bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract PR-9: Differences in effects on myocardium and mitochondria by VEGF receptor inhibitors suggest separate mechanisms of cardiotoxicity
Authors: French Kevin , Hu Catherine , Kumar Rakesh , Renninger Jon , Gales Tracy , Coatney Robert , Frazier Kendall 
Published: June 2012

Abstract
Reports have implicated vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors with mitochondrial injury and/or subsequent cardiovascular toxicity, suggesting an on-target pharmacologic effect by this class of promising anticancer agents. Investigative studies were performed to assess myocardiotoxicity and mitochondrial toxicity of 3 VEGFRi's (sunitinib, sorafenib and pazopanib). Mitotoxicity was evaluated in vitro using Laser Scanning Cytometry in neonatal rat ventricular myocyte cultures with endpoints including mitochondrial membrane potential (MMP), cell viability, apoptosis and ATP depletion. Cardiomyocytes were exposed with protein free concentrations of up to 4 micromolar of sunitinib, sorafenib or pazopanib for 48 hours. There were no changes in viability or apoptosis versus vehicle-treated cells. Mitochondrial membrane potential was slightly but significantly decreased with sunitinib treatment but not with sorafenib nor pazopanib. Dose-dependent intracellular ATP depletion was observed with sunitinib and sorafenib, but not with pazopanib. In separate in vivo studies, echocardiographic, histomorphologic and ultrastructural approaches were used to assess cardiotoxicity in rats concurrently exposed to the cardiac stressor dobutamine and one of the VEGFR inhibitors in rats for 21 days. Troponin I and TUNEL were also evaluated and were similar to controls. While hearts were morphologically unremarkable by routine microscopic examination, ultrastructural analysis of myocardiocytes by electron microscopy revealed mitochondrial swelling, dense deposits and matrix cavitation in 6/8 rats given sunitinib, disrupted mitochondrial cristae in 1/7 given sorafenib, but no effects with pazopanib. Echocardiographic abnormalities including premature ventricular contractions, alterations in heart rate, circumferential strain, and radial and circumferential strain rates were also noted with sorafenib, but not with sunitinib or pazopanib after dobutamine stress challenge. Our results indicate there are marked differences in the potential for myocardial toxicity and mitochondrial toxicity between VEGFR inhibitors. Since sunitinib and sorafenib have previously been shown to have differential effects on mitochondria, the mechanism of cardiac/mitochondrial injury with various VEGFRi's may not be a result of similar class-based VEGFR2 pharmacology, but instead reflect separate kinase selectivity profiles.
Citation Information: Mol Cancer Ther 2009;8(12 Suppl):PR-9.
Abstract A119: Photoimmunotherapeutic nanoparticles for combination therapy.
Authors: Dhar Shanta , Williams Anna M. 
Published: June 2012

Abstract
Photoimmunotherapy (PIT) is a promising field for cancer treatment that combines the phototoxic and immune stimulating ability of photodynamic therapy (PDT) with the widespread effectiveness of the immune system. We speculated that co-delivery of an immune-stimulant with a photosensitizer (PS) using a nanoparticle (NP) delivery platform will be a useful means to attack metastatic cancer. To probe this, we have initiated the construction of new PIT agents using a multifunctional NP delivery platform. Briefly, we encapsulated a PS within a polymeric NP core made up of poly(D,L-lactic-co-glycolic acid)-b-poly(ethylene glycol) (PLGA-b-PEG). After coating the outside of the polymeric core with gold nanoparticles, we modified the gold surface with CpG-ODN, a single-stranded DNA that is a known immunostimulant. Synthesis, biological activity, and immune stimulatory effects of these constructs will be presented.
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 A119.
Abstract A133: A novel class of selective estrogen receptor degraders regresses tumors in preclinical models of endocrine-resistant breast cancer.
Authors: Darimont Beatrice , Govek Steven , Joseph James , Grillot Katherine , Bischoff Eric , Aparicio Anna , Bonnefous Celine , Douglas Karensa , Julien Jackline , Kahraman Mehmet , Kaufman Joshua , Lai Andiliy , Lee Kyoung-Jin , Lu Nhin , Nagasawa Johnny , Prudente Rene , Qian Jing , Sensintaffar John , Shao Gang , Heyman Richard , Rix Peter , Smith Nicholas , Hager Jeffrey 
Published: June 2012

Abstract
60–75% of all breast cancers express the estrogen receptor (ER) and thus are treated with anti-hormonal therapies that directly block ER function (e.g. Tamoxifen) or hormone synthesis (Aromatase Inhibitors). While these therapies are initially effective, acquired resistance invariably emerges. Importantly, the majority of these tumors continue to express and depend on ER for growth and survival, suggesting that novel approaches to target ER signaling have tremendous potential to treat endocrine-resistant disease. We have identified novel ER antagonists that induce degradation of ER at picomolar concentrations resulting in significant reduction in steady state ER protein levels in breast cancer cell lines. These compounds yield regression in both Tamoxifen-sensitive and - resistant models of breast cancer in vivo. Based on their unique in vitro profile, good pharmacokinetics and oral bioavailability, these compounds represent a novel class of Selective Estrogen Receptor Degraders (SERDs) that hold tremendous promise as a next generation therapy for the treatment of ER+ 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 A133.
Abstract A14: Patient-derived tumor xenografts supporting development of targeted drugs.
Authors: Hoffmann Jens , Becker Michael , Jana Rolff , Rivera Maria , Merk Johannes , Zeisig Reinhard , Schlag Peter M. , Schwan Alexandra , Fichtner Iduna 
Published: June 2012

Abstract
Almost in parallel with the new millennium processes in drug development for cancer therapy have changed substantially. Insight in the cancer biology have revealed this disease as a complex genetic disorder leading to a high variety of phenotypes among the different individuals. Many tumors present a very specific pattern of molecular changes and this leads to a heterogenous individual response to drugs.
The correct identification of predictive biomarkers selecting the most appropriate therapies and avoiding unnecessary treatments for an individual patient is still a challenge. Patient-derived tumor xenografts allow preclinical investigations in a clinically relevant way. We performed investigations to improve the understanding of cancer complexity and to draw rational conclusions for therapy decisions.
Tumor models were established by direct transplantation of surgical specimens to immunodeficient mice and were maintained in early passages. We have shown a high correlation between original patient sample and xenograft both at gene and protein level. We established several large panels of tumor models: i.e. 10 breast, 30 colorectal, 25 lung, 6 ovarian, 10 sarcomas, and 30 leukemias (25 ALL and 5 AML).
During the characterization of the xenografts for response towards clinically used anticancer drugs, the analysis for mutations and of gene expression revealed interesting correlations. In NSCLC models upregulation of hypoxia marker genes correlated with resistance to microtubule targeted drugs. In the colon cancer xenografts KRAS mutations predicted resistance to cetuximab.
We further identified a potential set of 20 genes which may be predictive for oxaliplatin response. These results demonstrate, that the ability to assess anti-tumor activity in well-characterized xenografts in correlation with particular genetic or molecular characteristics may support the development of new therapeutic regimens.
Conclusions from what we discussed are:drug discovery, systems biology, and translational research are moving together to address all the new hallmarks of cancer - increasing the success rate of drug discoverypanels of patient derived xenograft models represent an important tool for translational research to address clinically relevant questions in a standardized and strictly controlled fashionpredictive value of the preclinical models is increasing steadily - they show a high concordance with the clinical specimens concerning marker expression and response to 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 A14.
Abstract A159: Epigenetic silencing of the M-type phospholipase A2 receptor gene in leukemic cells.
Authors: Menschikowski Mario , Platzbecker Uwe , Hagelgans Albert , Vogel Margot , Thiede Christian , Schoenefeldt Claudia , Eisenhofer Graeme , Siegert Gabriele 
Published: June 2012

Abstract
Background: The M-type phospholipase A2 receptor (PLA2R) plays a crucial role in a number of different signaling pathways and may act as tumor-suppressor. In the current study the expression and methylation of the PLA2R gene in the myeloid U937 cell line and blood leukocytes of patients with leukemia were analyzed. Methods. Expression of PLA2R in U937 cells was studied using RT-quantitative PCR. To determine methylation levels of the PLA2R locus, bisulfite-modified DNA fragments were sequenced. Identification of different 5′-CpG methylation sites in normal and leukemic patients was followed by methylation specific-high resolution melting (MS-HRM) analysis to quantify PLA2R methylations.
Results: Our data establish that expression of PLA2R is completely down-regulated in U937 cells. Simultaneously, a 100% methylation of PLA2R promoter and down-stream regions was found in this cell line; after exposure of the cells to 5-aza-2 -deoxycytidine, PLA2R was re-expressed. MS-HRM analyzes in 34 patients with different types of leukemia indicated an average PLA2R methylation of 30%±18%, whereas in 52 normal subjects methylation levels were below 10%. In a preliminary study of high-risk myelodysplastic syndrome patients (MDS), three patients had increased PLA2R methylations. In the course of treatment with azacitidine (Vidaza) as methyltransferase inhibitor, two of these patients were responders in contrast to one patient who was a non-responder with increased methylation levels in blood leukocytes during treatment. Another patient with minimal residual disease after treatment of AML underwent preemptive treatment with azacitidine to avoid hematological relapse (HR). After two azacitidine cycles a minor cell fraction with 100% methylated PLA2R was completely diminished. However, three weeks later methylation of the PLA2R promoter increased to 50%, with 9% blasts detectable in blood samples. After further azacitidine treatment cycle, blasts diminished in blood samples but the methylation of PLA2R in blood leukocytes remained at 35%. During the following seven weeks with no further azacitidine treatment blasts increased up to 44% suggesting that the treatment with azacitidine was effective but not efficient enough to prevent a HR in this patient.
Conclusions: The study shows for the first time that the PLA2R promoter and down-stream regions in leukemic cells are hypermethylated and that the determination of PLA2R methylation by MS-HRM may be useful as a biomarker in the diagnosis and therapeutic treatment of high-risk MDS and AML patients.
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 A159.
Abstract A181: IGF-IR expression predicts responsiveness to ionizing radiation in patients with locally advanced cervical cancer.
Authors: Moreno-Acosta Pablo , Cendales Ricardo , Gamboa Oscar , Romero Alfredo , Serra Joseph Balart , Magne Nicolas 
Published: June 2012

Abstract
Background: The aim of the present study was to evaluate a possible association of expression IGF-IR, IGF-I, IGF-II, GAPDH and hemoglobin levels with tumor response to radiotherapy alone in patients HPV 16 positive with locally advanced cervical cancer.
Methods: In this study of case-control nested in a cohort, 38 patients were included to whom tumor sample in fresh of the transformation zone of cervix was taken them before treatment. All of them were treated with exclusive pelvic external beam radiotherapy plus intracavitary brachytherapy. Response was defined as no evidence of residual disease after clinical examination by measuring tumor size, three months after the completion of the therapeutic sequence. Gene expression levels before radiotherapy were compared between complete response and non response.
Results: A major increase was observed in gene expression IGF-IR (34%), followed by the expression of IGF-II (24%) in the cases of cancer in comparison with either the control group or normal tissue samples of the transformation zone of cervix obtained from non-oncologic patients treated by hysterectomy. GAPDH expression was directly correlated with the IGF-IR & IGF-II co expression under hemoglobin lower than 11g/dl (p=0.05). Patients with IGF-IR expression had 26.8 times more risk of treatment failure (p=0.018).
Conclusion: This is the first report in the clinical setting that relates the expression of IGF-IR as a strong marker of responsiveness. Therefore, the IGF-IR can be considered as a molecular target for optimizing the treatment of cervical cancer with radiotherapy.

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 A181.
Abstract A199: The plekstrin-homology-domain-containing protein PLEKHA7 is a novel target for selectively inhibiting mutant KRAS colon cancer cell proliferation.
Authors: Jeung Hei-Cheul , Kiriakova Galina , Kirkpatrick Lynn , Indarte Martin , Powis Garth 
Published: June 2012

Abstract
KRAS harbors oncogenic mutations that yield a constitutively active protein in approximately 40% of colorectal cancer. Randomized clinical trials have indicated that the wild-type KRAS (wt-KRAS) is predictive for resistance to anti-EGFR therapy and there is currently no effective therapy for mutant KRAS (mut-KRAS) tumors that is associated with a poor prognosis. Therefore, mut-KRAS tumors are an unmet medical need in colorectal and other cancers. In a search for target genes that when down-regulated selectively inhibit the growth of cells with mut-KRAS but not the cells without mut-KRAS, we used a global synthetic lethal small interfering RNA screen of MiaPaCa-2 and HCT-116 cells (mut-KRAS). The screen identified the gene encoding PLEKHA7 (pleckstrin homology (PH) domain containing, family A member 7). Other PLEKHA family members did not show this effect. PLEKHA7 is a component of the epithelial adherens junction belt that links E-cadherin to the cytoskeleton, and through which KRAS may signal its effects on cell proliferation, invasion and metastasis. PLEKHA7 and KRAS levels were measured by RT-PCR in a panel of 23 colon cancer cell lines (10 wt-KRAS and 13 mut-KRAS) and showed a positive correlation with KRAS levels (R2 = 0.943), and a Wilcoxon Rank test showed that the median expression of PLEKHA7 was higher in cell lines with mut-KRAS than with wt-KRAS (P=0.02). Targeted knockdown of PLEKHA7 using siRNA resulted in growth inhibition for mut-KRAS cells (HCT116, DLD-1, SK-CO-1, SW480, HCT15, and LOVO), but not for wt-KRAS cells (SW48, CACO-2, SW1417, and HT29). Paradoxically, targeted knock-down of KRAS caused an increase in PLEKHA7 mRNA levels in mut-KRAS cells. PLEKHA7 contains a PH-domain in a three-dimensional protein fold that binds to plasma membrane phosphoinositide-3-phosphates (PIP3) formed by phosphatidyl-3-phosphate kinase. We have previously shown that PH-domains can be selectively targeted by small molecules, blocking the binding to PIP3, and inhibiting the function of PH-domain proteins such as Akt and PDPK1. The findings of the present study imply that PLEKHA7 offers a potentially druggable target for inhibiting mut-KRAS-related signaling and cancer-related functions, providing an approach for inhibiting cancer progression of colorectal cancer with KRAS mutation.
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 A199.
Abstract A203: Identification of FoxM1/Bub1b signaling pathway as a molecular target in rhabdomyosarcoma.
Authors: Wan Xiaolin , Yeung Choh , Kim Su Young , Asaudt Louis M. , Helman Helman J. 
Published: June 2012

Abstract
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. Intensive multi-modal therapeutic regimens have increased overall survival in the last 25 years, but 25% of patients still succumb to disease, thus necessitating the identification of novel targets for therapy. In this study, we identified that Bub1b is necessary for the growth and survival of both ARMS and ERMS cells using a loss of function high-throughput shRNA screen. Using many additional Bub1b shRNA sequences, we were able to confirm that human RMS cells were more sensitive to Bub1b knockdown compared to human fibroblasts or human ovarian cancer cells. Knockdown of Bub1b also resulted in significant suppression of RMS xenografts growth in vivo. Mechanistically, flow cytometry analysis of knockdown Bub1b cells had an increase in &gt;4N DNA content. Live-cell time-lapse microscopy studies provided direct evidence that knockdown of Bub1b promotes endoreduplication, eventually causing mitotic catastrophe. Further, ChIP assay demonstrated that Forkhead Box M1 (FoxM1), an essential transcriptional factor for G1/S transition and mitotic progression, directly binds to the Bub1b promoter. Luciferase reporter assay showed that FoxM1-binding region is critical for the activation of the Bub1b promoter. Suppression of FoxM1, either by shRNA or the inhibitor siomycin A, led to reduction of Bub1b expression and inhibition of cell growth and survival in vitro. These findings indicate that the FoxM1-Bub1b axis is important for the growth and survival of RMS cells and may be a target for RMS therapy in the future.
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 A203.
Abstract A227: Antitumor activities of ASP3026 against EML4-ALK-dependent tumor models.
Authors: Kuromitsu Sadao , Mori Masamichi , Shimada Itsuo , Kondoh Yutaka , Shindoh Nobuaki , Soga Takatoshi , Furutani Takashi , Konagai Satoshi , Sakagami Hideki , Nakata Mari , Ueno Yoko , Fushiki Hiroshi , Saito Rika , Sasamata Masao , Mano Hiroyuki , Kudou Masafumi 
Published: June 2012

Abstract
EML4-ALK is an oncogenic fusion kinase, which was first identified in non-small cell lung cancer (NSCLC), and is regarded as an attractive therapeutic target for treating a subpopulation of NSCLC patients. Crizotinib, which is inhibitor for MET and ALK, was recently approved by FDA (26 August 2011) for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.
We synthesized and screened chemical compounds utilizing an ALK kinase inhibition assay aimed at the EML4-ALK target for drug discovery, and found ASP3026, a novel and selective inhibitor for the ALK kinase. ASP3026 potently inhibited ALK kinase activity and was more selective than crizotinib in a Tyr-kinase panel. In an anchorage independent in vitro cell growth assay, ASP3026 inhibited the growth of NCI-H2228, a human NSCLC tumor cell line endogenously expressing EML4-ALK variant 3 and that of 3T3 cells expressing EML4-ALK variant 1, 2 and 3. The plasma and tumor concentrations of ASP3026 in mice xenografted with NCI-H2228 tumor were determined using high-performance liquid chromatography-tandem mass spectrometry. Significant tumor penetration was observed. The antitumor activities were evaluated using mice bearing subcutaneous NCI-H2228 tumor xenografts. ASP3026, (daily oral dosing for 14 days) induced dose dependent anti-tumor effects starting at 1 mg/kg with marked regression at 10, 30 and 100 mg/kg. Body weights were unaffected. Crizotinib, (twice daily oral dosing) was less potent, with growth inhibition at 10 mg/kg, and tumor regression at 30 mg/kg. A dose of 100 mg/kg of crizotinib was poorly tolerated. Resistance mutations in ALK kinase domain against crizotinib were reported following sequence analysis of tumor cells derived from crizotinib-relapsed patients. The position of the mutation is the so-called gatekeeper mutation and is thought to be one of the causes of crizotinib relapse. In an EML4-ALK driven tumor model with gatekeeper mutation, ASP3026 showed potent anti-tumor effects while crizotinib was ineffective even at 100 mg/gk qd. In summary, ASP3026 has a broad safety margin and inhibitory activity at the gatekeeper mutation. Therefore, ASP3026 may still effective in EML4-ALK fusion positive NSCLC patients, that have relapsed to crizotinib.
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 A227.