bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A191: The application of three-dimensional cell cultures in combination with the Virtual Tumor for designing optimal drug dosing schedules.
Authors: Brightman Frances , Fernandez Eric , Orrell David , Fell David , Chassagnole Christophe 
Published: June 2012

Abstract
There is currently a great deal of interest in determining synergistic drug combinations, however, it is not easy to determine which schedules should be tested, since the number of different possible schedules increases combinatorially when more than one drug is considered. We have therefore developed a predictive PK-PD “Virtual Tumor” model that allows rational design of schedules for drug combinations. We previously built a Virtual Tumor that was capable of successfully simulating the outcome of various drug combination schedules in xenografts; using this model we were also able to propose new optimal administration schemas. Although xenografts represent a convenient and relatively inexpensive approach to assessing the likely efficacy of proposed dosing regimens in vivo, the number of permutations that can be tested is still limited by practical considerations. We have therefore explored the use of three-dimensional tumor cell cultures (microtissues) as a more cost-effective alternative to xenografts for validating Virtual Tumor predictions. Here we present a microtissue Virtual Tumor that is analogous to our xenograft model, and a comparison of the utility of each in simulating and optimising drug dosing schedules. The application of microtissues in combination with the Virtual Tumor technology can be used to design new regimens with proprietary compounds as well as standards of care, small molecules or biotherapeutical agents; help test possible schedules for combinations of different drugs that would be effectively impossible to investigate experimentally; and allow prioritisation of the most effective drug combinations.
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 A191.
Abstract A206: Chk1 protects normal cells from HDAC inhibitor-induced cell death.
Authors: Lee Ju-Hee , Choy Megan L. , Ngo Lang , Venta-Perez Gisela , Marks Paul A. 
Published: June 2012

Abstract
Histone deacetylase inhibitors (HDACi) are a new class of selective anti-cancer agents that inhibit zinc-dependent histone deacetylases. HDACi in clinical trials have shown anti-cancer activity at well-tolerated doses. The mechanisms of resistance to HDACi are important in developing these agents for cancer therapy. We previously showed that vorinostat induces DNA damage in both transformed and normal cells. Normal cells can repair the DNA damage, while transformed cells cannot and undergo apoptosis and death. This study found Chk1, a component of the G2 checkpoint, protects normal cells from HDACi-induced cell death. Culture with HDAC inhibitor plus Chk1 inhibitor (UCN-01, AZD7762 or CHIR124) killed normal cells, while there was no cell death in culture of normal cells with HDAC inhibitor alone. Chk1 inhibitor also increased cell death of transformed cells cultured with HDACi. In culture with both HDACi and Chk1 inhibitor, mitotic abnormalities which included loss of sister chromatid cohesion and chromosomal disruption were observed in normal and transformed cells. These findings show that intact Chk1 is important for the resistence of normal cells to HDACi and suggest that combined treatment of HDACi with Chk1 inhibitor may cause substantial toxicity.
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 A206.
Abstract A214: F14512, a novel targeted cytotoxic agent exhibits a marked antileukemic activity, alone and in combination with AraC.
Authors: Kruczynski Anna , Pillon Arnaud , Creancier Laurent , Vandenberghe Isabelle , Gomes Bruno , Annereau Jean-Philippe , Fournier Emmanuel , Sarry Jean-Emmanuel , Demur Cécile , Delabesse Eric , Pourtau Sandrine , Cartron Valérie , Marty Fabien , Roy Sabine , Chansard Nathalie , Blanchet Jean-Christophe , Verdier Jérôme , Ricome Christel , Offrete Vanessa , Gras Stéphane , Guminski Yves , Recher Christian , Bailly Christian , Guilbaud Nicolas 
Published: June 2012

Abstract
Chemotherapy remains mainly used for the treatment of Acute Myelogenous Leukemia (AML). However, in the past 3 decades limited progress has been achieved in improving the long-term disease-free survival. Therefore the development of more effective drugs for AML represents a high level of priority. F14512 combines an epipodophyllotoxin core targeting topoisomerase II with a spermine moiety introduced as a cell delivery vector. In fact the polyamine moiety facilitates F14512 selective uptake by tumor cells via the polyamine transport system, a machinery frequently overactivated in cancer cells. In this study, we report the in vivo antileukemic activity of F14512 against human AML models, established from patient samples. AML cells, collected from 3 different patients, were established onto NSG mice (LAM-2, LAM-7 and LAM-18). These 3 AML samples exhibited a normal karyotype, with FLT3-ITD, NPM1 and DNMTA3 mutations which proved stable over serial transplantations in vivo. After multiple i.v. administrations of F14512, 3 times a week for 3 weeks, an extensive reduction of AML cell number (98–99%) was observed in LAM-2 and LAM-7 - bearing mice. This antileukemic activity was recorded on the basis of flow cytometry, q-PCR and histology assessments. The effects of F14512 on LAM-18 bearing mice were marginal with an inhibition of AML cell growth of 42%. We also show in vitro and in vivo synergistic effects of F14512 in combination with AraC, one of the frontline chemotherapeutic agents for AML. These results were obtained using the HL-60 cell line. The activity of F14512 in combination with AraC will be further investigated in patient AML models. Collectively, these results demonstrate that F14512 exhibits a marked in vivo antileukemic activity, supporting its clinical development. Phase I clinical trials in onco-hematology are on going with this novel promising drug candidate.
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 A214.
Abstract A217: The HSP90 inhibitor AT13387 demonstrates potent antitumor activity in both imatinib-sensitive and imatinib-resistant gastrointestinal stromal tumor models.
Authors: Smyth Tomoko , Van Looy Thomas , Curry Jayne , Wozniak Agnieszka , Rodriguez-Lopez Ana , Schoffski Patrick , Lyons John , Thompson Neil , Wallis Nicola 
Published: June 2012

Abstract
Background: Activating mutations in the receptor tyrosine kinase, KIT, are found in the majority of gastrointestinal stromal tumors (GIST) and further secondary resistance mutations in KIT frequently arise upon treatment with tyrosine kinase inhibitors such as imatinib. KIT and its mutant forms are sensitive clients of HSP90 and it has been suggested that HSP90 inhibition could be an effective treatment for both imatinib-sensitive and imatinib-resistant GIST, which can occur simultaneously in different clones within the same patient.
Methods: AT13387 is a fragment-derived, potent HSP90 inhibitor, which is currently being evaluated in clinical trials. To evaluate its anti-tumor activity against GIST, AT13387 was tested in both imatinib-sensitive (GIST882, GIST-PSW) and imatinib-resistant (GIST430, GIST48) in vitro and in vivo GIST models.
Results: AT13387 inhibited the proliferation of GIST cell lines at sub-100 nM potencies, irrespective of their sensitivity to imatinib. Treatment of GIST882, GIST430 and GIST48 cells with AT13387 induced HSP70, a marker of HSP90 inhibition, whilst reducing the levels of the client proteins KIT, AKT and their phosphorylated forms. A concomitant decrease in the levels of phospho-ERK and phospho-S6 demonstrated that KIT signaling was being inhibited in all cell lines, whilst an increase in cleaved PARP indicated apoptosis. In contrast, treatment with imatinib inhibited KIT signaling only in the imatinib-sensitive line, GIST882.
In vivo, the efficacy of AT13387 was tested in imatinib-sensitive (GIST-PSW) and imatinib-resistant (GIST430) xenograft models. AT13387, dosed once a week, inhibited the growth of both xenografts; depletion of phospho-KIT and inhibition of KIT signaling were again seen in these tumors. As expected, treatment with imatinib caused significant regression of the GIST-PSW tumors but not of GIST430. The combination of imatinib and AT13387 significantly enhanced tumor growth inhibition (T/C 21%) over either of the monotherapies (T/C 30% for AT13387, 46% for imatinib) in the GIST430 xenograft. Importantly, the combination was well tolerated.
Conclusions: AT13387 is currently being evaluated in a Phase II GIST trial both as single agent and in combination with imatinib. These results support the potential efficacy of the compound in both imatinib-sensitive and imatinib-resistant GIST and its current testing in this disease.
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 A217.
Abstract A220: The efficacy of varying concentrations of intravesical apaziquone on murine bladder cancer in an animal model.
Authors: Reddy Guru , Denes Bela , Kovacs G. 
Published: June 2012

Abstract
Introduction and Objectives: Apaziquone is a novel bioreductive alkylating agent in development for intravesical therapy of nonmuscle invasive bladder cancer. The standard dose of apaziquone in all ongoing clinical studies is 4 mg/ 40 mL (0.1mg/mL). The objective of this study was to test the efficacy of varying concentrations of apaziquone versus placebo in an animal model of bladder cancer.
Methods: A total of 1×105 MB49 cells were instilled into the bladder of C57BL/6 mice after electrocauterization to establish the tumor model. Mice bearing orthotopic tumors were administered varying concentrations of apaziquone (0.05, 0.1, 0.4, and 0.8 mg/mL) or placebo (0.85% saline) via intravesical instillation (0.1 mL) one week after tumor implantation. Instillations were continued once a week for 4 weeks. Tumor incidence, overall and median survival is reported.
Results: At the end of the observation period (80 days), all animals in the control (0.85% saline) and 0.05 mg/mL groups had died (fig. 1). The median survival of mice receiving apaziquone at concentrations of 0.1 mg/mL (42.5 days); 0.4 mg/mL (40.5 days) and 0.8 mg/mL (49 days) was longer than that of mice treated with 0.05 mg/mL (30 days) and 0.85% saline (27 days). Statistically significant differences in survival were observed in control vs apaziquone-treated groups [0.1 mg/ml(P &lt; 0.05); 0.4 mg/mL(P &lt; 0.01); 0.8 mg/mL (P &lt; 0.01)], and in the low concentration (0.05 mg/mL) vs 0.1 mg/mL (P &lt; 0.05), 0.4 mg/mL (P &lt; 0.01) and 0.8 mg/mL (P &lt; 0.01), respectively.
The median survival of the 0.1, 0.4 and 0.8 mg/mL treated groups did not differ, but 33.3% in the 0.1 mg/mL cohort, and 14.3% in the 0.4 mg/mL cohort were long-term survivors (&gt;80 days). All other animals (n = 37) had died of cancer by the end of the observation period. Three mice did not survive anesthesia. At necropsy all mice had advanced local disease with deep invasion of the muscularis propria, and usually with multiple lung metastases.
Conclusion: Apaziquone at the 0.1 mg/mL concentration demonstrates excellent antitumor activity compared to placebo or 0.05 mg/mL solutions. In this model there was no significant difference in the median survival between 0.1 mg/mL and higher concentrations of apaziquone (0.4 and 0.8 mg/mL) supporting continued development with the current clinical dose (0.1mg/mL).
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 A220.
Abstract A237: Elevated Mnk kinase activity is associated with malignant progression and reduced patient survival in human prostate cancer and can be therapeutically inhibited in human prostate cancer cells by the novel, orally bioavailable Mnk inhibitor cercosporamide.
Authors: Konicek Bruce , Hall Chad , Dumstorf Chad , Colligan Bruce , Dong Sucai , Na Songqing , Deddens James , Douglass Larry , Carter Julia , Graff Jeremy R. 
Published: June 2012

Abstract
In a wide variety of malignancies, progressive disease and reduced patient survival have been linked to increased function of eukaryotic translation initiation factor 4E (eIF4E), which selectively enhances the translation of potent growth and survival factors and oncoproteins (e.g. c-myc, VEGF, cyclin D1, Mcl-1, MMP-9, etc.). Recent published reports have shown that the oncogenic activity of eIF4E is critically dependent on the activity of the MNK kinases (Map kinase interacting kinase 1 and 2), which phosphorylate eIF4E at S209 (p4ES209). Increased p4ES209 has been linked to a variety of advanced cancers, notably head and neck and non-small cell lung cancers. Herein, we report that p4ES209 is significantly elevated in human prostate cancer (CaP) tissues (n=133) and associated with reduced patient survival. p4ES209 is elevated In both low grade (Gleason score ≤ 6) and high grade (Gleason score ≥ 7) CaP vs. adjacent normal prostate tissue (BPH) (p &lt; 0.02 and p &lt; 0.0001, respectively). Elevated p4ES209 in invasive CaP is related to significantly reduced patient survival (p = 0.0216) and increased risk of death from CaP (hazard ratio = 2.729). Moreover, p4ES209 is evident in the LNCaP, LNAI, CWR22Rv1 CaP cell lines, with levels being highest in the castrate-resistant cells (LNAI and CWR22Rv1). shRNA-mediated knock-down of MNK 1 and 2 reduced p4ES209 levels and specifically triggered apoptosis. Similarly, treatment of these cell lines with the novel, orally-bioavailable MNK inhibitor, cercosporamide, reduced p4ES209 in a dose-dependent manner and induced apoptosis coincident with reduced expression of key translationally controlled proteins (e.g. Mcl-1). Further, oral administration of this inhibitor can suppress p4ES209 in normal mouse tissues and in xenografted human cancers within 30 minutes, lasting at least 4 hours in tumor tissue. These data demonstrate the utility of cercosporamide in probing MNK function in vitro and in vivo and highlight the potential utility of targeting MNK for prostate 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 A237.
Abstract A242: A novel AKT inhibitor, PH427, prevents UVB-induced signaling in human squamous skin carcinomas.
Authors: Meuillet Emmanuelle J. , Mash Eugene A. , Olsen Erik , Moses Sylvestor A. , Morgan Sherif S. 
Published: June 2012

Abstract
Non-melanoma skin cancers (NMSC) are a significant and increasing health problem in the United States that occur primarily on sun-exposed areas of the body and are strongly associated with chronic sun exposure. Recent advances in our understanding of the molecular basis of carcinogenesis have lead to the identification of potential molecular targets that might be used to prevent the progression of early skin cancer. AKT (protein kinase B), a pleckstrin homology (PH) lipid binding domain and a serine/threonine kinase containing protein is a key component of the phophatidylinositol-3-kinase (PtdIns3-K) cell survival signaling pathway which is activated in skin cancers. In this study, we describe the effects of a novel inhibitor of AKT (PH427) that binds to the PH domain of AKT thus preventing its binding to PtIns-(3,4,5)P3 at the plasma membrane and subsequent activation. PH427 inhibits AKT activity at low micromolar concentrations in HaCat human keratinocytes and HaCat-II,4, a ras transformed human keratinocyte cell line. We demonstrate that PH427 is able to prevent UVB-induced AKT activation and expression in both cell lines. PH427 also induced apoptosis in both HaCat and HaCat II,4 keratinocytes. Moreover, the compound is lipophilic and penetrates the skin in SKH-1 mice when applied topically. Short term in vitro studies showed that PH427 prevents UVB-induced AKT activation and UVB-induced signaling, as measured by p70S6 Kinase and p-GSK3-activation. Long-term in vivo studies utilizing SKH-1 mice have also shown significant reduction of UVB-induced skin tumors when PH427 is topically applied when compared to acetone-only control or PH427 alone. Additionally, drug treated mice exhibit reduced levels of phospho-Ser473AKT in the epidermal layers. We conclude that the topical application of PH427 may be beneficial for preventing NMSC.
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 A242.
Abstract A27: The combination of navitoclax and PLX4720 in melanoma in vitro and in vivo.
Authors: Hoff Taylor , Cho Daniel , Panka David , Sepehr Alireza , Curtis Lauren , Mier James W. , Sullivan Ryan J. 
Published: June 2012

Abstract
Introduction: Approximately 40–50% of patients with melanoma have a tumor which harbors a BRAF mutation (BRAF+). Vemurafenib is a highly selective inhibitor of mutant BRAF which has recently been FDA-approved for the treatment of patients with BRAF+ advanced melanoma. While response rates to vemurafenib are high, the vast majority of patients will develop resistance. Identification of therapeutic strategies to enhance the efficacy of vemurafenib is a high priority. Navitoclax is a BH3-only mimetic which has single agent activity in tumors with low Mcl-1 and enhances the toxicity of agents which inhibit or downregulate MCL-1. As recent data suggests that selective BRAF inhibitors inactivate Mcl-1 through upregulation of BIM, we therefore studied the effects of combining PLX4720, a selective BRAF inhibitor very similar to vemurafenib, with navitoclax in vitro and in vivo.
Methods: Three BRAF mutant melanoma cell lines (A2058, A375, SKMel5) were selected for in vitro analysis and treated for 6 hours with DMSO, navitoclax (1 uM), PLX4720 (1 uM), or the combination. Cells were then lysed after 6 hours of treatment and western blot analysis was performed probing for vinculin, PARP, total and phosphorylated Erk, Mcl-1, BIM, BID, AKT, pS6, and NOXA. Xenografts were generated from the A375 and A2058 cell lines in nude beige mice and grown to 10 mm in size. Mice were then treated with vehicle, navitoclax (100 mg/kg/day), PLX4720 (100 mg/kg/day), or the combination once daily by gavage for 14 days. Tumor measurements were taken daily.
Results: Treatment of melanoma cell lines with PLX4720 resulted in downmodulation of Mcl-1 and induction of BIM both in vitro and in vivo. In vitro, the combination of navitoclax and PLX4720 led to greater PARP cleavage than either agent alone. In vivo, the navitoclax enhanced the efficacy of PLX4720 in both xenograft models. Interestingly, the two xenograft models showed differential sensitivity to treatment with the respective single agents.
Conclusion: The combination of a selective BRAF inhibitor with a BH3-mimetic may be a promising therapeutic strategy to enhance the clinical efficacy of BRAF inhibitors. Efforts are underway to assess such a combination clinically.
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 A27.
Abstract A30: Inhibition of PMCA4 as a strategy to increase the effectiveness of Bcl-2 inhibitor-mediated cell death in breast cancer cells.
Authors: Roberts-Thomson Sarah J. , Curry Merril C. , Luk Nicole A. , Monteith Gregory R. 
Published: June 2012

Abstract
Intracellular calcium is a vital cell signaling molecule that can influence a myriad of important cellular functions, including those deregulated in the cancer cell. Consequently Ca2+ levels within the cell must be precisely controlled. Amongst the suite of proteins controlling calcium homeostasis are the plasma membrane calcium ATPases (PMCAs), which belong to a family of druggable proteins. PMCAs are pumps that reside on the plasma membrane and are responsible for the efflux of intracellular Ca2+ and thus are important in maintaining basal cellular calcium levels. Sustained increases in intracellular Ca2+ can be a trigger for cell death and agents that induce alterations in calcium signaling could be a strategy to restore the sensitivity of a cancer cell to death stimuli. The aim of this study was to explore the effectiveness of inhibiting two PMCA isoforms, PMCA1 and PMCA4, on the augmentation of cell death initiated by a Ca2+ionophore (ionomycin) and a Bcl-2 inhibitor (ABT-263) in MDA-MB-231 breast cancer cells. Ionomycin represents a caspase-independent mechanism of cell death and ABT-263 enhances cell death via a caspase-dependent mechanism. PMCA1 and PMCA4 were inhibited using siRNA and the effect on cell death was measured by staining with Hoechst 33342 and propidium iodide using high content imaging (ImageXpress). Intracellular Ca2+ was determined using a FLIPRTETRA with cells loaded with the calcium sensor Fluo4-AM. Inhibition of PMCA1 was associated with significant changes in global cytosolic free Ca2+ induced by purinergic receptor activation, whereas the same effect was not seen with PMCA4 inhibition. Consistent with effects on global calcium levels, ionomycin (3 μM)-induced cell death was significantly augmented by PMCA1 but not PMCA4 siRNA. However, ABT-263 (3 μM)-induced cell death was augmented only by inhibition of PMCA4, suggesting that PMCA4 siRNA-mediated inhibition of ABT-263 apoptosis is mediated through effects on local and/or specific calcium signaling processes. PMCA4 can alter the activity of calcium-dependent transcription factors in cardiac myocytes independent of global cytosolic calcium. In MDA-MB-231 cells, the effects of PMCA4 inhibition appear to be associated with alterations in the activity of NFkappaB. These results highlight the specificity of different isoforms of PMCA in the modulation of cell death pathways in MDA-MB-231 breast cancer cells. Inhibition of PMCA4 may be a viable adjuvant therapy when combined with Bcl-2 family inhibitors for the treatment 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 A30.