation with therapeutics. We have extended this concept to develop more refined signatures that can dissect the complexities of many of the known signaling pathways, providing a more precise capacity to probe the activity or deregulation of the pathway and linking to a broader array of therapeutics. This approach, when combined with the capacity to predict chemotherapy use, has the potential to identify therapeutic strategies that make use of all available drugs, matched to the characteristics of the individual patient and thus an approach towards the development of personalized treatment options for the individual patient.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):IA3-2.
Abstract IA3-3: Genetic testing for breast and ovarian cancer: From risk assessment to therapeutic targeting
Authors: Domchek Susan M. 
Published: June 2012

Abstract
Germline genetic variation can be used in a number of ways to improve the care of patients. First, such information can be used to predict the development of disease. Knowledge of risk can lead to targeted preventative strategies. Finally, understanding the genetic etiology for the development of an individual's cancer has the potential to lead to targeted drug development. Inherited BRCA1 and BRCA2 mutations are a model for this paradigm. Since these genes were identified in 1994 and 1995, much work has been done to establish mutation-associated cancer risks and potential management strategies. Deleterious mutations in both genes are associated with a high risk of breast and ovarian cancer, as well as lower risks of other tumor types. Risk-reducing salpingo-oophorectomy significantly reduces the risk of breast and ovarian cancer in mutation carriers and work is ongoing to establish the optimal timing of this procedure as well as the potential for hormone replacement therapy. Women with BRCA1 or BRCA2 mutations require increased breast screening with the addition of breast MRI at the minimum. Prophylactic mastectomy is a valid option. More recently attention has turned to the impact of the biological basis of disease in BRCA1/2 mutation carriers with breast and ovarian cancer on decisions regarding systemic therapy. Due to the role of BRCA1 and BRCA2 proteins in cellular functions such as homologous DNA repair, an enhanced sensitivity to platinum agents and reduced sensitivity to spindle poisons has been postulated and supported by in vitro studies and early clinical data. An additional pathway to target that has been recently identified is poly(ADP-ribose) polymerase (PARP). PARP is a key enzyme in the base-excision repair pathway. In vitro, PARP inhibitors given to BRCA1 or BRCA2 deficient cell lines have led to cell death through synthetic lethality. Early clinical trials have demonstrated efficacy for PARP inhibitors in BRCA1 and BRCA2 mutation carriers with advanced breast and ovarian cancer, with objective response rates in heavily pretreated patients of greater than 40%. Genetic testing for BRCA1 and BRCA2 mutations can be seen as a model for translating the biology of a disease into risk assessment, prevention and treatment, thus demonstrating the potential for inherited genetics to directly impact the care of patients.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):IA3-3.
Abstract IA4-1: Gene-based trial matching
Authors: Yeatman Timothy J. 
Published: June 2012

Abstract
In 2006, the Moffitt Cancer Center initiated an ambitious initiative in personalized medicine called Total Cancer Care. One goal of the project was to develop a protocol and informed consent, a biorepository and a clinical and molecular database that would support the next generation of clinical trials. To date, the single protocol has accrued more than 57,000 patients and over 17,000 tumor samples, of which more than 12,000 have been molecularly profiled on a global gene expression microarray. Sequencing analyses now suggest there are a finite number (~12) of cancer pathways activated by specific driver genes. Emerging data suggest gene expression profiles may provide more inclusive portraits of pathway activation than simple canonical gene mutation analysis. The resultant clinical and molecular database we are developing holds promise for developing new trial approaches that may be faster, require fewer patients, and may increase response rates by finding the right patients for the right trials through gene based trial matching. New approaches to trial development and design that leverage a database, and the associated technical and regulatory challenges, will be discussed.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):IA4-1.
Abstract IA5-2: Evolutionary games in cancer therapy
Authors: Gatenby Robert 
Published: June 2012

Abstract
A number of successful systemic therapies are available for treatment of disseminated cancers. However, tumor response to these treatments is almost invariably transient and therapy fails due to emergence of resistant populations. The latter reflects the temporal and spatial heterogeneity of the tumor microenvironment as well as the evolutionary capacity of cancer phenotypes to adapt to therapeutic perturbations. Interestingly, although cancers are highly dynamic systems, cancer therapy is typically administered according to a fixed, linear protocol. Treatment is changed only when the tumor progresses but successful tumor adaptation begins immediately upon administration of the first dose. Applying evolutionary models to cancer therapy demonstrate the potential advantage of using more dynamic, strategic approaches that focus not just on the initial cytotoxic effects of treatment but also on the evolved mechanisms of cancer cell resistance and the associated phenotypic costs. The goal of evolutionary therapy is to prevent or exploit emergence of adaptive tumor strategies. Examples of this approach include adaptive therapy and double bind therapy. The former continuously alters therapy to maintain a stable tumor volume using a persistent population of therapy-sensitive cells to suppress proliferation of resistant phenotypes. The latter uses the cytotoxic effects of an initial therapy to promote phenotypic adaptations that are then exploited using follow-on treatment.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):IA5-2.
Abstract IA5-3: HIFs, hypoxia, and tumor progression
Authors: Simon M. Celeste 
Published: June 2012

Abstract
Hypoxia-inducible factor (HIF)-1α and −2α display unique and sometimes opposing activities in regulating cellular energy homeostasis, cell fate decisions, and oncogenesis. To fully characterize hypoxic adaptations, distinct functions of HIF-1α versus HIF-2α must be elucidated. Macrophages accumulate both HIF-αS under hypoxia, but HIF-2α overexpression in tumor-associated macrophages (TAMs) is specifically correlated with high-grade human tumors and poor prognosis. HIF-1α regulates myeloid-mediated inflammatory and antibacterial activities, in part through control of glycolysis and ATP production. However, the precise role of HIF-2α during macrophage-mediated inflammatory responses remained unclear. We demonstrate here that mice lacking myeloid HIF-2α are resistant to lipopolysaccharide-induced endotoxemia and display a marked inability to mount inflammatory responses to cutaneous and peritoneal irritants. Furthermore, HIF-2α directly regulates pro-inflammatory cytokine/chemokine expression in macrophages activated in vitro. Using independent murine hepatocellular and colitis-associated colon carcinoma models, we show that HIF-2α -deficient macrophages exhibit migratory defects associated with reduced tumor cell proliferation and progression. Of note, HIF-2α modulates macrophage migration by regulating the expression of cytokine receptor M-CSFR and chemokine receptor CXCR4, without altering intracellular ATP levels. Collectively, our data identify HIF-2α as an important regulator of innate immunity, suggesting it may be a useful therapeutic target for treating inflammatory disorders and cancer.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):IA5-3.
Abstract IA8-1: Pancreatic cancer stem cells and metastasis
Authors: Matsui William H. 
Published: June 2012

Abstract
Emerging evidence suggest that cells within an in individual tumor are phenotypically and functionally heterogeneous despite their clonal origins. Moreover, in several human cancers, the capacity to form tumors ectopically in immunodeficient mice is restricted to specific cell populations. The sustained proliferative capacity of these tumor initiating cells or cancer stem cells (CSC) has suggested that they play a major role in disease initiation and relapse, but their role in disease progression is less clear. We have studied the expression of aldehyde dehydrogenase (ALDH), an intracellular enzyme highly expressed in normal stem cells, in pancreatic adenocarcinoma. We found that ALDH+ pancreatic cancer cells are highly clonogenic both in vitro and in vivo and their presence in resected pancreatic primary tumors is significantly associated with shortened overall survival. ALDH+ cells were also commonly found in metastatic pancreatic cancer lesions even in patients whose primary tumors lacked ALDH expression. Progression to metastatic disease requires cell migration to ectopic sites in addition to clonogenic growth potential, and we found that ALDH+ cells expressed lower levels of E-CADHEDRIN and higher levels of SLUG consistent with the epithelial to mesenchymal transition (EMT). Moreover, compared to ALDHneg cells, ALDH+ pancreatic cancer cells were more invasive and migratory in vitro and metastatic in vivo. Therefore, in pancreatic carcinoma, CSC express key functional properties that suggest a major role in the formation of metastases and disease progression.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):IA8-1.
Abstract IA9-1: Is taxol resistance related to tubulin isotypes?
Authors: Horwitz Susan Band 
Published: June 2012

Abstract
Microtubules are an important component of the euraryotic cytoskeleton and are essential for normal cell division. They are also a validated target for antitumor drugs, such as taxol, that bind to the – tubulin subunit in the microtubule polymer. Endogenous resistance or the development of drug resistance during treatment with taxol is a serious clinical problem. Understanding the emergence of taxol resistance and being able to predict patient response would enhance the efficacy of the drug. A number of mechanisms, such as overexpression of P-glycoprotein that acts as an ATP-dependent drug-efflux pump, or mutations in the drug-binding site in tubulin, have been described. Of particular interest to our research, is the aberrant expression of β-tubulin isotypes in cancer.
Tubulin is composed of α- and β-tubulin subunits that exist as heterodimers. In humans, there are seven β-tubulins and eight β-tubulins, each the product of a distinct gene located on different chromosomes. Each isotype can undergo extensive posttranslational modifications such as acetylation, phosphorylation, polyglutamylation, polyglycylation and reversible tyrosination, all of which add to the complexity of the tubulin/microtubule system. Most of the divergence between the isotypes is found in the last 15-20 amino acids at the carboxyl end of tubulin and in addition, most posttranslational modifications of tubulin occur in this region.
For the most part, tubulin isotypes have been detected at the mRNA level or at the protein level with isotype-specific antibodies. Our laboratory has developed proteomic methods, including highresolution isoelectrofocusing, CNBr cleavage and mass spectrometry that allow us to determine the isotype content and posttranslational modifications of tubulin in cells and tissues in a single experiment. We have utilized taxol, which enhances tubulin polymerization, to isolate sufficient tubulin from cells and are developing methods to quantify tubulin isotype expression by mass spectrometry.
The overexpression of βIII-tubulin has been associated with resistance to taxanes in a range of tumor types and in taxol-resistant cells generated in our laboratory. βIII-tubulin is normally expressed only in neuronal cells. However, it is aberrantly expressed in numerous malignant tissues and could be a meaningful prognostic factor for treatment outcome. As has been shown by others in different tumors, in our laboratory an immunohistochemical analysis of 47 tumor specimens from head and neck patients determined that overexpression of β-III tubulin was highly prognostic of survival.
Citation Information: Clin Cancer Res 2010;16(14 Suppl):IA9-1.