bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PL07-02: Whole genome approaches to identify pharmacogenomic markers of anticancer agents
Authors: Stark Amy , Delaney Shannon , Im Hae Kyung , Wheeler Heather , Gamazon Eric , Dolan M. Eileen 
Published: June 2012

Abstract
Preclinical and clinical genome-wide association studies (GWAS) in oncology provide an unprecedented opportunity for a comprehensive and unbiased assessment of the heritable factors associated with drug response. For chemotherapeutic drugs, there are many challenges with performing a clinical GWAS, including staggering costs because a homogenous population of patients treated with the same dosage regimen and minimal confounding variables is required. To get around these issues, we have developed preclinical cell-based models as a pharmacogenomic discovery tool but also a means to replicate or validate findings from clinical GWAS. Our model utilizes HapMap lymphoblastoid cell lines (LCLs) derived from individuals within different world populations (Caucasian, African, Asian, African American) that are evaluated for drug sensitivity to chemotherapeutic agents (platinating agents, antimetabolites, cyclophosphamide, paclitaxel). Evaluation of inter-ethnic differences revealed that LCLs from Africans tend to be more sensitive to antimetabolites and less sensitive to platinating agents than Caucasian derived LCLs. These LCLs are rich in genetic data as many are part of the International HapMap and the more recent 1000 Genome project. We utilized this data to identify disproportionately more expression quantitative trait loci (eQTLs, indicating that a SNP genotype is associated with the transcript abundance level of a gene) associated with pharmacologic traits than expected by chance based on minor allele frequency. We are attempting to unravel the functional consequence of top pharmacologic GWAS SNPs with local and distant regulatory roles in cellular resistance to chemotherapeutic agents. For example, we discovered a SNP (master regulator) that is local to PRPF39 and distant to more than 100 genes that is associated with cisplatin-induced cytotoxicity in LCLs derived from African populations. Our cell-based model provides potential targets for therapeutic intervention and provides us with a greater understanding of the genetic contribution to interethnic variation in chemotherapeutic sensitivity.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PL07-02.
Abstract PL08-01: Differential splicing of oncogenes and tumor suppressor genes between African and Caucasian Americans: Contributing factor in prostate cancer health disparities?
Authors: Lee Norman H. , Wang Bi-Dar , Patierno Steven R. 
Published: June 2012

Abstract
There are striking population disparities in prostate cancer (PCa) risk and survival outcome borne out of current health statistics data. This is particularly evident between African Americans (AA) and their Caucasian American (CA) counterparts. Epidemiologic studies have shown that higher mortality and recurrence rates of PCa is still seen in AA men even after adjustment for socioeconomic status, environmental factors and health care access. To test whether differential mRNA splicing may play a role in PCa health disparities, RNA from PCa and patient-matched normal prostate needle biopsies from AAs and CAs was processed and hybridized onto the Affymetrix human Exon 1.0 ST arrays. A 4-way statistical design (10% FDR, &gt;1.5 fold-change) was employed in the following comparisons: AA normal vs. CA normal, AA cancer vs. CA cancer, AA cancer vs. AA normal, and CA cancer vs. CA normal. Our analysis identified &gt;800 genes undergoing differential mRNA splicing between AA and CA cancer specimens. Notably, many of these genes reside within canonical oncogenic signaling pathways. To further delineate the functional consequences of these splice variants, exon-specific and/or exon junction-specific small interfering RNAs (siRNAs) were employed to suppress splice variants for 4 oncogenes (PIK3CD, FGFR3, MET and RASGRP2) in PCa cell lines derived from the AA and CA patient populations. The targeted knockdown of population-specific splice variants appears to have differential effects on cell proliferation and invasive. For example, the splice variant for phosphoinositide-3 kinase delta (PI3KCD) found in AA PCa specimens encodes a more aggressive version of the gene (i.e., leading to greater proliferation and invasion of cancer cells) compared to the variant counterpart found in CA PCa specimens. Taken together, our data suggest that differential mRNA splicing may be critical in PCa health disparities between the AA and CA populations. These findings should advance our knowledge on the molecular mechanisms underlying PCa health disparities, and may facilitate the development of novel strategies for PCa detection, diagnosis, prognosis, and therapy in the AA population. This work was supported by NCI grant 5U01-CA-116937, ACS-IRG-08-091-01 and the Affymetrix Collaborations in Cancer Research Program.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PL08-01.
Abstract PL08-02: Fine mapping of genetic associations in African American colorectal cancer
Authors: Ellis Nathan A. , Kupfer Sonia S. 
Published: June 2012

Abstract
Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified risk variants in 14 genomic regions through the study of Europeans with CRC. In genotype analysis of a European American CRC case-control group, effects sizes and directions of association for 24 SNPs tested, which localize to 10 of the 14 previously identified regions, were consistent with GWAS results; in contrast, in an African American CRC case-control group, the associations ran in the opposite direction for 9 of 22 SNPs tested, indicating significant genetic heterogeneity in CRC associations in African Americans compared to European Americans. We conclude that genetic markers that identify CRC risk in persons of European ancestry do not identify CRC risk in African Americans. Two hypotheses may explain the genetic heterogeneity between European and African Americans: (i) The risk alleles in both populations are the same, however, the genetic architecture differs such that other SNPs that are linked to these same risk alleles will make better markers for African American CRC risk. (ii) The underlying risk alleles are different between the two populations. A corollary of this hypothesis is that the allele frequencies of the risk alleles must be low (&lt;5%), because most the frequent genetic polymorphisms are shared between European and African populations. Distinguishing these hypotheses is important because genetic risk associated with rare alleles could have larger effect sizes (ORs&gt;2, for example), which could make genetic risk modeling more determinative. Furthermore, identification of multiple rare alleles, each with a moderate risk effect, could explain the missing heritability problem. To address these hypotheses, we have drilled down on each of the genetic regions identified in the European GWAS using systematic genotyping and deep re-sequencing in African American CRC cases and population-matched controls. Analysis of tagSNPs in two genes so far analyzed, GREM1 and BMP4, have demonstrated multiple, independent SNP associations, which are not correlated with SNPs previously identified in persons of European descent. Because novel SNP associations are detected in each of these genes, we suggest that rare alleles underlie these genetic risk associations. We are presently using the deep re-sequencing analysis to identify candidate risk variants, which we will then test in functional studies. Ultimately, the analysis will permit better quantification of CRC risk, and it may lead to risk assessment models that can be used clinically for screening and surveillance.
Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):PL08-02.
Abstract A111: A phase I, dose escalation study of TB-403, a monoclonal antibody directed against PlGF, in patients with solid tumors
Authors: Lassen Ulrik , Nielsen Dorte , Sørensen Morten , Rønnengart Eva , Eldrup Katrine , Bentzon Karin , Winstedt Lena , Niskanen Titti , Pakola Steve , Stassen Jean-Marie , Glazer Steven 
Published: June 2012

Abstract
Rationale and Objectives: TB-403 is a humanised recombinant immunoglobulin G isotype 1 monoclonal antibody expressed in Chinese hamster ovary cells and directed to the receptor-binding site of placental growth factor (PlGF). The antibody is highly specific and does not cross-react with vascular endothelial growth factor A (VEGFA). PlGF levels are low in normal tissues, but up-regulated in several pathological conditions, including several types of cancer. TB-403 has been shown to significantly inhibit tumor growth in xenograft tumor models. The primary objective of the phase 1 study was to determine the maximum tolerated dose (if &lt; 30 mg/kg) and to evaluate safety and tolerability of TB-403 in patients with advanced solid tumors. Secondary objectives included evaluation of pharmacokinetics (PK), objective tumor response and drug effect on PlGF and other molecular markers.
Methods: In this multi-center study, cohorts of 3 patients were treated with 8 weekly doses of 1.25, 5, or 10 mg/kg or 3 doses of 20 and 30 mg/kg once every three weeks (q3w). Six additional patients were treated with 30 mg/kg q3W. Patients showing objective tumor response or stable disease (SD) after 8 weeks were offered extended therapy. Main eligible criteria were: solid tumor with no other treatment options, ECOG performance status 0–1, normal organ function, and no prior anticancer therapy within 30 days (bevacizumab within 60 days).
Results: A total of 23 patients were accrued. No DLT, changes in ECG, laboratory findings or urine analysis were seen, except for one patient with an unrelated biliary stenoses. Of related or possibly related grade III or IV adverse events only one episode of pulmonary embolism, one case of dyspnoea and a case of dry skin were observed. Related or possibly related grade I and II adverse events included skin rash (1 patient), fatigue (5 patients), fever (1 patient), diarrhoea (1 patient), and hypertension (1 patient). No objective responses according to RECIST criteria were observed but five patients had SD ≥ 8 weeks, including 2 patients (pancreatic adenocarcinoma and esophageal squamous carcinoma) treated with weekly 5 mg/kg TB-403 with SD &gt; 10 months.
Conclusion: TB-403 was well tolerated. MTD was not established due to lack of dose-limiting toxicity up to a dose of 10 mg/kg weekly and 30 mg/kg q3w. Prolonged SD (&gt; 10 months) was seen in two patients treated with 5 mg/kg weekly TB-403. Pharmacokinetic and molecular pharmacodynamic data will be presented.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A111.
Abstract A123: MGMT and MMR testing: NSCLC susceptibility to temozolomide
Authors: Emery Ivette F. , Battelli Chiara , Cai Li , Hayes Daniel 
Published: June 2012

Abstract
Background: The functional status of DNA repair systems impacts the sensitivity of tumors to chemotherapeutics. The anti-neoplastic activity of alkylating agents, such as temozolomide, is affected by the direct repair enzyme, O6-Methylguanine-DNA methyltransferase (MGMT), and by the mismatch repair system (MMR). Lack of MGMT makes a tumor susceptible to temozolomide, while a non-functional MMR renders the tumor resistant to this agent. We assayed these repair systems in a group of patients affected by Non-small cell lung cancer (NSCLC) in order to investigate the potential benefit of temozolomide to these patients, a group with one of the highest mortality rate and for which alkylating agents are not currently used.
Method: The status of MGMT and MMR were determined by MGMT promoter hypermethylation and by Microsatellite Instability (MSI) testing on 96 paraffin-embedded NSCLC samples. MGMT hypermethylation results in gene silencing and low levels of the protein. This test was conducted at OncoMethylome by methylation-specific PCR of the gene's promoter sequences. MSI testing was conducted at LabCorp by multiplex PCR of six microsatellite regions. Samples with a normal MMR system show genomic stability in the microsatellite regions, while samples with an impaired MMR system show instability in one or more of these regions.
Results: Ninety three (93) samples yielded interpretable results. Most of them (80) had no detected defects in the two repair mechanisms assessed. Nine (9) samples (10%) had hypermethylation of the MGMT promoter and four (4) samples (4%) had microsatellite instability. The defects were not overlapping. These results indicate that NSCLC has a low rate of MGMT silencing by promoter hypermethylation and also a very low rate of mutations in the MMR proteins Conclusions: MGMT silencing by promoter hypermethylation sensitizes cells to apoptosis by temozolomide, but only in the presence of a functional MMR system. If MMR is disabled, apoptosis is not triggered. Our results indicate that although NSCLC is not particularly susceptible to alkylating agents, there are no indications that it has active mechanisms of resistance to them. Our understanding of the molecular characteristics of NSCLC suggests that alkylating agents such as temozolomide, in combination with inhibitors that artificially lower the expression of MGMT, may be viable option to treat NSCLC.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A123.
Abstract A131: Tissue distribution and tumor uptake of novel folate receptor targeted epothilone, BMS-745493 in CD2F1 mice after systemic administration
Authors: Gan Jinping , Wang Lifei , Shen Hong , Jian Wenying , Menard Krista , Hong Yang , Yuan Tian , Zhang Duxi , Bonacorsi Samuel , Lee Francis 
Published: June 2012

Abstract
BMS-753493 is an epothilone folate conjugate targeting folate receptor over-expressing tumor cells. The tissue distribution of radioactivity in tumor bearing mice was studied using quantitative whole body autoradiography (QWBA) after a single intravenous administration of [3H]BMS-753493 or its active epothilone moiety, [3H]BMS-748285, to female CD2F1 mice bearing bilateral tumors: murine lung tumor M109, and its folate receptor expressing variant 98M109.
[3H]BMS-753493 derived radioactivity was extensively distributed to tissues. Organs that had the highest radioactivity were gastrointestinal tract and contents, liver, kidney, heart, bone marrow and tumors. In contrast, very little radioactivity was observed in the brain and spinal cord. Folate receptor over-expressing tumor 98M109 had higher radioactivity levels than M109 tumors at all time points, and 98M109 tumor had higher radioactivity than all normal tissues at 24 and 48 h post dose. Similar to [3H]BMS-753493 distribution, [3H]BMS-748285 derived radioactivity was extensively distributed to tissues after IV administration of [3H]BMS-748285. However, no difference in radioactivity was observed between the 98M109 tumor and all normal tissues at 24 and 48 h post dose, although slightly higher radioactivity was observed in 98M109 tumor as compared to M109 tumor. The preferential distribution of BMS-753493-related material to folate receptor expressing tumor 98M109 was further demonstrated in a study with unlabeled materials followed by LC/MS/MS measurement. After administration of BMS-753493, levels of BMS-748285 were much higher in 98M109 tumors than in M109 tumors, while no difference was observed between those two tumors after administration of BMS-748285. Similarly, much lower levels of BMS-748285 were observed in the heart and kidney tissues after administration of BMS-753493 as compared to those observed after dosing of BMS-748285. The relatively lower levels of active epothilone in normal tissues after BMS-753493 dosing suggest a potential wider therapeutic window for BMS-753493.
In summary, this study has clearly demonstrated that the epothilone folate conjugate, BMS-753493, enabled the preferentially distribution of the active epothilone to the folate receptor over-expressing 98M109 tumor. This preferential distribution supports targeted delivery of cytotoxics through the folate receptor and correlates well with in vivo antitumor activity observed in mouse xenograft models over-expressing folate receptors.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A131.
Abstract A15: A phase I and pharmacokinetic study of the vascular disrupting agent AVE8062 in combination with docetaxel, administered once every 3 weeks to patients with advanced solid tumors
Authors: Tresca Patricia , Tosi Diego , Van Doorn Leni , Fontaine Helene , Van der Gaast Ate , Veyrat-Follet Christine , Oprea Corina , Dieras Veronique , Eskens Ferry Alm 
Published: June 2012

Abstract
Background: AVE8062 is a Vascular Disrupting Agent, derivative of Combretastatin A4, which targets endothelium and causes shutdown of blood perfusion. Preclinical synergy between AVE8062 followed by docetaxel prompted clinical exploration of this combination.
Methods: Objectives were to determine dose-limiting toxicities (DLTs), maximum tolerated dose (MTD) and PK profile of intravenous AVE8062 on day 1 followed by D 75 mg/m2 on day 2 administered once every 3 weeks. Anti-tumor activity was assessed every 2 cycles.
Results: Twenty-nine adult pts with advanced solid tumors (M/F 11/18), median age 51 (range 28–71), were enrolled and treated at AVE8062 dose levels of 11.5 mg/m2 (N=3), 15.5 mg/m2 (N=5), 20 mg/m2 (N=3), 25 mg/m2 (N=6), 30 mg/m2 (N=3), 35 mg/m2 (N=3) and 42 mg/m2 (N=6). Median number of cycles per patient was 3 (range 1–14).
The most common tumor types were breast (n=10) and oesophagus (n=7).
At 25 mg/m2 AVE8062, neutropenic infection at cycle 1 defined DLT in one patient (pt), whereas at 42 mg/m2 AVE8062 grade 3 headache and asthenia in two pts defined DLTs. Additional grade 3 or 4 study drug related adverse events (AE) included sepsis, febrile neutropenia and respiratory failure in one pt at 20 mg/m2 AVE8062, and nail toxicity in 1 pt at 25 mg/m2. The most common grade 3 or 4 haematological toxicity was neutropenia (11/29 pts). No other grade 3 or 4 adverse events were experienced by more than 2 pts. Grade ¾ related AEs were: grade 3 anemia, grade 4 sepsis, grade 3 respiratory failure, grade 4 febrile neutropenia, grade 3 neutropenic infection, grade 3 nail toxicity, grade 3 oesophageal fistula, grade 3 headache and grade 3 fatigue.
The PK profile of AVE8062, its main metabolite RPR258063 and D were similar to those found in monotherapy studies.
The MTD for the combination AVE8062/D was set at 35/75 mg/m2. Ten additional patients will be enrolled at this dose level then new dose levels of AVE8062 with D 100 mg/m2 will be studied.
Among 23 evaluable pts, 3 had partial responses (breast cancer) and 13 had stable disease (mainly oesophageal cancer, head and neck, pancreatic adenocarcinoma, liver and unknown origin carcinoma).
Conclusion: AVE8062 in combination with D was well tolerated. The recommended dose for this combination is 35 mg/m2 AVE8062 day 1 and 75 mg/m2 D day 2, every 3 weeks.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A15.
Abstract A156: Mechanisms of resistance to Aurora kinase B inhibitors in leukemia: Development and characterization of in vitro models
Authors: Failes Timothy W. , Mitic Gorjana , Abdel-Halim Heba , Liu Marjorie , Bray Mark R. , Hibbs David E. , Kavallaris Maria 
Published: June 2012

Abstract
Aurora kinase inhibitors are generating great interest as new mitosis targeting drugs in cancer chemotherapy. Whilst these new agents are progressing through clinical trials against both solid and haematological malignancies, knowledge of the molecular factors that influence sensitivity and resistance remains limited. Development of optimal treatment modalities and the design of next generation Aurora inhibitors requires an understanding of processes and pathways of drug sensitivity mechanisms. In this study we report the development and characterisation of an in vitro derived leukaemia model of resistance to the Aurora B inhibitor ZM447439. CCRF-CEM cells were selected for resistance in 4uM ZM447439 and designated CEM/AKB4 cells. Cytotoxicity assays showed that CEM/AKB4 cells were 13.2 fold resistant to ZM44739 compared to parental CEM cells. Resistance was not associated with the multi-drug resistance phenotype and CEM/AKB4 cells showed no cross-resistance to a number of tubulin-targeting mitotic poisons or DNA-damaging agents. The CEM/AKB4 cells remained sensitive to the Aurora kinase A inhibitor, ENMD-2076. Cell cycle analysis revealed that exposure of CEM cells to ZM447439 (0.4–4 uM) caused extensive cell cycle disruption and cell death. In contrast, the cell cycle profiles of CEM/AKB4 cells at the same concentrations of drug were barely altered. Full length sequencing of the Aurora B gene revealed a single point mutation in the kinase domain corresponding to a G160E amino acid substitution. Molecular modelling of drug binding in Aurora B containing this mutation suggested that resistance is mediated by the glutamate substitution preventing formation of an active binding motif for Aurora B inhibitors. Moreover molecular docking of an Aurora B inhibitor with a novel binding motif was unchanged in the mutant enzyme suggesting this drug may abrogate resistance. Aurora kinase B inhibitor resistant cells are a valuable tool for identifying resistance mechanisms and the design of new kinase inhibitors active against Aurora kinase B mutations.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A156.
Abstract A159: The Redox/ Fyn/c-Cbl pathway and its interaction with Cool-1: A novel pathway that regulates chemosensitivity in glioblastoma
Authors: Stevens Brett , Folts Christopher , Cui Wanchung , Noble Mark 
Published: June 2012

Abstract
GBMs are the most common primary brain tumor, accounting for 52 percent of all diagnosed brain tumors. It is also the most devastating of all brain tumors, with a five-year survival rate of 3.3 percent. One of the reasons for this poor prognosis is resistance of tumor cells to treatment with chemotherapy.
We have discovered a novel means by which GBMs become chemoresistant, based on inhibition of the redox/Fyn/c-Cbl pathway by overexpression of Cool-1. The protein c-Cbl, a receptor tyrosine kinase adaptor protein, is responsible for the ubiquitination and degradation of epidermal growth factor receptor (EGFR) and other receptor protein kinases critical in cell division and cell survival. c-Cbl is activated by Fyn kinase, which itself can be activated by agents that make cells more oxidized. In normal glia and glial progenitor cells of the CNS, exposure to chemotherapy makes cells more oxidized, leading to sequential activation of Fyn and c-Cbl. In GBMs, in contrast, exposure of GBM cells to BCNU or to chemical pro-oxidants does not lead to c-Cbl activation. Further studies demonstrated that these agents did cause Fyn activation, suggesting that GBMs inhibit Fyn-mediated c-Cbl activation. This would lead to decreased degradation of EGFR, thus enabling continued cell division and providing resistance to chemotherapy. We therefore set out to test the hypothesis that reversal of this inhibition would decrease cell division and enhance susceptibility to chemotherapy-induced cell death. In this work we discovered that oxidant-associated c-Cbl activation can be restored by suppressing expression of the protein Cool-1, which is over-expressed in many cancers including GBM. Our data further demonstrates that Cool-1 and Cbl interact, that genetic reduction in Cool-1 levels by expression of small inhibitory RNAs restores normal c-Cbl-mediated degradation of RTKs (including EGFR) in response to exposure to pro-oxidants and BCNU, and that restoration of normal c-Cbl activation also increases sensitivity to this and other chemotherapeutic agents.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A159.