bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3573: The novel FASN inhibitor UCMG028 overcomes resistance to trastuzumab and lapatinib
Authors: Puig Teresa , Gómez Daniel , Urruticoechea Ander , Cufí Sílvia , Turrado Carlos , Aguilar Helena , Campuzano Òscar , Brugada Ramon , López-Rodríguez María Luz , Colomer Ramon 
Published: February 2011

Abstract
The vast majority of Her-2 positive advanced breast cancer patients develop resistance to trastuzumab based therapies within the first year of treatment. We have shown that inhibition of Fatty Acid Synthase (FASN) activity, an enzyme overexpressed and hiperactivated in breast carcinoma, shows marked synergic anticancer activity combined with anti-HER drugs. To examine the molecular mechanisms of acquired resistance to HER2, we have generated clones of FASN+ and HER2+ cell lines (AU565 and SK-Br3) resistant to trastuzumab (TTZ) and lapatinib (LAP) for longer than 9 months, and have evaluated the anticancer effect of UCMG028. We further characterized the effect of UCM028 in a mice model of HER2+ xenograft (BT474). TTZ and LAP-resistant cells displayed an increased sensitivity to UCMG028 compared to previously known FASN inhibitors (C75 and EGCG). Gene expression profiling of LAP and TTZ-resistant cells showed a significant differential expression in different sets of genes involved on cell cycle pathways. Mice BT474 xenografts showed tumor regression after long-term exposure to UCMG028. Preliminary toxicity data showed no weight loss, and histological studies (H&E, Masson's Tricromic, Sudan Black B and Picrosirius Red Stains) showed no structural myocardial abnormalities in treated mice with UCMG028-treated mice. Thus, UCMG028 is an effective anticancer treatment for HER2 + breast cancer and its activity remains unchanged in TTZ and LAP resistant cells. Taken together, these data suggest that FASN activity inhibition by UCMG028 could be a new therapeutic strategy in HER2 + breast cancer with potential to overcome resistance to standard anti-HER2 therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3573.
Abstract 3576: Pixantrone is chemically and mechanistically related to mitoxantrone (Mito) and doxorubicin (Dox) but lacks their iron binding properties and myocyte toxicity in vitro
Authors: Hacker Miles P. , Ata Tariq , Gesler Korie , Mazur Jakub , McKennon Marc , Singer Jack 
Published: February 2011

Abstract
The anthracyclines (Dox), anthracenediones (Mito) and anthrapyrazoles (losoxantrone) are all intercalating topoisomerase II inhibitors that have significant anti-tumor activity but have the potential to cause severe, treatment limiting cardiotoxicity. Each of these drugs contains at least one hydroxyquinone element capable of binding iron. Given the putative role of iron in free radical generation and drug induced cardiotoxicity, we synthesized Pixantrone (BBR 2778; Pix), an aza-anthracenedione heterocyclic compound devoid of hydroxyquinone moieties. Pix has recently successfully completed a Phase 3 clinical trial showing excellent anti-tumor activity. Results obtained in animal models demonstrated that Pix caused minimal cardiotoxicity in mice, even those pretreated with Dox. To determine whether Pix binds iron, we used a well established spectrophotometric method to assess drug: iron interactions. Adding increasing amounts of iron to a drug solution we noted the previously reported hypochromic and bathychromic shifts in drug absorption patterns for both Dox and Mito in a 3:1 and 2:1 drug: iron ratios, respectively. In contrast, no iron binding was noted when iron was added to Pix solution at iron: drug ratios ranging from 0.1 to 10.0. To assess the effect of pH on drug binding Pix was incubated with iron at pH of 5, 6, 7 and 8 and at no pH was iron binding detected. Further studies assessing the effect of incubation temperature (40C - 500C) and time of incubation (1 to120 min) demonstrated the lack of iron binding by Pix. Studies performed with the rat myocardial cell line H9C2 indicated that Pix (ID50&gt;50 μg/ml) was far less toxic to confluent myocardial cells than doxorubicin (ID50∼1μg/ml). Further, Pix did not induce a significant increase in reactive oxygen species (ROS) compared to vehicle treated controls. In summary, our results demonstrate that the lack of iron binding and concomitant lack of SOD production may provide the mechanism for lack of cardiotoxicity in animals and an apparent decrease in cardiotoxic potential in humans for Pix. Our results also substantiate the idea that ROS are not necessary for tumor cell cytotoxicity.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3576.
Abstract 3577: Sensitivity and resistance of non-small cell lung cancer to the telomerase inhibitor imetelstat
Authors: Frink Robin E. , Peyton Michael , Sullivan James P. , Wright Woodring E. , Schiller Joan , Shay Jerry W. , Minna John D. 
Published: February 2011

Abstract
Telomerase is expressed in the majority of lung cancers and functions to extend telomeres allowing for unlimited replication potential. Telomerase may also be essential in maintaining a cancer stem cell population making it an attractive therapeutic target. A new telomerase inhibitor, imetelstat (GRN163L), is currently in clinical trials for non-small cell lung cancer (NSCLC). Imetelstat, a lipidated 13-mer oligonucleotide N3′ P5′-thio-phosphoramidate, binds the functional RNA template of telomerase preventing telomerase from extending telomeres and thus potentially leading to telomere loss associated cancer cell death. In the present studies we treated multiple NSCLC cell lines (representing the full spectrum of oncogenotypes and chemotherapy drug response phenotypes) with imetelstat (1 μM, a concentration achieved in patients) continuously over several months and all tumor lines showed loss of telomerase activity and shortening of telomeres. NSCLC lines with initially short telomeres (NCI-H2073-initial telomere length (ITL) 2.7 Kb, Calu-3 (ITL 1.5 Kb), and NCI-H2087 (ITL 3 Kb)) either suffered massive apoptotic associated cell death (H2073) within one week, or developed very short telomeres and ceased proliferating at 2.5 weeks (Calu-3) or 20 weeks (H2087) of treatment, demonstrating primary sensitivity. However, a small subpopulation in H2073 continues to grow in culture in the presence of drug and is being tested for telomere length and sensitivity to higher concentrations of imetelstat. NSCLC lines with long telomeres (NCI-H1819 (ITL 15Kb) and NCI-H157 (ITL 14.5Kb)) treated with 1 µM imetelstat twice weekly for 32 weeks showed reduction of telomeres to 1.8 and 2 Kb respectively with no effect on mass culture proliferation but, in some cases, showed inhibition of colony formation. Removal of imetelstat resulted in return of telomerase activity and telomere re-growth. With continued 1 μM treatment, however, H1819 telomere length stabilized at 1.8Kb while H157 cells showed re-growth of telomeres to parental length and now requires &gt;5 μM imetelstat to robustly inhibit telomerase. In summary, we have found a panel of NSCLC lines demonstrate several imetelstat response phenotypes: extreme initial sensitivity, maintenance of shortened telomeres with inhibition of colony formation, and acquired resistance to imetelstat therapy. We conclude that NSCLCs exhibit a diverse spectrum of responses to telomerase targeted therapy emphasizing the need to have tumor biomarker signatures for personalizing imetelstat therapy in NSCLC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3577.
Abstract 3593: Genetic variants in NER pathway genes and ovarian cancer risk and outcomes
Authors: Gong Yilei , Lin Jie , Ye Yuanqing , Wu Lei , Pu Xia , Wu Xifeng , Liang Dong , Lu Karen 
Published: February 2011

Abstract
Nucleotide excision repair (NER) pathway is critical for protecting against damage from carcinogens. In this case-control study, we evaluated the associations between genetic variations in NER pathway and ovarian cancer risk in 339 Caucasian ovarian cancer cases and 349 Caucasian healthy controls. A comprehensive panel of 217 SNPs in 28 NER pathway genes was analyzed to assess their association with ovarian cancer risk. For the cases who received surgery and platinum-based chemotherapy, we also analyzed the association of these SNPs with overall survival and response to chemotherapy. Individually, 12 SNPs were significantly associated with the ovarian cancer risk. The most significant association was observed for SNP rs4150667 from GTF2H1 (OR = 0.64, 95% CI 0.47- 0.86). A strong gene-dosage effect was observed when these top 12 SNPs were combined for unfavorable genotype analysis. Compared to subjects carrying ≤ 2 unfavorable genotypes, individuals carrying 3 (OR = 2.11, 95% CI = 1.32−3.39), 4 (OR = 2.32, 95% CI = 1.47 − 3.66) or ≥ 5 (OR = 4.31, 95% CI = 2.75 − 6.78) unfavorable genotypes exhibited significantly increased risk for ovarian cancer (P for trend &lt; 0.0001). Classification and regression tree (CART) analysis further revealed potential high order gene-gene interaction among the top 12 SNPs and identified 7 terminal nodes with the percentage of ovarian cancer cases in each terminal node range from 27% to 64%. In the clinical outcome study, there were 10 SNPs that exhibited significant association with overall survival. The unfavorable genotype analysis showed the median survival times for individuals carrying ≤3, 4∼7, and ≥ 8 unfavorable genotypes were 83.3, 40.0, and 24.7 months, respectively, indicating a strong gene-dosage effect (P for trend &lt; 0.0001). We also observed significant gene-dosage effect in chemotherapy response. In summary, this pathway-based approach demonstrated that increasing numbers of unfavorable genotypes in the NER predispose susceptible individuals to increased risk of ovarian cancer and affect clinical outcomes in ovarian cancer patients. These findings warrant further replications in independent populations.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3593.
Abstract 3604: Significant effect of polymorphisms in CYP2D6 and DT-1 on clinical outcomes of adjuvant tamoxifen therapy for breast cancer patients
Authors: Zembutsu Hitoshi , Kiyotani Kazuma , Mushiroda Taisei , Imamura Chiyo K. , Hosono Naoya , Kubo Michiaki , Tanigawara Yusuke , Flockhart David A. , Skaar Todd C. , Desta Zeruesenay , Aki Fuminori , Hirata Koichi , Takatsuka Yuichi , Okazaki Minoru , Ohsumi Shozo , Yamakawa Takashi , Sasa Mitsunori , Nakamura Yusuke 
Published: February 2011

Abstract
PURPOSE: The clinical efficacy of tamoxifen is suspected to be influenced by the activity of drug-metabolizing enzymes and transporters involved in the formation, metabolism and elimination of its active forms. We investigated relations of polymorphisms in transporter genes as well as CYP2D6 to clinical outcome of patients with tamoxifen treatment. PATIENTS AND METHODS: We enrolled 282 hormone receptor-positive, invasive breast cancer patients receiving tamoxifen monotherapy. We investigated the effects of allelic variants of CYP2D6 and tag-SNPs of DT-1, DT-2 and DT-3 on recurrence-free survivals using Kaplan-Meier and Cox regression analyses. Plasma concentrations of tamoxifen metabolites were measured in 98 patients taking 20 mg/day of tamoxifen. RESULTS: CYP2D6 variants were significantly associated with shorter recurrence-free survival (P = 3.6×10−5; hazard ratio (HR) 9.52 [95% CI 2.79-32.45] in patients with 2 variant alleles vs without variant allele). Among 51 tag-SNPs in transporter genes, a significant association was found at SNPY in DT-1(P = 1.7×10−4; HR 10.64 [95% CI 1.44-78.88] in patients with AA vs GG genotypes). The number of risk alleles of CYP2D6 and DT-1 showed cumulative effects on recurrence-free survivals (P = 5.5×10−8). The patients carrying 4 risk alleles had 45.25-times higher risk compared to those with ≤1 risk allele. CYP2D6 variants were associated with lower plasma levels of endoxifen and 4-hydroxytamoxifen (P = 4.3×10−6 and 5.2×10−4), whereas no significant difference was found among DT-1 genotype groups. CONCLUSION: Our results indicated that polymorphisms in CYP2D6 and DT-1 are important predictors for the prognosis of breast cancer patients treated with tamoxifen.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3604.
Abstract 3609: MGCD265, an orally active Met/VEGFR multitargeted kinase inhibitor in Phase II clinical development, potently inhibits clinically relevant Met mutants
Authors: Beaulieu Normand , Dupont Isabelle , Bonfils Claire , Dubay Marja , Ste-Croix Hélène , Isakovic Lubo , Claridge Stephen , Saavedra Oscar , Raeppel Franck , Raeppel Stephane , Mannion Michael , Vaisburg Arkadii , Besterman Jeffrey M. , Maroun Christiane R. 
Published: February 2011

Abstract
MGCD265 is a multitargeted receptor tyrosine kinase inhibitor in Phase II clinical development, which inhibits the activation of regulators of cancer development and progression by targeting Met, the three members of the VEGFR family, Tie-2 and Ron. Met is a key player in the epithelial-mesenchymal transition (EMT) and Met deregulation is described in several types of cancer. The mechanisms involved in Met activation include co-expression of Met with its ligand HGF, overexpression of the Met protein, Met and/or HGF gene amplification or activating mutations. Originally found in hereditary papillary renal carcinoma (HPRCC), activating missense mutations in the kinase domain provided the first evidence that Met activation was causative of this disease. Mutations outside of the tyrosine kinase domain, such as those in the juxtamembrane and extracellular sema domains have also been analyzed, and found in NSCLC, SCLC, melanoma, head and neck cancer, mesothelioma and pancreatic cancer. For the clinical development of MGCD265, we demonstrated the ability of MGCD265 to inhibit clinically relevant Met mutants described in a variety of cancers, including HPRCC and NSCLC. In cell-based assays, MGCD265 inhibits the activation of Met kinase domain mutants (e.g. Y1230C) as well as mutants within the juxtamembrane region (e.g. R988C), and the extracellular domain (e.g. N375S) with nanomolar potency. This is of particular interest, as several kinase domain mutations confer resistance of Met to Met-selective agents such as PF-4217903. MGCD265 also inhibits signaling pathways activated downstream from Met mutants. The phosphorylation of Gab1 multisubstrate docking protein following the activation of Met mutants is inhibited by MGCD265 as is the ensuing activation of the Erk pathway. Furthermore, MGCD265 inhibits the motility of renal carcinoma cells expressing an extracellular domain Met mutant, and blocks tumor growth in a NSCLC cell line expressing a juxtamembrane domain Met mutant. These results, together with our previous findings, demonstrate that MGCD265 is particularly efficient at inhibiting tumor growth in animal models in which wild-type Met or Met mutants are active, suggesting that MGCD265 may particularly benefit patients with activated Met.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3609.
Abstract 362: TR-FRET binding assays for PI3K family inhibitors
Authors: Hereley Sara B. , Wolken Jill K. , Frazee William J. , Eliason Hildegard C. , Riddle Steven M. 
Published: February 2011

Abstract
There is a great clinical need to develop selective, high affinity kinase inhibitors. While many high throughput kinase activity assays have become readily available, easy-to-use and cost-effective, activity-based assays have significant limitations in terms of both the extent of target coverage and the type of information they can provide about compounds. We have developed a competitive TR-FRET binding assay platform for characterization of protein kinase inhibitors. This assay platform has several advantages over traditional activity-based assays, in part due to simplicity of the assays as well as the ability to measure binding events in real time. To extend the breadth of target coverage of this platform, we have developed novel tracers for Class I PI3-kinases and the related protein kinase mTOR. We present a comparison of inhibitor potencies measured in binding assays relative to kinase activity assays for a diverse set of commonly used PI3 kinase family inhibitors. These novel assays enable simple, rapid measurements of IC50 values for PI3 kinases and mTOR.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 362.
Abstract 3628: JNJ-38877605: A selective oral Met inhibitor for the treatment of cancer
Authors: King Peter , Janssens Boud , Verhulst Tinne , Argent Richard , Kumari Rajendra , Watson Susan , Andries Luc , Mevellec Laurence , Page Martin , Perera Tim 
Published: February 2011

Abstract
JNJ-38877605 is a potent and selective Met receptor tyrosine kinase inhibitor that has substantial pre-clinical antitumor activity. We recently described JNJ-38877605 as an ATP-competitive, inhibitor of the catalytic activity of Met kinase (IC50 4 nM) with a unique binding mode that leads to selectivity, exhibiting a 600-fold selectivity (vs cFMS IC50 2.6μM; the next potently inhibited kinase) for Met compared with a panel of 250 diverse tyrosine and serine-threonine kinases. Previously, JNJ-38877605 was shown to inhibit Met phosphorylation in tumor xenografts up to 16 h following a single oral dose, and that inhibition of receptor phosphorylation was associated with dose-dependent tumor growth inhibition. Herein we describe the activity of JNJ-38877605, on a broader range of preclinical solid tumor xenograft models, at doses below MTD and with different schedules of administration. In addition, we now also show data with primary patient-tumor derived xenografts where we have dosed JNJ-39977605 at the MTD using gastric, colorectal and liver metastatic (derived from primary CRC) samples.
JNJ-38877605 was observed to induce significant tumor regression in large well established MET gene amplified gastric cancer models and in Met pathway activated (autocrine or paracrine) models. Significant growth inhibition was achieved when dosing JNJ-38877605 at MTD (and lower doses) with T/C &lt; 42% in tumors of MKN-45, GTL-16, SNU-5 and Kato II met gene amplified models. Significant inhibition was also observed in K-ras mt (dependent) NCI-H441 NSCLC xenografts. Regression of U87 MG PTEN negative glioblastoma tumors (autocrine loop), grown either as subcutaneous or orthotopic models was also observed.
Using primary patient derived xenograft models, we have shown that differential expression of the c-Met/HGF axis and epithelial-mesenchymal transition (EMT)-related gene markers between primary colorectal carcinomas and liver metastases in primary tissue, play a role in the activity of this compound in vivo.
The strong preclinical properties of the JNJ-38877605 compound has resulted in the selection of this potent and uniquely selective Met inhibitor for clinical evaluation. JNJ-38877605 is currently in Phase I clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3628.
Abstract 363: Therapeutic targeting of insulin receptor-A with a dual IGF-1R/IR inhibitor: Overcoming a potential escape mechanism from IGF-1R-specific signaling inhibition in insulin receptor-A transfected cancer cells
Authors: Hillerman Stephen M. , Greer Ann F. , Hurlburt Warren , Huang Fei , Reeves Karen , Ryseck Rolf , Finckenstein Friedrich Graf , Dhar Arindam , Kramer Robert A. , Gottardis Marco M. , Carboni Joan M. 
Published: February 2011

Abstract
Type I Insulin-like Growth Factor Receptor (IGF-1R) is a tyrosine kinase receptor that is activated by binding to IGF-1 and IGF-II ligands; IGF-1R has been shown to play a role in cancer development and progression and therapies targeting IGF-1R have resulted in clinical benefit in cancer patients. Insulin Receptor (IR) which is closely related to IGF-1R, is expressed in normal tissues and tumors, and is expressed as two isoforms, IR-A and IR-B. IR-A exhibits mitogenic activity and is preferentially found in fetal tissue and cancer cells, whereas IR-B regulates glucose metabolism in response to insulin. Both IR isoforms bind insulin, and IR-A also binds IGF-II. Several cancer cell types that express IR-A also overexpress IGF-II, suggesting a possible autocrine loop that enhances tumor survival. Since IGF-1R antibodies bind specifically to IGF-1R and not to IR, IR signaling could represent a potential escape mechanism to antibody treatment through the IR-A pathway. BMS-754807, a small molecule inhibitor with dual activity against IGF-1R and IR, recently entered clinical development. It is anticipated that BMS-754807 can prevent or overcome therapeutic resistance resulting from increased IR-activated signaling. The goal of the presented studies was to demonstrate whether dual IGF-1R/IR inhibition by BMS-754807 may prevent IR-mediated resistance to IGF-1R inhibition.
To test this hypothesis, a human rhabdomyosarcoma cell line, Rh41 expressing IGF-1R, but little IR, was engineered to express either IR-A (Rh41-IR-A) or IR-B (Rh41-IR-B). IR expression was confirmed by PCR analysis of specific IR isoforms. Rh41-IR-A cells showed phosphorylation of IR after stimulation with IGF-II and/or insulin. MAB391, a neutralizing monoclonal antibody to IGF-1R, inhibited the proliferation of parental Rh41 and Rh41-IR-B cells in vitro, but Rh41-IR-A cells exhibited no sensitivity to the IGF-1R mAb. Combination treatment with both IGF-1R and IR antibodies in Rh41-IR-A cells were strongly synergistic, suggesting dual receptor blocking is required for enhanced anti-tumor efficacy. Inhibition of IGF-1R and IR with BMS-754807 showed the same inhibitory activity in Rh41-IR-A cells as was observed in the parental Rh41 cells. Therefore, dual IGF-1R/IR inhibition by BMS-754807 treatment may overcome the ability of cancer cells to utilize the IR-A pathway and provide an advantage over IGF-1R specific antibodies in the treatment of cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 363.