bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A189: Influence of smoking on the pharmacology of taxane therapy.
Authors: de Graan Anne-Joy M. , Loos Walter J. , Friberg Lena E. , Baker Sharyn D. , van der Bol Jessica M. , Wiemer Erik AC , van der Holt Bronno B. , Verweij Jaap , Mathijssen Ron HJ 
Published: June 2012

Abstract
Background: Smoking interacts with the metabolism of several anti-cancer drugs such as erlotinib and irinotecan. It may also affect the incidence and severity of side effects and the efficacy of chemotherapy. The main objective of this study was to examine the effects of smoking on the bone marrow toxicities and pharmacokinetics (PK) of the taxanes docetaxel and paclitaxel. Both taxanes are metabolized through a CYP3A-based conversion.
Methods: 566 patients (429 non-smokers and 137 smokers) were treated with docetaxel or paclitaxel. We determined their toxicity profiles and PK parameters. PK samples were measured by HPLC or LC-MS/MS, and individual PK parameters were estimated from previously developed population PK models by non-linear mixed effects modeling in the software NONMEM. P-values were calculated by the Mann-Whitney U or 2 tests, while multivariate logistic regression analysis was used to adjust for covariates.
Results: Smokers treated with docetaxel (43% vs 57% p = 0.03) or paclitaxel (11% vs 25% p = 0.02) showed less grade 3–4 leucopenia (white blood cell count (WBC) &lt; 2.0×109/L) than non-smokers. These effects remained apparent in a multivariate analysis correcting for dose and co-medication (docetaxel: odds ratio (OR) = 0.56, 95% confidence interval 0.32–0.97, p = 0.04; and paclitaxel: OR = 0.3, 95% CI 0.13–0.83, p = 0.02). There was also significantly less grade 4 neutropenia (absolute neutrophil count (ANC) &lt; 0.5×109/L) in smokers than in non-smokers (OR = 0.46, 95% CI = 0.26–0.81, p = 0.007) in docetaxel treated patients. However, the incidence of neutropenic fever did not differ between smoking groups. Furthermore, the percentage decrease in WBC and ANC from baseline to nadir did not differ between smoking groups. The protective effect of smoking on bone marrow counts is probably attributable to smokers having higher baseline WBC (9.2 vs. 7.5 ×109/L; p &lt; 0.0001) and ANC (6.7 vs. 5.1 ×109/L; p = 0.002) than non-smokers. Docetaxel and paclitaxel clearance did not differ between smokers and non-smokers (docetaxel: 39.1 vs. 39.4 L/h; p = 0.99; paclitaxel: 463 vs. 450 L/h; p = 0.77).
Conclusion: This is the first large study on the effects of smoking on the treatment of docetaxel and paclitaxel. Smokers had lower incidence of leucopenia and neutropenia, possibly because smoking induces bone marrow growth. However, this did not affect the incidence of neutropenic fever. As no effect on PK was seen, the inductive effect of smoking on CYP3A suggested by previous studies might be substrate dependent or less apparent.
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 A189.
Abstract A194: A QT/QTc and multi-dose pharmacokinetic (PK) study of abiraterone acetate (AA) plus prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Pili Roberto , Chi Kim , Shore Neal , Papadopoulos Kyriakos , Smith Lon , Beeram Muralidhar , Molina Arturo , Acharya Milin , Kheoh Thian , Jiao James , Gonzalez Martha , Pankras Catherine , Trinh Angela , Tran NamPhuong , Tolcher Anthony 
Published: June 2012

Abstract
Background: AA is the prodrug of abiraterone (A), an androgen biosynthesis inhibitor that selectively inhibits CYP17, thereby blocking testicular, adrenal, and prostatic intratumoral androgen biosynthesis. In a phase 3 study, AA+P demonstrated survival improvements in post-docetaxel mCRPC pts (De Bono ESMO 2010). ADT with an LHRH analog (LHRHa) has been associated with median QTc interval prolongation of 9–21 msec (Garnick ASCO 2004). Primary objective: effects of AA+P on QT/QTc interval duration in mCRPC pts receiving LHRHa. Secondary objectives: pharmacokinetics (PK) of AA and abiraterone (A) after single/multiple doses of AA.
Methods: In this open-label, single-arm phase 1b study (COU-AA-006/NCT00910754), 33 mCRPC pts with disease progression after failure of GnRH hormone therapy, a PSA ≥2 ng/mL and ≤1 course of prior chemotherapy, received AA 1000mg orally QD + P 5mg orally BID. ECGs were collected in triplicate using 12-lead Holter monitoring. Baseline ECGs were obtained on Cycle (C)1 Day (D)-1. Serial ECG recordings and time-matched PK blood samples were collected over 24 hrs on C1D1 and C2D1. Serial PK blood samples were also collected over 24 hrs on C1D8.
Results: After AA administration, the upper bound of the 2-sided 90% CI for the mean baseline-adjusted QTcF change was &lt;10 msec; no subjects discontinued due to QTc prolongation or AEs. Most AA plasma concentrations were below the quantification limit; thus AA PK analysis was not performed. A linear mixed-effects model showed no apparent relationship between change in QTcF and A plasma concentrations (estimated slope [90%CI): 0.0031 [−0.0040, 0.0102]). Exposure to A after multiple AA dosing on C1D8 and C2D1 increased versus exposure after single dose on C1D1; accumulation ratios for C1D8 (1.8–2.0) and C2D1 (2.0–2.2) were similar. The most commonly reported treatment-emergent AE (TEAE) was dizziness (12%); all TEAEs were grade 1; except 1 grade 3 AE (increased ALP) with no grade 4 TEAEs.
Conclusions: There is no significant effect of AA+P on the cardiac QT/QTc interval in mCRPC pts. No relationship between change in QTcF and A plasma concentration was observed.
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 A194.
Abstract A198: Identification and preclinical testing of novel targeted therapies for human triple-negative breast cancer.
Authors: Mittereder Lara R. , Tomlinson Christine C. , Bennett Christina N. , Michalowski Aleksandra , Caplen Natasha , Green Jeffrey E. 
Published: June 2012

Abstract
Basal-like triple negative breast cancer (BTNBC) is characterized by the absence of estrogen receptor, progesterone receptor, and Her2 expression, and represents an estimated 15% of all human breast cancers. This subtype is highly prevalent in African American women (35%) and is associated with distant metastasis and poor prognosis. As there are currently no targeted therapies for this subtype of breast cancer, our research focuses on the development of improved therapies to increase patient survival. We have previously shown that primary mammary tumors from the C3(1)/SV40-TAg genetically engineered mouse (GEM) model express a critical proliferation/ DNA repair/ cell cycle gene signature (TAg signature) that is shared with human BTNBC. SV40-TAg functionally inactivates p53 and pRb, two critical tumor suppressor genes whose functions are lost in most human BTNBC. We hypothesize that targeting dysregulated genes and biological networks present in the TAg signature will lead to the identification of novel targets and potential combination therapies.
To test this idea we developed a custom siRNA library screen to inhibit the expression of individual genes represented in the TAg signature using human MDA-MB-231 BTNBC cells. Additionally, we performed a synthetic lethal screen in which TAg signature genes were knocked down in MDA-MB-231 cells using pooled siRNAs in combination with either UCN-01 or gemcitabine, small molecule inhibitors of CHK1 and RRM1/2 respectively. It was found that the knockdown of BMI-1, EZH2, GeneA, GeneB, or GeneC significantly decreased cell proliferation with the addition of UCN-01 or gemcitabine. A second synthetic lethal screen was performed in which the above genes were knocked down using four deconvoluted siRNAs per gene with the addition of gemcitabine, UCN-01, or AZD7762 (a more specific CHK1 inhibitor). Synergistic activity was shown between the siRNA knockdown of these genes and UCN-01 and AZD7762 compared to siRNA alone. To determine whether the knockdown of these genes alters sensitivity to gemcitabine or CHK1 inhibitors, the EC50 values of these drugs are currently being evaluated in stable knockdown MDA-MB-231 cell lines expressing shRNA to the selected genes. Our results suggest that using GEM models to help identify new targets may be useful in the development of novel therapeutics for BTNBC in combination with available CHK1 inhibitors and/or gemcitabine. These studies will enhance our understanding of BTNBC and allow us to identify innovative combination therapies to treat this challenging form of breast cancer.
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 A198.
Abstract A210: Mechanism of action of MM-151, a potent mixture of three human antibody antagonists targeting EGFR.
Authors: Tan Gege , Kearns Jeffrey D. , Gerami-Moayed Nastaran , Kohli Neeraj , Werner Shannon L. , King Anne M. , Sloss Callum M. , Bukhalid Raghida , Nielsen Ulrik B. 
Published: June 2012

Abstract
Epidermal growth factor receptor (EGFR) is a key regulator of cancer cell proliferation, apoptosis, invasion, and metastasis. However, the clinical benefits of EGFR targeted agents such as erlotinib and cetuximab have been modest. Using Merrimack's Network Biology platform, a computational systems analysis was performed to identify how best to inhibit signaling through the EGFR-ERK network. These simulations predicted that enhanced inhibition is required to overcome the robust signal amplification inherent to this network and is best achieved through treatment with a combination of at least two noncompetitive ligand antagonists. The MM-151 therapeutic was developed to achieve the simulated design criteria and consists of a mixture of three fully human monoclonal antibodies directed against distinct non-overlapping epitopes in EGFR. Detailed in vitro and on-cell binding experiments, supported by computational simulations, with single component antibodies and their monovalent Fab variants, display a rich complexity of antibody affinity and avidity. All three antibodies are shown to have subnanomolar monovalent affinity to EGFR but to vary in the degree to which they functionally crosslink receptor (two antibodies display high avidity while the third has weak avidity). Ligand competition experiments with saturating antibody concentrations (EC90 of on-cell binding) demonstrate that two of the antibodies are each complete ligand antagonists while the third antibody is a partial (approx. 25%) antagonist. When combined into the MM-151 mixture, these antibodies simultaneously engage and robustly crosslink receptor to form a highly antagonistic therapeutic. Treatment of human tumor-derived cell lines with MM-151 elicits complete inhibition of ligand-mediated ERK signaling over a wide range of both EGF receptor density (as high as 2×10∘6 receptors per cell in the A431 cell line) and ligand burden (8 and 80nM EGF). In contrast, monoclonal EGFR targeted therapeutics, such as cetuximab and panitumumab, as well as oligoclonal inhibitors similar to MM-151, show weaker or even no effect on ERK signaling under similar conditions. Furthermore, the potency of monovalent MM-151 (Fab variants) is diminished in EGF mediated EGFR and ERK signaling, highlighting the importance of receptor crosslinking through antibody avidity as a determinant of efficacy. Together, these data demonstrate that MM-151 is a potent inhibitor of the EGFR-ERK signaling axis with the potential of improved efficacy over current EGFR targeted therapies.
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 A210.
Abstract A219: Efficacy of a spectrum-selective cathepsin inhibitor in a mouse model of bone cancer.
Authors: Holsinger Leslie J. , Ondoua-Lozano Alysia , Rodriguez Jade , Hanlon Katherine , Bilsky Edward J. , Havelin Joshua , Dener Jeffrey M. , Booth Robert , Vanderah Todd W. 
Published: June 2012

Abstract
Introduction: Increased cathepsin levels and activity have been shown to play a role in a variety of tumors, including lung and breast malignancies, and are correlated to poor patient prognosis. Proteolytic activity of cathepsins S, L, B and K may play a role in degradation of the basement membrane and extracellular matrix allowing a loss of cell adhesion and facilitating tumor metastasis. Cathepsin K inhibition has been reported to suppress bone resorption in women with breast cancer by inhibiting osteoclast function. Studies with cathepsin S inhibitors have demonstrated a reduction in nociception in animals, suggesting a role for cathepsin S in tumor-associated neuropathy. We report the efficacy of the spectrum-selective cathepsin inhibitor VBY-825 in a mouse model of metastatic breast cancer.
Results and Discussion: VBY-825 is a potent ketoamide-based inhibitor of cathepsins S, B, K, V, and L with pM or single digit nM affinity on this spectrum of cysteine proteases. VBY-825 has been shown to have potent anti-tumor activity in a spontaneous mouse model of pancreatic cancer (Elie et al, 2010, Biochimie). VBY-825 potently inhibited angiogenesis in tumor cell lines, endothelial cell co-cultures and tumor matrix invasion when assayed in an in vitro 3D tumor cell growth assay. Pharmacokinetic behavior of VBY-825 supported once daily dosing resulting in plasma levels sufficient for sustained inhibition of the target cathepsins. Efficacy of VBY-825 was assessed in a murine bone cancer model in which murine 66.1 breast cancer cells are injected and confined to the intramedullary space of the femur of non-immunocompromised mice. Beginning on post surgical day 7 animals received either VBY-825, zoledronic acid, or 5% dextrose vehicle once daily for 14 days. Similarly to the bisphosphonate, VBY-825 in this model significantly reduced bone matrix degradation. VBY-825 also reduced behaviors associated with spontaneous pain including flinching and guarding with significantly greater efficacy than zoledronic acid suggesting that VBY-825 may also induce analgesia against bone cancer pain.
Conclusions: These studies demonstrate that the cathepsin inhibitor VBY-825 is effective in a model of bone cancer and associated chronic pain, demonstrating both analgesic activity as well as protection from bone matrix loss and remodeling. These studies support the role of multiple cathepsins as therapeutic targets in metastatic and primary bone cancer.
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 A219.
Abstract A226: Mechanism of action of iniparib: Stimulation of reactive oxygen species (ROS) production in an iniparib-sensitive breast cancer cell line.
Authors: Licht Stuart , Cao Hui , Li Zhifang , Zhang Jingxin , Liu Feng , Brittain Scott , Shen Junqing , Zhang Bailin , Hopke Joern , Newcombe Rick , Reiling Stephan , Pollard Jack , Watters James , Cheng Hong , Reddy Venkateshwar , Bergstrom Donald A. 
Published: June 2012

Abstract
Iniparib (BSI-201) holds substantial promise as an anti-cancer agent, and knowledge about its mechanism of bioactivity is evolving. While PARP inhibition has been proposed as iniparib's primary mechanism of action, the low potency of iniparib against PARP observed in a number of assays and models suggests that other mechanisms account for its bioactivity. These mechanisms are likely to include metabolic conversion of iniparib to a bioactive species. Here, we present an integrated analysis of profiling experiments (transcriptional and proteomic) and synergy screens (bioactive compound and shRNA) designed to identify the pathways associated with iniparib bioactivity. Proteomic and transcriptional profiling in MDA-MB-453 cells indicate that, at concentrations close to its in vitro potency as a cytotoxic agent, iniparib induces activation of the Nrf2 transcription factor, a known mediator of cellular anti-oxidant/anti-xenobiotic defense. Furthermore, Gene Set Enrichment Analysis (GSEA) comparing iniparib's transcriptional profile to drugs with known mechanism of action reveals similarity between iniparib and inhibitors of the mitochondrial electron transport chain. Bioactive compound and shRNA synergy screens also identify both Nrf2 and the components of the mitochondrial electron transport chain as genes required for maximum iniparib bioactivity. Cell-based imaging studies indicate that iniparib stimulates the production of reactive oxygen species (ROS). Taken together, these results are consistent with a mechanism in which a component of the Nrf2-mediated antioxidant response and/or the mitochondrial electron transport chain converts iniparib to its putative active metabolite, and this metabolite uncouples electron transport from oxidative phosphorylation, leading to the production of ROS at cytotoxic levels. The results of the integrated analysis may assist in the discovery of biomarkers for iniparib sensitivity.
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 A226.
Abstract A234: Identification and characterization of inhibitor-resistant mutants of the protein-tyrosine kinase c-Fes.
Authors: Hellwig Sabine , Gray Nathanael S. , Smithgall Thomas E. 
Published: June 2012

Abstract
Lack of target selectivity is a well-known limitation to the use of chemical inhibitors to pinpoint individual kinase functions in the intricate network of cellular signaling pathways that often involve closely related kinases or unrelated off-target effects. A possible solution to this problem involves the use of inhibitor-resistant mutants of the targeted kinase. Such mutants can be employed in rescue experiments, in which introduction of the mutant kinase reverses the phenotype resulting from chemical inhibition of the endogenous kinase. This chemical genetics approach has been successfully used by our group to dissect roles for individual members of the Src kinase family in embryonic stem cell differentiation and chronic myelogenous leukemia, despite close structural homology within this kinase family. In the present study, we used this approach to validate the specificity of a series of potent inhibitors of the c-Fes kinase that we recently identified in a kinase-biased chemical library screen. The c-Fes protein-tyrosine kinase is involved in multiple cellular signaling pathways that modulate differentiation, the innate immune response, vasculogenesis and tumorigenesis. Using site-directed mutagenesis, we systematically altered residues around the inhibitor-binding pocket defined in a recent crystal structure of the c-Fes SH2-kinase region bound to the diaminopyrimidine inhibitor, TAE684. We first mutated the gatekeeper methionine (Met636) of Fes, which helps mediate TAE684 binding in the crystal, but found that substitutions at this position inactivated kinase function. Additional point mutations that retained kinase activity were then tested against TAE684 and other potent small molecule inhibitors of c-Fes. This screen identified a leucine residue near the gatekeeper position (Leu638) to be critical in conferring sensitivity to both TAE864 and the more Fes-selective pyrazolopyrimidine, WZ-4-49-8. Replacement of this Leu638 with a bulkier tyrosine or phenylalanine rendered c-Fes very resistant to WZ-4-49-8, with IC50 values increasing from the low nanomolar range for wild-type Fes to the micromolar range for the mutants in an in vitro kinase assay. These data implicate Leu638 as an important specificity determinant for future design of more potent and selective inhibitors of c-Fes. Ongoing studies are using this resistant mutant to validate novel roles for Fes in biological systems impacted by TAE684 and WZ-4-49-8 treatment, including differentiation of macrophages (a major site of c-Fes expression) to osteoclasts.
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 A234.
Abstract A246: Blockade of CSF-1R/CSF-1 signaling by PLX3397 attenuates prostate cancer cell growth in bone, prostate cancer-induced skeletal pain, and pathological bone remodeling.
Authors: Jimenez-Andrade Juan Miguel , Bloom Aaron P. , Kaczmarska Magdalena J. , Burton Elizabeth A. , Zhang Jiazhong , Lin Paul S. , West Brian L. , Mantyh Patrick W. 
Published: June 2012

Abstract
Prostate tumors that have metastasized to bone frequently proliferate in bone and induce significant bone pain and pathological remodeling, all of which are difficult to control fully using currently available therapies. Colony stimulating factor-1 (CSF-1) regulates the survival, proliferation, differentiation and function of cells in the monocyte lineage including macrophages and osteoclasts. Human studies have reported a greater expression of CSF-1 and its receptor, CSF-1R (also known as c-Fms), in tumor and stromal cells of metastatic prostate cancers versus non-metastatic prostate cancers. To assess the role of CSF-1R in pain and disease progression in bone from prostate cancer, a novel small molecule inhibitor of CSF-1R, PLX3397, was administered to mice that were injected in the femur marrow space with ACE-1 canine prostate cancer cells. Intrafemoral injection of prostate cancer cells resulted in significant growth of tumor, which in turn induced significant skeletal pain and massive formation of pathological, disordered, woven bone. Sustained administration of PLX3397 started on day 12 after the tumors were well established and pathological bone remodeling was evident. Six weeks treatment with PLX3397 significantly attenuated (∼50%) prostate tumor cell growth (p=0.018), bone cancer pain behaviors (p&lt;0.001) and the prostate cancer cell induced pathological remodeling of the bone (p&lt;0.001). These results suggest that blockade of CSF-1R/CSF-1 signaling by PLX3397 is highly effective in not only reducing prostate cancer growth in the bone, but also prostate cancer induced bone pain and pathological remodeling. PLX3397 is currently undergoing Phase 2 clinical testing in patients with a variety of tumors, and these data further support its evaluation in patients with prostate cancer.
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 A246.