bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B39: Action of EC8042 in triple-negative breast cancer.
Authors: Pandiella Atanasio , Montero Juan Carlos , Cuenca-Lopez Lolin , Re-Louhau Florencia , Moris Francisco , Ocana Alberto 
Published: June 2012

Abstract
Breast cancer represents one of the most common tumoral pathologies in women. Although continuous advances in its treatment have improved its outcome, in the metastatic setting the disease still represents an important medical problem. For this reason, the incorporation of novel therapies is required. Immunohistochemical characterization of breast cancers led to their division into three main subtypes: hormone receptor positive, HER2 positive, or triple negative breast cancers. Triple negative breast cancers (TNBC) are characterized by the absence of hormonal and HER2 receptors, and represents around 15% of all breast tumors. TNBC are aggressive from the clinical perspective, and their therapy is mainly based on classical chemotherapeutic agents, with limited success in the metastatic setting. Here we have explored the action of a novel drug, named EC8042, in TNBC. The drug, which is a mithramycin derivative, decreased MTT uptake of several TNBC cell lines. The IC50 values obtained were in the nM range, indicating that the drug had a potent effect on these cell lines. Mechanistically, the drug caused accumulation of cells in the S phase of the cell cycle at doses of 100 and 500 nM in the cell lines HBL100 and MDA-MB231. Biochemically, EC8042 caused an increase in cyclin E, cyclin A, cyclin D3, cyclin B, and p27, and decreased cyclin D1 and Rb phosphorylation at serine 780. These data are consistent with an action of EC8042 on the cell cycle. Moreover, the increase in wee1 and pY15-CDK1 are in line with an effect of the drug blocking cell cycle progression through the S phase. Cell cycle analyses using propidium iodide staining also revealed an increase in the subG0 proportion of cells, especially in HBL100, suggestive of a potential indiction of cell death by EC8042. Annexin V staining indicated that treatment of HBL100 with 500 nM of EC8042 provoked apoptosis, which was also revealed by PARP processing. The treatment reduced the amounts of MCL1, BCLXL, and XIAP, but did not affect BCL2 levels. Together, our results indicate that EC8042 has a strong antitumoral action on TNBC cells, which is caused by increased apoptosis and a decrease in cell cycle progression, and opens the possibility for further development of this drug in TNBC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B39.
Abstract B40: The melphalan prodrug melphalan-flufenamide shows cytotoxic effect in bladder cancer cell lines and triggers JNK and caspase-3 mediated apoptotic signaling.
Authors: Juntti Therese , Zakharchenko Olena , Haag Petra , Zong Dali , Laitinen Sara , Larsson Rolf , Spira Jack , Lewensohn Rolf , Viktorsson Kristina , Ullen Anders 
Published: June 2012

Abstract
Background: Bladder cancer is the 4th most common cancer associated death in men in the western world. Cisplatin-based polychemotherapy (1st line) and vinflunine (2nd line) are the only chemotherapy regimens which show survival benefit in patients with metastatic disease. Hence, there is a major need to identify new effective treatment alternatives for patients with this disease. We have developed a prodrug of melphalan, Melphalan-flufenamide (Mel-flufen) which show enhanced cytotoxic efficacy compared to melphalan in several tumour types. Treatment with Mel-flufen gives 10–20 fold higher intracellular drug levels compared to the same dose of melphalan. Mel-flufen is currently undergoing Phase I/II clinical trials. Here we studied if this drug might be a useful in bladder cancer by analyzing its effects in a panel of bladder cancer cell lines.
Material and Methods: The bladder cancer cell lines J82, RT4, 5637 and TCC-SUP were profiled for Mel-flufen and melphalan sensitivity using MTT and FMCA cell viability assay. Mel-flufen signaling was measured as caspase-3 and Bak/Bax activation in flow cytometry and PARP cleavage, JNK phosphorylation, p53 and p21WAF1/Cip1 induction on western blot respectively.
Results: Mel-flufen caused a dose and time dependent inhibition of cell growth in all the four bladder cancer cell lines studied. Comparison with the parental drug revealed an enhanced cytotoxic effect of Mel-flufen at equimolar doses. Molecular profiling of the apoptotic response showed that Mel-flufen induced activation of the Bcl-2 proteins Bak and Bax followed by caspase-3 activation and induction of apoptotic morphology. Albeit Mel-flufen induced activation of p53, the cytotoxic effect was not dependent on p53 as it was also observed in p53-mutant bladder cancer cell lines. A prominent activation of JNK1/2 was observed in response to Melflufen. Importantly, this JNK activation preceded induction of Melflufen-induced apoptotic signaling and was critical for the induced cytotoxicity in these bladder cancer cell lines.
Conclusion: Our data demonstrate that the melphalan prodrug Mel-flufen significantly inhibits bladder cancer cell growth in vitro. Importantly, we show that Mel-flufen is more efficient in inhibiting bladder cancer growth than the parental drug melphalan and causes a more pronounced apoptotic signaling. Taken together these data suggests that Mel-flufen may be a good candidate for bladder cancer treatment.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B40.
Abstract B5: Tumor-cell-induced angiopoietin-2 secretion from endothelial cells results in destabilization of the endothelial/smooth muscle cell interaction of blood vessels.
Authors: Molnar Nikolett , Siemann Dietmar W. 
Published: June 2012

Abstract
The angiopoietin-Tie2 axis is considered to be a key contributor in tumor associated angiogenesis. Angiopoietin-2 (Ang-2) is an endothelial cell secreted protein that is upregulated by angiogenic stimuli that leads to vessel destabilization by facilitating the disruption of cell-cell contacts between endothelial and periendothelial cells (ie. smooth muscle cells) in the vasculature. Ang-2 is stored in Weibel-Palade bodies and quickly secreted by stimuli such as hypoxia and inflammation; conditions commonly found in solid tumors. In the present study, the effect of renal cell carcinoma tumor cells (Caki-1, Caki-2) on endothelial cell secretion of Ang-2 and the ability to destabilize endothelial-smooth muscle cell co-culture spheroids was evaluated. As anticipated, enzyme-linked immunosorbent assay (ELISA) showed only minimal Ang-2 secretion from Caki tumor cells; 0.02 ng/ml (Caki-1) and 0.005 ng/ml (Caki-2). However, stimulation of endothelial cells with Caki conditioned media showed high levels of Ang-2 secretion from endothelial cells; 1.9 ng/ml (Caki-1) and 3.6 ng/ml (Caki-2), a 95-fold and 720-fold increase respectively. Furthermore, a greater increase in the level of Ang-2 secretion was observed when endothelial cells were stimulated with Caki cells maintained under hypoxic conditions; 3.5 ng/ml (Caki-1) and 5.5 ng/ml (Caki-2), a 1.8-fold and 1.5-fold increase, respectively, compared to cells maintained under normoxic conditions. When media collected from Caki-1 and Caki-2 cells were added to endothelial-smooth muscle cell co-culture spheroids, endothelial cells were rapidly lost from the smooth muscle cell core. Consistent with the levels of Ang-2 secretion, media collected from Caki-2 cells had a greater effect on endothelial cell dissociation from the co-culture spheres than did media from Caki-1 cell culture. This endothelial cell loss was further enhanced when co-culture spheres were exposed to media derived from tumor cell cultures maintained under hypoxic conditions. Using an in vitro endothelial-smooth muscle cell co-culture sphere model we demonstrate that tumor cells can modulate endothelial cell Ang-2 secretion and thereby destabilizing the endothelial cell/smooth muscle cell association of blood vessels. These results support a rationale for targeting Ang-2 as a novel anti-angiogenic strategy in cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B5.
Abstract B58: Phase I study of the IGF-1R antibody ganitumab (AMG 479) in combination with everolimus in patients with advanced solid tumors.
Authors: Vlahovic Gordana , Meadows Kellen , Arrowood Christy , Meadows Jennifer , Morse Michael , Uronis Hope , Riedel Richard , Crawford Jeffrey , Zafar S. Yousuf , Hurwitz Herbert 
Published: June 2012

Abstract
Background: Preclinical data suggests the combination of IGF-1R inhibitor Ganitumab and mTOR inhibitor everolimus may increase anti-tumor activity compared to each agent alone. Therefore we evaluated the maximum tolerated doses/recommended phase II dose for the doublet combination, Ganitumab (G) plus Everolimus (E) followed by an expanded cohort to better understand the safety and tolerability profile.
Methods: For dose escalation, eligible patients had advanced solid tumors with adequate organ function and no increased risk for class-related toxicities. G was given intravenously, and E was orally administered; cycle length was 28 days. G was dosed at 12 mg/kg every 14 days; E was dosed at 5 mg daily in cohort one and 5 mg three times weekly in cohort −1. An intermediate dose of E at 5 mg five times weekly was added to better maximize dose intensity. Dose limiting toxicity (DLT) was assessed in cycle 1.
Results: Dose escalation is complete with 17 subjects evaluable for DLT toxicity and 16 evaluable for efficacy. Two out of 5 subjects experienced DLTs in cohort one due to dose holdings related to grade 3 hematologic toxicities: thrombocytopenia and neutropenia plus thrombocytopenia. No DLTs were observed out of 6 subjects in cohort −1; one DLT was observed out of 6 subjects in the intermediate cohort due to dose holding related to grade 2 intolerable skin rash and oral mucositis. Possible grade 3 treatment-related adverse events included neutropenia, thrombocytopenia, elevated AST/ALT, hypertriglyceridemia, vomiting and erythema multiforme minor. There were no grade ≥4 treatment-related toxicities. One non treatment- related death was due to disease progression. Two subjects had clinically significant skin rashes which resulted in protocol discontinuation. Twelve subjects have available efficacy data; 4 subjects have not yet been restaged. Two subjects with refractory NSCLC achieved a complete response. Six additional subjects had stable disease as best response.
Conclusion: The recommended phase II dose for this doublet combination is G at 12 mg/kg every two weeks and E at 5 mg five times weekly. At this dose, this novel regimen is well-tolerated with potential activity in NSCLC. Enrollment in the expanded cohort has started.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B58.
Abstract B67: Correlation of pharmacokinetics (PK), pharmacodynamics (PD) and in vivo antitumor activity of BMN 673 in preclinical models.
Authors: Feng Ying , Shen Yuqiao , Musson Don , Zhou Huiyu , Scholler Oriane , Post Leonard E. 
Published: June 2012

Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors are emerging as an exciting class of novel chemotherapeutic agents for the treatment of cancers with specific DNA-repair defects, such as homologous recombination (HR) deficiency as a result of mutations of the BRCA genes. We have developed a specific, orally active PARP-1 and -2 inhibitor, BMN 673, that is highly potent in blocking PARP-1 enzyme activity (IC50 = 0.57nM) and can selectively kill tumor cells harboring BRCA1 and BRCA2 mutations (ED50 = 0.3 nM for BRCA1−/− MX-1 cells). Inhibition of PARP enzyme activity is associated with decreased intracellular PARylated proteins (PAR), thus PAR is selected as pharmacodynamic (PD) marker to monitor PARP inhibitor activities in preclinical models. Here we describe the pharmacokinetics (PK) of BMN 673 in a mouse model during 14-day repeat oral daily administration and the antitumor efficacy of BMN 673 in MX-1 xenograft mouse model, suggesting BMN 673 is a highly potent anti-cancer agent in vivo. In addition, a rat PK/PD study was conducted with BMN 673 at 0.3, 0.1 and 0.03 mg/kg, both in single dose and in 5-day repeat daily dose. Various rat tissues including bone marrow, muscle, and peripheral blood mononuclear cells (PBMCs) were harvested after BMN 673 exposure to examine tissue PAR levels or PAR formation from PBMCs using a sensitive functional PD assay. Corresponding plasma samples were also collected to monitor BMN 673 drug level. The PK/PD results demonstrated that BMN 673 was effective at blocking PARP activity in vivo at the lowest dose tested (0.03 mg/kg), and the tissue PAR level (PARP inhibition) is correlated with BMN 673 dose and plasma exposure. BMN 673 is currently being evaluated in Phase I clinical trials.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B67.
Abstract B76: In vitro screen to identify ALK mutations conferring crizotinib resistance.
Authors: Nicolas Jean-Paul , Dassencourt Laurent , Herve Francoise , Wolfrom Meredith , Lennon Amanda , Delarbre Laure , Hoffmann Dietmar , Leroy Vincent , Calvet Loreley , Garcia-Echeverria Carlos , Valtingojer Iris 
Published: June 2012

Abstract
Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. Activating mutations in ALK are oncogenic and cause 10 to 15% of neuroblastoma cases. Similarly, activating ALK fusions have been detected in several cancers, including ALCL (NPM-ALK in 70% of patients) and NSCLC (EML4-ALK in 3–7% of patients). ALK inhibitors from different compound classes and kinase selectivity profiles are currently undergoing clinical development, among which crizotinib has recently received marketing approval from the US FDA. This non-selective ALK inhibitor has provided clinical benefit to lung cancer patients, but its sustained efficacy seems to be impaired by acquired drug resistance and several publications have already described ALK secondary mutations identified in patients who progressed while on crizotinib therapy. In this study, we have used the Ba/F3 system to identify EML4-ALK mutations able to confer resistance to crizotinib. To this end, we have generated a cDNA library containing random mutations in EML4-ALK using an E. Coli strain deficient in DNA repair pathways. The library was then subcloned in a retroviral vector and used to infect Ba/F3 cells. The cells were plated in 96 well microplates at an appropriate dilution and allowed to grow in the presence of 500 nM of crizotinib. The resistant cells were cultured and EML4-ALK was sequenced.
Overall, this screen identified mutations at 24 positions in the ALK kinase domain. Some of these mutations (L1152R, C1156Y, F1174L) correspond to the ones known to cause resistance in lung cancer patients treated with crizotinib. Ba/F3 cell lines stably expressing a selected number of the 24 mutations have been generated and used to evaluate the activity of in-house and reference ALK kinase modulators. This work has shown that several mutations known to activate ALK in neuroblastoma are also able to confer resistance to crizotinib.
The Ba/F3 cell lines expressing EML4-ALK mutants have been useful tools to characterize the activity profile of a range of ALK kinase inhibitors and several of our in-house compounds have been identified as active against the crizotinib-allele resistant mutants.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B76.
Abstract B87: Multiplexed, bioluminogenic probes for evaluating histone deacetylase inhibitor efficacy and safety.
Authors: Somberg Richard L. , Evans Nathan , Kirkland Thomas , Niles Andrew 
Published: June 2012

Abstract
Aberrant epigenetic modifications are known to contribute to hematological and solid cancer malignancies. Members of an important class of chromatin modifying enzymes, histone deacetylases (HDACs), have been found to be dysregulated in many tumor types. Their specific contribution to oncogenesis is unknown, but numerous studies have linked increased HDAC inhibition to transcriptional repression of gene expression, cell cycle checkpoint activation and other tumor suppression activities. Therefore, HDAC inhibitors (HDACi) are an emerging and important class of modulators for use as single agents or in combination with other anti-neoplastics. Many current HDACi have undesirable off-target toxicities, which may be related to inhibition of specific HDAC isozymes that are required for normal cellular function. In an effort to rapidly and efficiently understand the beneficial and detrimental effects of new HDACi within a cellular context, we have developed a set of selective and pan-active bioluminogenic assay probes for evaluating the effects of HDACi. When multiplexed with same well fluorescent viability and cytotoxicity assays, these probes provide a functional readout of HDACi on-target efficacy and off-target safety in primary or cancer cell models.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B87.
Abstract C10: Class III β -tubulin predicts pathological response to neoadjuvant docetaxel-based chemotherapy in breast cancer patients.
Authors: Moon Yongwha , Koo Ja Seung , Han Hyunju , Park Byeong-Woo , Kim Seung Il , Park Seho , Chung Hyun Cheol , Kim Joo-Hang , Sohn Joo Hyuk 
Published: June 2012

Abstract
Background: Class III β-tubulin has been suggested as a potential predictor of taxane response for several cancers including breast cancer, although controversies exist. We evaluated correlations between class III β-tubulin and docetaxel response in neoadjuvant setting of breast cancer, focusing on pathological response which is considered the most powerful predictor of outcome.
Materials and Methods: Fifty-five patients with primary breast cancer who had undergone neoadjuvant doxetaxel and adriamycin were included in this study. Class III β-tubulin was measured by immunohistochemistry in prechemotherapy paraffin-embedded tumor tissues. The cutoff value of ‘high’ and ‘low’ expression of class III β-tubulin was set at 50% of tumor cell staining. ‘Good pathological response’ was defined by pathological complete response (pCR) or microscopic residual disease (i.e., breast tumor ≤1cm and negative axillary node). The counterpart was designated as ‘poor pathological response’.
Results: Before chemotherapy, 14 patients were in clinical stage II and 41 were in clinical stage III. After the median 4 cycles of preoperative chemotherapy, clinical downstaging was observed in 40 patients whereas clinical staging did not change in the remaining patients. Eleven patients (20%) showed good pathological response (pCR, 6; microscopic residual disease, 5) and 44 (80%) showed poor pathological response. Thirty-six (65.5%) and 19 patients (34.5%) were categorized into low and high class III β-tubulin groups, respectively. Low class III β-tubulin was associated with low histologic grade (P=0.052). However, in multivariate logistic regression adjusted by known prognostic factors including histologic grade, low expression of class III β-tubulin (hazard ratio = 11.1; P = 0.049) and triple negative status (hazard ratio = 6.86; P = 0.022) were independent predictors of good pathological response. At the median follow-up of 40.8 months after surgery, recurrence occurred in 11 patients (5 in low class III β-tubulin group; 6 in high). Low expression of class III β-tubulin showed a favorable risk of relapse (P=0.152) which did not reach statistical significance probably due to short follow-up period.
Conclusions: Low expression of class III β-tubulin by immunohistochemistry predicts good pathological response to neoadjuvant docetaxel in breast cancer, suggesting implications for improving chance to define docetaxel-beneficial group in this setting.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C10.