bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B50: Design, synthesis, and functional characterization of new cycle-peptides inhibitors for C-X-C chemokine receptor-4
Authors: Portella L. , Napolitano M. , Consales C. , Polimeno M. N. , D'Alterio C. , Arra C. , Vitale R. , Amodeo P. , De Luca S. , Monfregola L. , Castello G. , Scala S. 
Published: January 2011

Abstract
Inhibition of the axis CXCR4/CXCL12 can affect tumor growth and metastases. Moreover, CXCR4 inhibition increases hematopoietic stem cell mobility in patients undergoing autologous transplantation for myeloma and non-Hodgkin lymphoma. Although several inhibitors were described neither one reached satisfactory efficacy, bioavailability and acceptable toxicity.
To develop new CXCR4 inhibitors through a rationale design approach, comparative studies were undertaken evaluating the N-terminal structure of the ligand CXCL12 and v-MIP II, an inhibitory chemokine like produced by the herpes virus 8-Kaposi associated. A common amino acidic motif (RFF) was identified in both structures although in inverted orientation. Having as a core this small domain, a new library (20 units) of cycle-peptide molecules was generated. 20 units of cycle-peptide molecules were synthesized that consists of 5 and 7 amino-acid residues cycled by a S-S bridge designed to interact with the receptor CXCR4. The peptides were characterized for functionally CXCR4 interaction through: 1. inhibition of CXCR4 binding; 2. inhibition of migration CXCL12-induced; 3. inhibition of calcium CXCL12-induced; 4. Inhibition of P-Erk CXCL12-induced. Four peptides were identified as possible CXCR4 inhibitors. These four CXCR4 inhibitory peptides were further evaluated for the in vivo efficacy through inhibition of metastasis formation. B16 mouse melanoma cells transfected with CXCR4 were injected in the vein tail in C57 Bl mice and peptide treatment followed for 10 days. Dramatic reduction in number and size of lung metastases were registered in mice peptides-treated. Moreover, xenograft of human renal cancer cells SN12C-EGFP were subcutaneously injected and systemic peptides treatment followed for 10 days. Statistically significant decrease in tumor growth was showed in peptides treated mice.
Taken together the data define three new CXCR4 inhibitory peptides, designed through innovative strategy, effective in “in vivo” deserving further development.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):B50
Abstract CN1-2: Mutations and expression profile to guide treatment in sarcomas and GIST
Authors: Blay Jean-Yves 
Published: January 2011

Abstract
Recent progress in the understanding of the biology of soft tissue sarcomas and locally aggressive connective tissue tumors have enabled the identification of distinct molecular and pathological entities: six molecular subgroups of connective tissue tumors may be distinguished: 1) sarcoma with specific translocations generating fusion gene whose protein products modulate transcription or may act as growth factors (e.g. EWS/Fli1 in Ewing sarcomas, PDGF-col1a1 in DFSP); 2) sarcomas with mutated activated kinases (KIT in GIST); 3) sarcomas with deletion of tumor suppressor genes such as NF1 sarcomas, or rhabdoid tumors (INI1); 4) Sarcomas with simple genetic alterations (mdm2/cdk4 amplification in WD/DD liposarcomas; 5) Sarcomas with gross genetic alterations (e.g. leiomyosarcomas); 6) Tumors with alterations of the intercellular adhesion pathways (aggressive fibromatosis with APC deletion or β catenin mutations). This classification is rapidly evolving.
The identification of the “driver” mutation in some of these diseases paved the way for the selection of efficient targeted therapies. One of the most demonstrating examples is the identification of KIT and PDGFRA kinase mutations in GIST which led to the development of imatinib, sunitinib, and more recently hsp90 inhibitors. Imatinib is also active in DFSP, a PDGF driven tumor and in giant cell tumor of the soft part (pigmented villonodular synovitis), an M-CSF driven tumor. Within the 1st molecular subgroup of tumors, in Ewing sarcoma, whose fusion gene product regulates IGFBP3, anti-IGF1R Ab yielded responses in now several phase I and II trials. Within the 4th molecular subgroup of tumors, CDK4 inhibitors and MDM2 inhibitors are currently being investigated in the clinical setting in well differentiated liposarcomas. In addition to these examples, more empiric approaches are also developed, with anti-angiogenics (pazopanib, sorafenib) and mTOR inhibitors (deforolimus) showing efficacy in phase II trials in subtypes of sarcomas; mTOR inhibitors are also currently evaluated in phase II and III trials.
The understanding of the driver molecular alterations of these tumors now guides the development of targeted treatment inhibiting driver mutations. Translational research is critical for the development of new treatments, and will be essential to understand the biological mechanisms of response and resistance in these tumor models
Citation Information: Clin Cancer Res 2010;16(7 Suppl):CN1-2
Abstract CN4-1: Genome-wide discovery and clinical validation of pharmacogenomic markers for chemotherapy
Authors: Huang R. Stephanie 
Published: January 2011

Abstract
Pharmacogenomics is emerging as an important component in facilitating both new drug development and in improving the utility of existing chemotherapeutic agents. However, the process of identifying these genetic variants is still evolving and there are a number of different approaches that can be employed. Typically, identification of the genetic contribution to drug response comes from clinical observations; but these clinical studies are limited by our inability to control environmental factors in vivo, the difficulty of manipulating the in vivo system to evaluate biological changes and the lack of single drug regimens in large oncology trials. Therefore, we have developed a whole genome, cell-based model for identifying genetic variation(s) important in chemotherapeutic agent-induced cytotoxicity using lymphoblastoid cell lines (LCLs) from samples included in the International HapMap project as well as extended CEPH pedigrees that have been subject to extensive genotyping for linkage mapping studies. We have identified that SNPs associated with chemotherapeutic sensitivity are enriched in expression quantitative trait locus (eQTLs). The presentation will include an overview of current cell-based models used in pharmacogenomic discovery, replication and translation into the clinical arena. As technology advances, a more comprehensive evaluation of the human genome, including the examination of rare SNPs, copy number variations, tandem repeats, epigenetic effects, will further improve our understanding of the relationship between genetics and drug response in cancers.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):CN4-1
Abstract CN4-2: Genetic polymorphisms of ABC transporters in cancer chemotherapy: Development of SmartAmp2 method for clinical genetic testing
Authors: Ishikawa Toshihisa , Aw Wanping , Lezhava Alexander , Hayashizaki Yoshihide 
Published: January 2011

Abstract
Pharmacogenomics data can facilitate our understanding of the sources of variability in drug response, which can potentially lead to improved safety and efficacy of chemotherapy for individual patients. Genetic polymorphisms of human ABC transporter genes are reportedly related to the risk of diseases or patients' responses to medication. However, a key requirement for the development of individualized medicine or personalized therapy is the ability to rapidly and conveniently test patients for genetic polymorphisms and/or mutations. For rapid genetic diagnosis, we have recently developed a rapid and cost-effective method named “SmartAmp2” that enables us to clinically test genotypes. Since ABCB1, ABCG2, ABCC4, and ABCC11 genes are known to be critically involved in cancer chemotherapy, we have examined whether the SmartAmp2 method could detect SNPs in those ABC transporter genes. In our study using clinical samples, the SmartAmp2 method has been proven to accurately detect and discriminate all possible homozygotes and heterozygotes of the SNPs we tested. Furthermore, we developed SmartAmp2 primers to detect mutations of K-RAS and EGFR genes in colon and lung cancers. Since the SmartAmp2 method enables us to detect genetic polymorphisms or mutations within 30 to 45 min under isothermal conditions without DNA isolation and PCR amplification, this method would provide a practical tool of genetic testing in cancer chemotherapy.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):CN4-2
Abstract ED3-1: Genome-wide association studies in cancer: Insights in cancer etiology
Authors: Chanock Stephen J. 
Published: January 2011

Abstract
Genome-wide association studies (GWAS) in cancer have already discovered over 100 novel regions of the genome associated with cancer risk. For nearly all regions conclusively identified by GWAS, the estimated per allele effect sizes are less than 1.3 and the susceptibility alleles are common, with minor allele frequencies greater than 5%. Each common allele appears to confer a small effect overall, underscoring the complex nature of common genetic variants that contribute to primary carcinogenesis. Interestingly, none of the variant markers associated with etiology have been strongly associated with outcomes, such as metastatic disease or survival, which suggests that common genetic variation may influence distinct processes important for carcinogenesis as opposed to those associated with disease progression. GWAS have also demonstrated that the spectrum of cancers could have distinct genomic architectures (e.g., differential contributions of alleles with a range of frequencies and effect sizes). GWAS have identified perhaps as many as 30 regions in the genome associated with prostate cancer, whereas for lung cancer, only three so far, and one of them on chromosome 15q24/25 is also strongly associated with smoking behavior phenotypes. This observation could be related to the strong environmental effect of smoking on lung cancer. It is also notable that GWAS have mapped multiple cancers to two distinct regions, 8q24 and 5p15.33. Consequently, follow-up studies are needed to map the most promising variants, preferably in different populations that can point investigators towards the optimal variants for studies designed to investigate plausibility for the association. Consequently, parallel laboratory investigation of each region can lead to new insights into novel pathways and mechanisms associated with carcinogenesis. Though there has been considerable discussion of the promise of common variants as markers for disease risk, it is too early to apply the common variants to clinical and public health venues. The success of GWAS has opened new horizons for exploration and highlighted the complex genomic architecture of disease susceptibility.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):ED3-1
Abstract ED4-3: PET tracer for therapy monitoring
Authors: Wester Hans-Jürgen , Buck Andreas 
Published: January 2011

Abstract
Molecular or metabolic imaging with PET plays a crucial role not only for the individual patient management but also for further validation of new therapies. The concept of using PET and [18F]fluorodeoxyglucose (FDG) for assessment of response is based on early changes in tumor glucose use which correlate to the effectiveness of a specific treatment. However, FDG-PET is a suitable surrogate marker for response prediction only in intensely FDG-avid tumors. For imaging in the context of planning of a chemotherapeutic intervention and for therapy monitoring, tracers with higher specificity are required. With the advent of molecular imaging, tumor tissue can be non-invasively characterized by imaging probes targeting biological processes such as metabolism, cell growth and migration as well as vascularization and oxygen tension. Based on such measurements signals can be defined which detect and quantitatively describe pharmacologic effects in tumor tissues within a few days after initiation of therapy. Initial results suggest that therapeutic strategies can be successfully adapted based on molecular imaging results, which are able to identify responders with improved clinical outcome. These specific and sensitive imaging signals are needed to match therapeutic targets with imaging agents addressing the same or corresponding biologic processes. Inhibiting neoangiogenesis, for example, represents an attractive therapeutic option, which benefits from imaging probes addressing molecular targets such as integrins and VEGF receptors as well as measuring perfusion and blood volume. Prior to treatment, these tracers enable to define the expression of a specific target. Alternative probes for molecular cancer imaging address metabolic key processes, such as cell proliferation ([18F]FLT), protein biosynthesis ([18F]FET, [11C]MET), neoangiogenesis ([18F]Galacto-RGD), hypoxia ([18F]FAZA), somatostatin receptor expression ([68Ga]DOTATOC), estrogen receptor expression ([18F]FES) or new concepts, such as cytokine / chemokine receptor expression ([68Ga]CPCR4). For response evalu ation, the tracer uptake has to correlate with the therapeutic effect at all imaging time points. Here, tracers with high sensitivity are required, allowing for the early assessment of therapeutic effects and response evaluation.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):ED4-3
Cell-Penetrating TAT-FOXO3 Fusion Proteins Induce Apoptotic Cell Death in Leukemic Cells
Authors: Essafi Makram , Baudot Alice D. , Mouska Xavier , Cassuto Jill-Patrice , Ticchioni Michel , Deckert Marcel 
Published: January 2011

Abstract
FOXO proteins are Akt-regulated transcription factors involved in the control of cell cycle, DNA repair, stress defense, apoptosis, and tumor suppression. We reported that plasmid-based overexpression of constitutively active FOXO3 in cells from chronic lymphocytic leukemia (CLL) reduced their survival, suggesting that increasing FOXO3 activity in hematologic malignancies may represent a promising therapeutic strategy. The transactivating transcription factor (TAT) protein transduction domain (PTD) derived from the HIV TAT protein was shown to efficiently deliver macromolecular cargo in various cell types. In this study, wild-type FOXO3 and FOXO3 mutated on Akt sites [FOXO3 T32A/S253A/S315A or TM (triple mutant)] were fused to the TAT-PTD. Using biochemical techniques, flow cytometry, and microscopy analysis, we found a rapid and dose-dependent cell penetration into leukemic cells of unlabeled and fluorescein isothiocyanate-labeled TAT-FOXO3 fusion proteins followed by their accumulation within nuclear and cytoplasmic compartments. Treatment with TAT-FOXO3 TM—but not wild-type TAT-FOXO3—proteins induced Jurkat and K562 leukemic cell death and affected cell viability of other hematologic malignancies including primary cells from CLL. Cell transduction with TAT-FOXO3 TM induced apoptotic cell death as shown by morphologic changes, Annexin V/7-AAD (7-amino-actinomycin D) staining, activation of effector caspases, and PARP cleavage, caspase blockade through the use of the inhibitor Z-VAD, and expression of Bim and p27KIP1. By contrast, TAT-FOXO3 TM blocked cell proliferation of primary T cells, without affecting their viability. Together, our data show that cell penetrating TAT-FOXO3 TM fusion proteins constitute novel potential therapeutic agents in the treatment of lymphoproliferative disorders and hematologic malignancies. Mol Cancer Ther; 10(1); 37–46. ©2011 AACR.
Therapeutic Targeting the Loss of the Birt-Hogg-Dubé Suppressor Gene
Authors: Lu Xiaohong , Wei Wenbin , Fenton Janine , Nahorski Michael S. , Rabai Erzsebet , Reiman Anne , Seabra Laurence , Nagy Zsuzsanna , Latif Farida , Maher Eamonn R. 
Published: January 2011

Abstract
Brit-Hogg-Dubé (BHD) syndrome, an autosomal dominant familial cancer, is associated with increased risk of kidney cancer. BHD syndrome is caused by loss-of-function mutations in the folliculin (FLCN) protein. To develop therapeutic approaches for renal cell carcinoma (RCC) in BHD syndrome, we adopted a strategy to identify tumor-selective growth inhibition in a RCC cell line with FLCN inactivation. The COMPARE algorithm was used to identify candidate anticancer drugs tested against the NCI-60 cell lines that showed preferential toxicity to low FLCN expressing cell lines. Fifteen compounds were selected and detailed growth inhibition (SRB) assays were done in paired BHD RCC cell lines (UOK257 derived from a patient with BHD). Selective sensitivity of FLCN-null over FLCN-wt UOK257 cells was observed in seven compounds. The most selective growth-inhibitory sensitivity was induced by mithramycin, which showed an approximately 10-fold difference in GI50 values between FLCN-null (64.2 ± 7.9 nmol/L, n = 3) and FLCN-wt UOK257 cells (634.3 ± 147.9 nmol/L, n = 4). Differential ability to induce caspase 3/7 activity by mithramycin was also detected in a dose-dependent manner. Clonogenic survival studies showed mithramycin to be approximately 10-fold more cytotoxic to FLCN-null than FLCN-wt UOK257 cells (200 nmol/L). Following mithramycin exposure, UOK257-FLCN-null cells were mainly arrested and blocked in S and G2-M phases of the cell cycle and low dose of rapamycin (1 nmol/L) potentiated mithramycin sensitivity (1.5-fold in G2-M population and 2-fold in G2-M period time, 2xGI50, 48 hours). These results provide a basis for further evaluation of mithramycin as a potential therapeutic drug for RCC associated with BHD. Mol Cancer Ther; 10(1); 80–9. ©2011 AACR.
A Combined Preclinical Therapy of Cannabinoids and Temozolomide against Glioma
Authors: Torres Sofía , Lorente Mar , Rodríguez-Fornés Fátima , Hernández-Tiedra Sonia , Salazar María , García-Taboada Elena , Barcia Juan , Guzmán Manuel , Velasco Guillermo 
Published: January 2011

Abstract
Glioblastoma multiforme (GBM) is highly resistant to current anticancer treatments, which makes it crucial to find new therapeutic strategies aimed at improving the poor prognosis of patients suffering from this disease. Δ9-Tetrahydrocannabinol (THC), the major active ingredient of marijuana, and other cannabinoid receptor agonists inhibit tumor growth in animal models of cancer, including glioma, an effect that relies, at least in part, on the stimulation of autophagy-mediated apoptosis in tumor cells. Here, we show that the combined administration of THC and temozolomide (TMZ; the benchmark agent for the management of GBM) exerts a strong antitumoral action in glioma xenografts, an effect that is also observed in tumors that are resistant to TMZ treatment. Combined administration of THC and TMZ enhanced autophagy, whereas pharmacologic or genetic inhibition of this process prevented TMZ + THC-induced cell death, supporting that activation of autophagy plays a crucial role on the mechanism of action of this drug combination. Administration of submaximal doses of THC and cannabidiol (CBD; another plant-derived cannabinoid that also induces glioma cell death through a mechanism of action different from that of THC) remarkably reduces the growth of glioma xenografts. Moreover, treatment with TMZ and submaximal doses of THC and CBD produced a strong antitumoral action in both TMZ-sensitive and TMZ-resistant tumors. Altogether, our findings support that the combined administration of TMZ and cannabinoids could be therapeutically exploited for the management of GBM. Mol Cancer Ther; 10(1); 90–103. ©2011 AACR.
Glutathione-Conjugate Transport by RLIP76 Is Required for Clathrin-Dependent Endocytosis and Chemical Carcinogenesis
Authors: Singhal Sharad S. , Wickramarachchi Dilki , Yadav Sushma , Singhal Jyotsana , Leake Kathryn , Vatsyayan Rit , Chaudhary Pankaj , Lelsani Poorna , Suzuki Sumihiro , Yang Shaohua , Awasthi Yogesh C. , Awasthi Sanjay 
Published: January 2011

AbstractTargeted depletion of the RALBP1-encoded 76-kDa splice variant, RLIP76, causes marked and sustained regression of human xenografts of lung, colon, prostate, and kidney cancers without toxicity in nude mouse models. We proposed that the remarkable efficacy and broad spectrum of RLIP76-targeted therapy is because its glutathione-conjugate (GS-E) transport activity is required for clathrin-dependent endocytosis (CDE), which regulates all ligand-receptor signaling, and that RLIP76 is required not only for survival of cancer cells but also for their very existence. We studied RLIP76 mutant proteins and the functional consequences of their expression into RLIP76−/− MEFs, identified key residues for GS-E binding in RLIP76, established the requirement of RLIP76-mediated GS-E transport for CDE, and showed a direct correlation between GS-E transport activities with CDE. Depletion of RLIP76 nearly completely blocked signaling downstream of EGF in a CDE-dependent manner and Wnt5a signaling in a CDE-independent manner. The seminal prediction of this hypothesis—RLIP76−/− mice will be deficient in chemical neoplasia—was confirmed. Benzo[a]pyrene, dimethylbenzanthracene, and phorbol esters are ineffective in causing neoplasia in RLIP76−/−. PMA-induced skin carcinogenesis in RLIP76+/+ mouse was suppressed completely by depletion of either PKCα or RLIP76 by siRNA or antisense and could be restored by topical application of RLIP76 protein in RLIP76−/− mouse skin. Likewise, chemical pulmonary carcinogenesis was absent in female and nearly absent in male RLIP76−/− mice. In RLIP76−/− mice, p53, p38, and JNK activation did not occur in response to either carcinogen. Our findings show a fundamental role of RLIP76 in chemical carcinogenesis. Mol Cancer Ther; 10(1); 16–28. ©2011 AACR.
Bortezomib Sensitizes Malignant Human Glioma Cells to TRAIL, Mediated by Inhibition of the NF-κB Signaling Pathway
Authors: Jane Esther P. , Premkumar Daniel R. , Pollack Ian F. 
Published: January 2011

Abstract
Previous studies have shown that the tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has significant apoptosis-inducing activity in some glioma cell lines, although many lines are either moderately or completely resistant, which has limited the therapeutic applicability of this agent. Because our recent studies showed that inhibition of proteasomal function may be independently active as an apoptosis-inducing stimulus in these tumors, we investigated the sensitivity of a panel of glioma cell lines (U87, T98G, U373, A172, LN18, LN229, LNZ308, and LNZ428) to TRAIL alone and in combination with the proteasome inhibitor bortezomib. Analysis of these cell lines revealed marked differences in their sensitivity to these treatments, with two (LNZ308 and U373) of the eight cell lines revealing no significant induction of cell death in response to TRAIL alone. No correlation was found between sensitivity of cells to TRAIL and expression of TRAIL receptors DR4, DR5, and decoy receptor DcR1, caspase 8, apoptosis inhibitory proteins XIAP, survivin, Mcl-1, Bcl-2, Bcl-Xl, and cFLIP. However, TRAIL-resistant cell lines exhibited a high level of basal NF-κB activity. Bortezomib was capable of potentiating TRAIL-induced apoptosis in TRAIL-resistant cells in a caspase-dependent fashion. Bortezomib abolished p65/NF-κB DNA-binding activity, supporting the hypothesis that inhibition of the NF-κB pathway is critical for the enhancement of TRAIL sensitization in glioma cells. Moreover, knockdown of p65/NF-κB by shRNA also enhanced TRAIL-induced apoptosis, indicating that p65/NF-κB may be important in mediating TRAIL sensitivity and the effect of bortezomib in promoting TRAIL sensitization and apoptosis induction. Mol Cancer Ther; 10(1); 198–208. ©2011 AACR.