bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A11: Phase II trial of letrozole (L), cyclophosphamide (C) and sorafenib (S) as neoadjuvant therapy in breast cancer patients (BC): Pharmacokinetic (PK) and pharmacodinamic (PD) analysis
Authors: Bazzola Letizia , Foroni Chiara , Andreis Daniele , Ferrozzi Francesco , Dogliotti Luigi , Berruti Alfredo , Fox Stephen B. , Harris Adrian L. , Generali Daniele , Bottini Alberto 
Published: January 2011

Abstract
Introduction: This trial assessed the PK and PD of letrozole-cyclophosphamide-sorafenib combination as neoadjuvant setting in patients (pts) with operable breast cancer (BC).
Methods: 13 estrogen receptor-positive postmenopausal BC pts with T2-4 N0-1 were enrolled to receive oral letrozole (L) 2.5 mg daily, 50 mg daily metronomic cyclophosphamide (C) and 400 mg twice daily sorafenib (S). S was introduced after 6 days of LC therapy. For PK analysis blood samples were collected on day 5 of cycle 1 and on day 1 of cycle 2 (day 29). At basal time and after 14 days, tumour size evaluation, Ki67 expression and MRI were performed.
Results: A significant reduction in Ki67 expression was observed in all the 13 patients after 14 days only (median 20.7% (range 3-36%) and 9.75% (range 0-20%) at 15th respectively, p&lt;0.0001) with a concomitant reduction in tumour size detected by MRI (median 37 mm (range 15-90 mm) and 31 mm (range 13.4-90 mm) respectively, p=0.047). Three patients attained a partial response at MRI (RECIST criteria) after 15 days. The changes in ki67 expression did not correlate with changes in tumor size evaluated by MRI (Spearman r: −0.37). 10 patients out of 13 showed a clinical complete response at the end of the treatment. The most common drug-related grade 2 (G2) adverse events were skin rush (46%), hand-foot syndrome (46%), anorexia (38%), fatigue (15%), and G3 diarrhea (23%). Mean plasma concentrations of C were consistently lower following concomitant administrations of L, S and C compared to administration of L and C. This trend was confirmed by the comparison of corresponding AUC (0-24) and Cmax values from Day 5, Cycle 1 and Day 1 of Cycle 2. No influence was detected by co-administration with L.
Conclusions: These toxicity and PK results indicated that the combination feasible but sorafenib interpheres in non significant manner with the bioavailability of C. Moreover, the PD data indicated that the association of the already tested LC combination (Bottini at al, JCO 2006) with S is promising. A randomised study of LC vs LCS is ongoing.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):A11
Abstract A14: Lack of tumor eradication of chemotherapy-sensitive BRCA1;p53-deficient mouse mammary tumors
Authors: Rottenberg Sven , Pajic Marina , Kersbergen Ariena , Banishki Nikola , Xu Guotai , Jonkers Jos , Borst Piet 
Published: January 2011

Abstract
Many breast cancers respond to chemotherapy or hormonal therapy, however, the lack of tumor eradication is a central clinical problem preceding the development of drug resistant tumors. We have previously studied responses of mammary tumors generated in the K14cre;Brca1F5-13/F5-13;p53F2-10/F2-10 mouse model for hereditary breast cancer to clinically relevant anti-cancer drugs such as doxorubicin, topotecan, cisplatin and the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib (1-4). The BRCA1- and p53-deficient tumors generated in this model are hypersensitive to these drugs and never become resistant to cisplatin due to the large, irreversible deletion in Brca1 (5).
We show here that even dose-dense treatment with a maximum tolerable dose of cisplatin does not result in tumor eradication. This is not due to the trivial possibility that the drug-resistant remnants are poorly accessible to drug, since we found a homogeneous distribution of the platinum-DNA adducts throughout the tumor. To explain this result we have addressed the hypothesis that the lack of eradication of drug-sensitive tumors is due to increased in vivo chemotherapy resistance of tumor-initiating cells (TICs). Using the CD24 and CD49f cell surface markers which detect normal mouse mammary stem cells, we have identified TICs in BRCA1- and p53-deficient tumors. In addition to the Lin-/CD24+/CD49f+ subpopulation, we show that a larger population of Lin-/CD24+/CD49f-cells also has tumor-initiating capability in at least two serial orthotopic transplantations, suggesting that these are not more differentiated transit-amplifying cells. However, we did not find an enrichment of TICs in cisplatin-treated tumor remnants.
We conclude that in this model the resistance of cisplatin-surviving cells cannot be attributed to special biochemical defense mechanisms of TICs. Instead we will present data supporting the hypothesis that surviving TICs arrest in their cell cycle and ‘hibernate’ until the drug is gone. Using Brca1−/−;p53−/− cell lines derived from the mouse tumors we found that only Brca1−/−;p53−/− cells that were in the G0/G1 phase of the cell cycle 24h after cisplatin treatment were capable of forming new colonies, whereas cells in G2 or M were not. Hence, a p53-independent arrest in G0/G1 appears to underlie the lack of eradication of residual Brca1−/−;p53−/− cells.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):A14
Abstract A17: miRNA silencing in malignant melanoma: Mechanisms, regulation, and potential implications
Authors: Leibowitz-Amit Raya , Zehavi Liron , Avni Dror , Sidi Yehezkel 
Published: January 2011

Abstract
Metastatic melanoma is a devastating disease with limited treatment options. miRNAs are small RNA species within cells whose aberrant expression has been implicated in cancerous transformation, in some cases by a mechanism of cellular de-differentiation. The role of miRNA in melanoma is still not known.
We recently observed that the expression of miRNAs from a large intergenic miRNA cluster is significantly down-regulated or absent in melanoma cell lines in comparison to normal melanocytes. This cluster resides within a parentally imprinted chromosomal region implicated in development and differentiation, and the miRNAs in this region are normally expressed selectively only in brain and skin. This chromosomal region was shown to be involved in the pathogenesis of ovarian carcinoma, and several of the miRNAs within it were shown to have tumor suppressor functions in other cellular models.
Our results demonstrate that in some melanoma cell lines, there is a chromosomal deletion or loss of heterozygosity in the cis-acting differentially-methylated regulatory region of this cluster. Conversely, in other cell lines we were able to re-express some of these miRNAs using epigenetic modifiers (de-methylating agents and histone de-acetylase inhibitors), suggesting that epigenetic aberrations take part in their silencing. We are now assessing whether miRNA re-expression or ectopic expression decreases the tumorigenic and metastatic potential of melanoma cells.
Our results suggest that aberrant regulation of this chromosomal region has a role in the pathogenesis of melanoma, and may even lead, in the future, to the development of new therapeutic strategies and bio-markers in this yet incurable disease.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):A17
Abstract A20: Tumor selective delivery of chemotherapeutics via branched peptides
Authors: Falciani Chiara , Brunetti Jlenia , Lelli Barbara , Lozzi Luisa , Pini Alessandro , Ravenni Niccolò , Bencini Lapo , Menichetti Stefano , Moretti Renato , Bracci Luisa 
Published: January 2011

Abstract
Oligo-branched peptides, containing the sequence of the human regulatory peptide neurotensin (NT), have been used as specific tumor targeting agents, able to selectively and specifically deliver effector units for cell imaging or killing, to tumor cells that over-express NT receptors.
Tetra-branched peptides containing neurotensin (NT) sequence are described here as selective targeting agents for human colon, pancreas and prostate cancer. Fluorophore-conjugated peptides were used to measure tumor versus healthy tissue binding in human surgical samples, resulting in validation of neurotensin receptors as highly promising tumor-biomarkers. Drug-armed branched peptides were synthesized with different conjugation methods, resulting in uncleavable adducts or drug-releasing molecules. Human cell lines from colon (HT-29), pancreas (PANC-1) or prostate (PC-3) carcinoma were challenged with branched NT conjugated with 6-mercaptopurin, combretastain A-4, monastrol and 5-fluoro-deoxyuridine. Results indicated that branched NT conjugated with combretastain A-4 and 5-fluoro-deoxyuridine are the most active agents on HT-29 (EC50 1.1e-007 M) and PANC-1 (EC50 5.0e-007 M) respectively.
Tetra-branched NT armed with 5-FdU was used for in vivo experiments in HT-29-xenografted mice and produced a 50% reduction in tumor growth with respect to animals treated with the free drug. An unrelated branched peptide carrying the same drug was completely ineffective. In vitro and in vivo results indicated that branched peptides are valuable tools for tumor selective targeting.
The results reported in this presentation tell that branched-armed peptides are very promising pharmacodelivery options.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):A20
Abstract A25: Humanized immunoenzyme with enhanced activity for glucuronide prodrug activation in the tumor microenvironment
Authors: Chen Kaichuan , Leu Yu-lin , Prijovich Zeljko M. , Roffler Steve 
Published: January 2011

Abstract
Antibody-directed enzyme prodrug therapy (ADEPT) is one of potential therapies to overcome systemic toxicity caused by traditional chemotherapy. Our lab have designed and developed glucuronide prodrugs that can be converted to potent antineoplastic agents by β-glucuronidase (βG). Toxic drugs can be preferentially generated at the tumor site after βG is first targeted to tumor cells as an antibody-enzyme fusion protein (immunoenzyme). For utilization of this therapeutic strategy in clinic, the immunoenzyme need to be compatible with humans. We have recently employed directed evolution to generate a human βG mutant (S2) that enhanced activity at neutral pH. To investigate if the S2 variant would be beneficial for tumor-selective prodrug activation, a humanized cc49 scFv gene with specificity for the TAG-72 tumor-associated antigen was fused to the wild-type hβG or S2 genes to create hcc49-hβG and hcc49-S2, respectively. Here, we show that immunoenzymes have 100-folds lower KD than hcc49 scFv and retain enzymatic activities as wild-type hβG and S2 mutant proteins. In in vitro cytotoxicity assay, the data demonstrated that hcc49 immunoenzymes can preferentially activate glucuronide prodrugs at TAG-72 positive cells, and hcc49-S2 was about 10-fold more effective than hcc49-hβG as indicated by a lower IC50 value. Further in vivo experiment, we will examine if the enhanced immunoenzyme have better efficacy to hydrolyze anticancer glucuronide prodrugs at physiological condition.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):A25
Abstract A36: ImmunoSPECT and ImmunoPET imaging of IGF-1R expression in a model for triple negative breast cancer
Authors: Heskamp Sandra , Boerman Otto C. , Oyen Wim J.G. , Molkenboer-Kuenen Janneke D.M. , van der Graaf Winette T.A. , van Laarhoven Hanneke W.M. 
Published: January 2011

Abstract
Introduction: Triple negative breast cancer has a poor prognosis and chemotherapy is currently the mainstay of treatment. A potential new target for the treatment of triple negative breast cancer is the insulin-like growth factor 1 receptor (IGF-1R). Patients with triple negative breast cancer lesions that express the IGF-1R (30 to 40%) may be most suited to be treated with IGF-1R antibodies. Therefore, the aim of the present study was to develop a noninvasive, in vivo imaging method, using radiolabeled R1507, to visualize IGF-1R expression.
Material and methods: R1507, a monoclonal antibody directed against an epitope on the extracellular domain of the IGF-1R, was radiolabeled with 111Indium (111In), 125Iodine (125I) and 89Zirconium (89Zr). In vitro, the affinity and internalization kinetics of 111In-R1507 were determined using the IGF-1R expressing breast cancer cell line SUM149 (ER, PR and HER2 negative). In vivo studies were performed in BALB/c nude mice with subcutaneous SUM149 xenografts. To determine the pharmacodynamics of R1507, mice received an intravenous injection of 111In-R1507 and 125I-R1507. One, three and seven days post injection, mice were killed and ex vivo tumor uptake was measured. Non-specific uptake was determined by coinjection of an excess unlabeled R1507. A dose escalation study was performed with 111In-R1507 to determine the optimal protein dose of R1507 for in vivo imaging (dose range 1 – 1000 μg). Finally, SPECT and PET images were acquired of mice with subcutaneous SUM149 tumors one, three and seven days post injection of 111In-R1507 and 89Zr-R1507, respectively.
Results: 111In-R1507 (IC50 = 0.1 nM) was slowly internalized by SUM149 cells. 111In-R1507 specifically and efficiently accumulated in the SUM149 xenografts: the specific tumor uptake was 20% ID/g, 33% ID/g and 31% ID/g at one, three and seven days post injection, respectively. The dose escalation study showed that the optimal dose for imaging experiments was ≤ 3 μg (tumor uptake: 35% ID/g). MicroSPECT and microPET imaging of mice clearly visualized the subcutaneous SUM149 xenograft with increasing contrast at later time points.
Conclusion: 111In-R1507 SPECT and 89Zr-R1507 PET are excellent methods to visualize IGF-1R expression in vivo in triple negative breast cancer xenografts. In the future, these techniques may enable selection of patients with triple negative breast cancer for IGF-1R targeted therapy.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):A36
Abstract A41: Somatic mutations in human cancer cell lines predict sorafenib response
Authors: Rhodes Daniel R. , Kaufmann Scott H. , Meng Xue Wei , Wyngaard Peter , Daubresse Gary , Leopold Judith S. 
Published: January 2011

Abstract
It is now widely accepted that a spectrum of somatic alterations occur in human cancer and that particular alterations are associated with response or lack of response to anti-cancer therapies. Here, we undertook a systematic correlation analysis of somatic mutations, copy number aberrations and drug response across 300+ human cancer cell lines. We studied the RAF and VEGFR inhibitor, sorafenib, evaluating associations between sorafenib response and somatic mutations in 35 common cancer genes and high-level amplifications and homozygous deletions in more than 100 minimal common regions of gain and loss, which include many known oncogenes and tumor suppressor genes. Notably, we found that NRAS mutations, among other alterations, were significantly associated with sensitivity to sorafenib (odds ratio = 7, p-value = 0.003), whereas activating BRAF mutations were strongly associated with a lack of response (odds ratio = 4.9, p-value = 0.012). Specifically, 64% (7 of 11) of NRAS mutant cell lines were sensitive to sorafenib, while only 20% (34 of 170) of NRAS wild-type lines were sensitive. On the contrary, just 6.7% (2 of 30) of BRAF mutant lines were sensitive to sorafenib. Because NRAS mutations occur frequently in leukemia and no leukemia cell lines were included in the original analysis, we selected 5 NRAS mutant and 5 NRAS wild-type leukemia cell lines for further evaluation. Consistent with our previous observation, the four most sensitive leukemia cell lines were all NRAS mutant, each line exhibiting greater than 50% growth inhibition after 72 hours of exposure to 4μM sorafenib. These results confirm the original association and suggest that across both solid tumors and hematologic malignancies, NRAS mutations may identify a subset of cancers that are likely to respond sorafenib. In addition, this work demonstrates that systematic analysis of somatic alterations and drug response across a large collection of cancer cell lines is capable of discovering novel predictive biomarkers.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):A41
Abstract A42: The treatment of sporadic breast cancer with Poly(ADP-ribose) polymerase (PARP1) inhibitors (AZD2281, ABT888, AG14361) as single agents and in combination with chemotherapy
Authors: Fatima Naheed , Quick-Fountain Renee , De Soto Joseph A. 
Published: January 2011

Abstract
Introduction: It has been shown that poly(ADP-ribose) polymerase (PARP1) inhibitors may be useful in the treatment of BRCA1 and 2 hereditary breast cancers due to their deficiency in homologous repair. Many sporadic breast cancers may also be deficient in homologous repair due to deficiency's in RAD51, RAD54, DSS1, RPA1, NBS1, ATR, ATM, CH1, CHK2, FANCD2, FANCA, FANC or a down regulation of BRCA.
Methods: Human breast cancer cell lines representative of basal, Her2/neu, luminal A and luminal B subtypes were treated with PARP1 inhibitors alone or in combination with standard chemotherapeutic agents (alkylating, topoisomerase inhibitors, anti-metabolites, anti-mitotics and/or DNA intercalators) for 72 hours. IC50 values were determined by standard dose response curves of the PARP1) inhibitors (AZD2281, ABT888, AG14361), standard chemotherapeutic agents alone and in combination with each other. PARP1 inhibitor pharmacodynamic, PARP1 activity assays and the quantification of molecular markers from the apoptotic, DNA repair and mitotic pathways were also performed and correlated with IC50 values.
Results: There was no statistical difference in the IC50 of PARP1 inhibitors for BRCA1, non-BRCA1 triple negative or luminal human breast cancer tissue. Significant enhancement of chemotherapeutic cytotoxicity by PARP1 inhibitors was observed in not only hereditary (BRCA1 & BRCA2) breast cancer but, in sporadic breast cancer also. The results suggest that many sporadic breast cancers are deficient in homologous recombination and their ability to preserve DNA and chromosomal fidelity.
Conclusion: PARP1 inhibitors in combination with chemotherapy may be effective in treating sporadic breast cancer.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):A42
Abstract A5: Characterization of signaling pathways related to resistance of breast cancer cells against irreversible EGFR/HER/ErbB kinase inhibitors
Authors: Bruenner-Kubath Caroline , Shabbir Waheed , Saferding Victoria , Wagner Renate , Singer Christian F. , Valent Peter , Berger Walter , Marian Brigitte , Zielinski Christoph C. , Grusch Michael , Grunt Thomas W. 
Published: January 2011

Abstract
Epidermal growth factor (EGF) receptor-related antigens (EGFR, ErbB1-4, HER1-4) represent emerging drug targets in oncology. However, resistance against ErbB-targeting drugs occurs frequently in cancer patients. Drug-resistant cells may exhibit drug-refractory phosphatidylinositol 3-kinase (PI3K) or mitogen-activated protein kinase (MAPK) signaling, but the relative impact and contribution of these two downstream pathways to drug resistance are still controversially discussed. We examined the effects of the two very potent, irreversibly binding ErbB receptor tyrosine kinase inhibitors (RTKIs) pelitinib (EKB-569) and canertinib (CI-1033) on PI3K- and MAPK activity in ErbB RTKI-sensitive and ErbB RTKI-resistant breast and ovarian cancer cells. Western blot analysis revealed that ErbB phosphorylation was abrogated by the inhibitors in both drug-sensitive and drug-resistant cells, whereas AKT- and GSK3β phosphorylation were drug-dependently downregulated only in drug-sensitive cells. ErbB RTKI sensitivity did not correlate with expression of wildtype PTEN or PIK3CA, nor was it associated with drug-dependent silencing of ERK1,2 in the breast and ovarian cancer cell lines examined. Moreover, exogenous AKT, but not MEK, significantly induced drug resistance. Our data demonstrate that blocking AKT phosphorylation is essential and sufficient, whereas abrogation of ERK phosphorylation is not required for ErbB RTKI anticancer efficacy. AKT phosphorylation may thus be a useful biomarker of ErbB RTKI sensitivity in breast and ovarian cancer cells. Supported by ‘MedizinischWissenschaftlicher Fonds des Bürgermeisters der Bundeshauptstadt Wien’ (#08037) and ‘Initiative Krebsforschung’, Medical Univ. Vienna.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):A5
Abstract A8: GPNMB is an independent prognostic indicator of recurrence and a therapeutic target in triple negative breast cancer
Authors: Rose April , Grosset Andree-Anne , Dong Zhifeng , Bertos Nicholas , Simantov Ronit , Park Morag , Gaboury Louis , Siegel Peter 
Published: January 2011

Abstract
Purpose: While the murine orthologue of GPNMB (Glycoprotein non-metastatic B, DC-HIL, HGFIN), Osteoactivin, has been shown to promote breast cancer metastasis in an in vivo mouse model, its importance in human breast cancer is unknown. We have examined the significance of GPNMB expression as a prognostic indicator of recurrence and assessed its potential as a novel therapeutic target in breast cancer.
Experimental Design: The clinical significance of GPNMB expression in breast cancer was addressed by analyzing GPNMB mRNA levels in several published gene expression datasets and by determining GPNMB protein expression in two independent tissue microarrays derived from human breast tumors. Human breast cancer cell lines endogenously or exogenously expressing GPNMB were further used to validate a toxin-conjugated anti-GPNMB antibody as a novel therapeutic agent.
Results: GPNMB expression correlates with shorter times to recurrence and reduced overall survival of breast cancer patients. Epithelial-specific staining of GPNMB serves as an independent prognostic indicator for breast cancer recurrence. GPNMB is highly expressed in basal and triple-negative (TN) breast cancers and is associated with increased risk of recurrence within this subtype. GPNMB expression confers a more migratory and invasive phenotype on breast cancer cells. Treatment of mice harbouring endogenous GPNMB-expressing human breast cancer xenografts with CDX-011 (glembatumumab vedotin, CR011-vcMMAE), a GPNMB-targeted antibody-drug conjugate, induces and sustains tumor regression in vivo.
Conclusions: GPNMB expression is associated with the basal/TN subtype and is a prognostic marker of poor outcome in patients with breast cancer. CDX-011 (glembatumumab vedotin) is a promising new targeted therapy for patients with metastatic TN breast cancers, a patient population that currently lacks targeted-therapy options.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):A8