bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract C108: An expanded imaging cohort of pazopanib in children and adolescents with relapsed or refractory soft tissue sarcoma (ADVL0815): A Children's Oncology Group phase I consortium trial.
Authors: Glade-Bender Julia , Khrichenko Dmitry , Voss Stephan , Lee Alice , Ingle Ashish Mark , Ahern Charlotte H. , Weigel Brenda , Blaney Susan , Roberts Timothy 
Published: June 2012

Abstract
Background: Pazopanib (NCT00929903) is an orally available small molecule inhibitor of VEGFR 1–3, PDGFR α/β, and c-kit, which has been shown to prolong progression free survival in adults with soft tissue sarcoma (STS). Following a standard phase I dose escalation trial to determine the pediatric maximum tolerated dose (MTD), an expanded cohort of children and adolescents with relapsed and refractory STS and at least one lesion amenable to dynamic contrast enhanced MRI (DCE-MRI) was studied to explore changes in tumor blood volume and vascular permeability following initiation of pazopanib, and to correlate these changes with clinical outcome.
Methods: Oral pazopanib was administered at 450mg/m2 once daily in 28 day cycles, for up to 24 cycles. DCE-MRI scans were obtained at baseline and within 15 × 2 days after initiation of pazopanib. DCE-MRI data sets were analyzed using a two compartment kinetic model yielding estimates of fractional blood volume and the permeability transfer constant (Ki).
Results: 10 subjects were enrolled [5 male; median age 17 yrs (range, 8–23)], of whom 8 had paired DCE-MRI scans of sufficient quality to be evaluable. Subjects received a median of 4 cycles (range 1–7; 3 remain on study receiving courses 6, 7 and 8). One subject had a dose limiting toxicity of Gr3 back and extremity pain with Gr3 sensory neuropathy. Other non-dose limiting toxicities occurring in &gt;10% of subjects (n=10) during the first cycle included mild myelosuppression, sinus bradycardia, fatigue, diarrhea, nausea, vomiting, anorexia, dehydration, dizziness, headache, liver transaminase elevation and hyperglycemia. All subjects with evaluable DCE-MRI (n=8) experienced a decrease in tumor blood volume following initiation of pazopanib, with a mean pre-treatment level of 16% (range 1–29%) versus 7% (0–15%) post-treatment (p&lt;0.01). Similarly all subjects had a decrease in Ki with mean pretreatment values of 7.74 (range 2.31–20.38) ml/100g/min, decreasing post-treatment to 4.28 (range 0.19–12.60) ml/100g/min (p&lt;0.01). Although limited by the small sample size, there is a suggestion that patients with best response of stable disease appear to have lower tumor blood volume at baseline than those with progressive disease.
Conclusions: DCE-MRI changes in tumor blood volume and Ki in pediatric and adolescent patients with soft tissue sarcoma are supportive of physiological activity and the antiangiogenic mechanism of pazopanib.
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 C108.
Abstract C109: Association of TP53 gene polymorphism with response to platinum-based doublet chemotherapy in non-small cell lung cancer patients.
Authors: Shiraishi Kouya , Kunitoh Hideo , Tanai Chiharu , Goto Yasushi , Yamamoto Seiichiro , Nokihara Hiroshi , Yamamoto Noboru , Sekine Ikuo , Ohe Yuishiro , Tamura Tomohide , Yokota Jun , Kohno Takashi 
Published: June 2012

Abstract
Here we show that TP53 SNP is involved in chemotherapeutic responses in non-small cell lung cancer (NSCLC) patients. To identify polymorphisms in DNA repair genes that affect responses to platinum-based doublet chemotherapy, 640 NSCLC patients, who received platinum-based doublet chemotherapy and whose responses were evaluated by the Response Evaluation Criteria in Solid Tumors, were subjected to an association study between the response and genotypes for 30 SNPs in 27 DNA repair genes. Candidate SNPs were selected by screening of a discovery set of 201 cases and their associations were validated in an independent set of 439. Homozygotes for the TP53–72Pro allele of the TP53-Arg72Pro SNPs showed a better response rate (54.3%) than those for the TP53–72Arg allele (29.1%), and TP53–72Pro allele homozygotes had significantly longer progression-free and overall survivals than TP53–72Arg allele homozygotes. Minor allele carriers for a SNP, Lys940Arg, in the PARP1 (poly ADP-ribose polymerase 1) gene showed a better response rate to the regimen using paclitaxel (45.8%) than to the regimen using gemcitabine (10.5%). These results indicate that polymorphisms in the TP53 and PARP1 genes are involved in inter-individual differences in the response to platinum-based doublet chemotherapy in NSCLC 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 C109.
Abstract C112: Debrisoquine as a model substrate of the organic cation transporter OCT1.
Authors: Saadatmand Ali R. , Brockmoller Jurgen , Tzvetkov Mladen V. 
Published: June 2012

Abstract
Organic cation transporters are involved in the cellular uptake of chemotherapeutic drugs like cisplatin, oxaliplatin and imatinib. We have also shown that genetic polymorphisms in the liver-specific organic cation transporter OCT1 may affect pharmacokinetics and efficacy of supportive care drugs like the antiemetics ondansetron and tropisetron or the opioid tramadol. Here we tested whether debrisoquine, a model drug used to phenotype CYP2D6 activity, is a substrate of the liver-specific organic cation transporter OCT1 and whether genetic polymorphisms in OCT1 affect debrisoquine cellular uptake.
We measured the inhibition of OCT1 by debrisoquine and OCT1-mediated uptake of debrisoquine using HEK293 cells genetically engineered to overexpress wild type or loss-of-function OCT1 isoforms. We overexpressed OCT1 isoforms carrying the common loss-of-function amino acids substitutions in Caucasians Arg61Cys, Cys88Arg, Gly401Ser, Gly465Arg or deletion of Met420. Debrisoquine inhibited the uptake of the model OCT1 substrate MPP+ with IC50 below 10 μM. Debrisoquine uptake was significantly increased both in time and in concentration dependent manner in cells overexpressing wild-type OCT1 (KM of 5.9 ×1.5 μM and vMAX of 41.9 ×4.5 pmol/min/mg protein). OCT1-mediated uptake of debrisoquine was reduced or missing in cells expressing the common loss-of-function isoforms. The deletion of Met420 and the substitutions of Arg61Cys and Gly401Ser reduced vMAX by 48, 63 and 91%, respectively, but did not affect the Km of the OCT1-mediated debrisoquine uptake. The OCT1 isoforms carrying Cys88Arg or Gly465Arg substitutions completely lacked OCT1-mediated debrisoquine uptake.
In conclusion, debrisoquine is a substrate of OCT1 and common loss-of-function OCT1 polymorphisms affect debrisoquine uptake. Debrisoquine has a potential to be used as phenotyping marker for OCT1 activity. Moreover, known in vivo variations in debrisoquine pharmacokinetic and their relation to development of lung and bladder cancer may be related to variation not only in CYP2D6, but also in OCT1 activity.
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 C112.
Abstract C143: Combining siRNAs targeting thymidylate synthase and thymidine kinase 1 or 2 sensitizes human tumor cells to 5FUdR and pemetrexed.
Authors: Cresce Christine Di , Figueredo Rene , Ferguson Peter J. , Vincent Mark D. , Koropatnick James 
Published: June 2012

Abstract
Thymidylate synthase (TS) is the only de novo source of thymidylate (dTMP) for DNA synthesis and repair. Drugs targeting TS protein are a mainstay in cancer treatment, but off-target effects and toxicity limit their use. Cytosolic thymidine kinase (TK1) and mitochondrial thymidine kinase (TK2) contribute to an alternative dTMP-producing pathway, by salvaging thymidine from the tumor milieu, and may modulate resistance to TS-targeting drugs. Combined downregulation of these enzymes is an attractive strategy to enhance cancer therapy. We have previously shown that antisense targeting TS enhanced tumor cell sensitivity to TS-targeting drugs in vitro and in vivo. As both TS and TKs contribute to increased cellular dTMP, we hypothesized that TKs mediate resistance to the capacity of TS siRNA to sensitize tumor cells to TS-targeting anticancer drugs. We assessed the effects of targeting TK1 or TK2 with siRNA alone and in combination with siRNA targeting TS and/or TS-protein targeting drugs on tumor cell proliferation. Downregulation of TK with siRNA enhanced the capacity of TS siRNA to sensitize tumor cells to traditional TS protein-targeting drugs (5FUdR and pemetrexed). The sensitization was greater than that observed in response to any siRNA used alone, and was specific to drugs targeting TS. Upregulation of TK1 in response to combined 5FUdR and TS siRNA suggests that TK knockdown may be therapeutically useful in combination with these agents. TKs may be useful targets for cancer therapy when combined with molecules targeting TS mRNA and TS protein.
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 C143.
Abstract C146: In human lung carcinoma cells that contain estrogen receptor-α(ER), thyroid hormone-induced proliferation initiated at an integrin requires ER.
Authors: Meng Ran , Tang Heng Yuan , Mousa Shaker A. , Luidens Mary K. , Davis Faith B. , Davis Paul J. , Lin Hung Yun , Hercbergs Aleck A. 
Published: June 2012

Abstract
We examined the molecular basis of thyroid hormone-induced proliferation of two estrogen receptor-α (ER)-expressing human lung cancer cell lines, non-small cell carcinoma NCI-H522 and small cell carcinoma NCI-H510A. At a physiologic total L-thyroxine (T4) concentration (10[−7] M) and supraphysiologic 3,5,3'-triiodo-L-thyronine (T3) levels, thyroid hormone significantly increased proliferating cell nuclear antigen (PCNA) content of both cell lines. Neutralizing antibody to integrin αvβ3 and integrin-binding Arg-Gly-Asp (RGD) peptide inhibited cell proliferation stimulated by thyroid hormone. Tetraiodothyroacetic acid (tetrac) blocks binding of T4 and T3 to the hormone receptor on αvβ3 and inhibited thyroid hormone-induced cancer cell proliferation. Thus, the thyroid hormone effect is initiated nongenomically at the cell surface thyroid hormone receptor we have described on integrin αvβ3. The thyroid hormone isoforms also caused serine phosphorylation of ER in NCI-H522 and NCI-H510A cells. The ER antagonist, ICI 182,780 (fulvestrant) inhibited stimulation by T4 and T3 of ER phosphorylation, of PCNA accumulation and of radiolabeled thymidine incorporation by the cells. These results are consistent with existence of crosstalk between the plasma membrane receptor for iodothyronines and ER in these lung cancer cells. We conclude that endogenous T4 is a growth factor for ER-containing lung cancer cells and this hormonal action is subject to inhibition by tetrac and by fulvestrant.
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 C146.
Abstract C152: Mechanisms of KRAS dependency in pancreatic ductal adenocarcinoma.
Authors: Hayes Tikvah K. , Der Channing J. 
Published: June 2012

Abstract
Currently, pancreatic ductal adenocarcinoma (PDAC) has a dismal &lt;5% survival rate two years after initial diagnosis. Despite significant advances in development of signal transduction targeted therapies for some cancers, erlotinib, an EGFR inhibitor, in combination with gemcitabine, is the only targeted drug approved for treatment of PDAC. The frequency of KRAS oncogene mutations in PDAC is greater than 90%, thus inhibition of K-Ras4B protein function may have a significant impact on PDAC tumorigenesis. In support of this hypothesis, several recent studies demonstrated that KRAS mutant cancer cell lines display a strong dependence or addiction to mutant K-Ras for survival. Surprisingly, K-Ras addiction was not attributed to either the Raf or phosphoinositide 3-kinase (PI3K) effector pathways, which are two of the best-characterized Ras signaling effectors. These results suggest that other pathways are key for mutant KRAS dependency. Elucidating the effector mechanism(s) necessary for KRAS addiction may implicate signaling pathways, which harbor novel therapeutic targets for future anti-K-Ras drug development. To address this question, we first verified that shRNA silencing of mutant KRAS in a panel of pancreatic cell lines led to a strong reduction in anchorage-independent growth. Notably and in contrast to published studies, this was not due to decreased cell survival or increased anoikis. Using KRAS mutant PDAC cell lines, we purpose to use effector domain mutants of oncogenic K-Ras4B that are differentially impaired in effector interaction and constitutively activated effectors to define the key effector(s) involved in KRAS dependency. These studies will help to define key signaling activities of mutant KRAS that are critical for oncogenesis in PDAC.
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 C152.
Abstract C162: Influence of tumor genotype on aflibercept (VEGF Trap) antitumor activity in preclinical tumors.
Authors: Valence Sandrine , Guerif Stephane , Jouannot Erwan , Vrignaud Patricia , Vincent Loic , Dib Colette , Chiron Marielle 
Published: June 2012

Abstract
Aflibercept (also called VEGF Trap) is a novel anti-angiogenic agent currently tested in combination with standard chemotherapy in several phase 3 clinical trials including second-line metastatic colorectal cancer. It is a recombinant fusion protein consisting of Vascular Endothelial Growth Factor (VEGF)-binding portions from the extracellular domains of human VEGF Receptors 1 and 2 fused to the Fc portion of the human IgG1. Aflibercept acts as a soluble decoy receptor that binds to VEGF-A, with high affinity, as well as the related ligands PIGF and VEGF-B. It neutralizes all isoforms of VEGF-A, blocks angiogenesis and effectively suppresses tumor growth in vivo. Aflibercept also binds Placental Growth Factor (P1GF), which has been involved in pathological angiogenesis and tumor progression.
Preclinical studies were performed to assess the influence of somatic mutations on the activity of aflibercept against the growth of 37 human tumor xenografts in mice covering 17 different indications. These models were previously documented for KRAS, BRAF, and PIK3CA activating mutations and PTEN protein deficiency according to the Catalogue of Somatic Mutations in Cancer (COSMIC) database, literature, and internal studies. Aflibercept was administered twice weekly at 40 mg/kg. Aflibercept was found highly active in 6 models with tumor growth inhibition (ΔT/ΔC) ≤ 0%, very active in 9 models (ΔT/ΔC 0–10%), displayed some activity in 17 models (ΔT/ΔC 10–40%), and had no effect in 5 xenograft models (ΔT/ΔC &gt; 40%). We stratified the models into two groups according to the tumor response: the “partially reponsive and non-responsive models” with detectable tumor growth under treatment (22/37 models), and the “responsive models” with no detectable tumor growth or regression under treatment (15/37 models). Mutations in KRAS (G12D/V/S, G13D, Q61H) were present in both responsive (3 models) and partially responsive/non-responsive models (4 models). Ten of 28 (36%) KRAS wild-type tumors and 3 of 7 (43%) KRAS mutated tumors were responsive to aflibercept indicating that KRAS status has no significant influence on aflibercept activity on tumors (p=1; Fisher exact test). Similarly, tumor models were also found sensitive to the anti-tumor effects of aflibercept whatever the BRAF and PIK3CA genotype status, and PTEN protein expression status.

In summary, the status of KRAS, BRAF, PIK3CA and PTEN in these preclinical tumor models did not significantly influence the response to aflibercept. The impact of these genetic alterations on aflibercept activity will be further explored in 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 C162.
Abstract C170: The combination of statins and dipyridamole is effective preclinically in AML, MM, and breast cancer.
Authors: Pandyra Aleksandra , Sobol Paul , Sharmeen Sumaiya , Schimmer Aaron , Penn Linda 
Published: June 2012

Abstract
Statins are drugs that have been utilized for years to treat hyperlipidemia through inhibition of the rate-limiting enzyme of the mevalonate (MVA) pathway, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Preclinical evidence has demonstrated statins to possess anti-cancer properties against a wide range of tumors but not normal cells. Through the use of a chemical library screen, we hypothesize that the identification of compounds which potentiate the anti-cancer effects of statins will uncover novel molecular pathways and/or targets that can be exploited in combination with the MVA pathway to maximize tumor cell death.
A pilot 100-compound library, composed of off-patent pharmacologically active drugs clinically used for a wide spectrum of diseases was screened in the multiple myeloma (MM) KMS11 cell line. Dipyridamole (DP), a commonly prescribed anti-platelet agent potentiated the anti-cancer effects of atorvastatin. The DP-statin combination was synergistic and capable of inducing apoptosis in a variety of acute myelogenous leukemia (AML), MM and breast cancer cell lines. The DP-statin combination also induced apoptosis in primary AML patient samples, but was not toxic to normal PBSCs. In an in vivo AML tumor model, the DP-statin combination was found to be effective at inhibiting tumor growth.
DP is known to elicit numerous effects, amongst them, phosphodiesterase (PDE) inhibition. In AML cell lines, activators of the PKA pathway including other PDE inhibitors, also induced apoptosis in combination with statins similar to DP. Interestingly, the DP-statin combination prevented the increase of HMGCR, which occurs following statin treatment as part of a classic feedback response. Further mechanistic investigations to determine how DP potentiates statin-induced apoptosis are underway. As both statins and DP are pre-approved for use in humans, off-patent, and readily available, they have the potential to directly impact patient care.
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 C170.
Abstract C174: Integrated real-time photoacoustic diagnostic imaging and therapeutics of oral cancer cells via gold nanorod conjugate.
Authors: Wu Ping-Ching , Shieh Dar-Bin , Tsai Tsung-Lin 
Published: June 2012

Abstract
Cancer therapy is still a grand challenge due to their aggressive invasion and metastasis to adjacent tissues and distant organs. Only few reported integrated approaches capable of for simultaneous diagnosis and therapy. In this study, gold nanorods (AuNR) were synthesized to construct a novel theranostics platform. The characteristic tunable surface plasmon bands in the near-infrared region (800 nm) enabled efficient tissue penetration of the NIR activation light source. PEG and Her2 antibodies were conjugated on the AuNR for targeting oral cancer cells while present adequate biological stealth. The specific in vivo targeting and biodistribution of the AuNR800-PEG5K-Her2 were evaluated in mice implanted with tumor cells over-expression of Her2 by atomic absorption spectroscopy. Molecular photoacoustic imaging was performed using a hydrophone transducer containing a tunable pulsed laser system. A maximum signal of 4.2 dB was recorded within the tumor site 12 hours after injection. Moreover, AuNRs conjugated with Her2 antibodies significantly reduced non-specific liver and spleen uptake compared to AuNRs lacking the antibodies. For the evaluation of therapeutic efficacy, solid-state C.W. lasers at 808nm peak wavelength were established to scan the tumor lesions for laser induced hyperthermia. A significant increase in the tumor local temperature was observed in tumor-bearing mice injected with AuNRs conjugated with HER2 antibodies compared to PBS and AuNR control groups. Furthermore, AuNR800-PEG5K-Her2 treated mice exhibited an improved overall survival compared to the control groups.
In conclusion, we successfully demonstrate an integrated system capable of real-time photoacoustic imaging of the tumor lesions and perform laser induced hyperthermia therapy using AuNR800-PEG5K-Her2 as the probe and NIR laser as the light source.
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 C174.
Abstract C180: The effect of JS-K, a lead O2-arylated diazeniumdiolate anticancer agent, on the cellular glutathione status.
Authors: Holland Ryan J. , Maciag Anna E. , Rodriguez Luis G. , Saavedra Joseph E. , Keffer Larry K. , Shami Paul J. 
Published: June 2012

Abstract
JS-K is an O2-arylated diazeniumdiolate prodrug which has demonstrated pronounced selective cytotoxicity and antitumorigenic properties in a variety of cancer models both in vitro and in vivo. Mass spectrometric studies of the metabolic fate of JS-K were undertaken to understand the origin of the cytotoxicity. Consistent with model chemical reactions, the first step in the cellular metabolism of JS-K is the de-arylation of the diazeniumdiolate by glutathione (GSH) via a nucleophilic aromatic substitution reaction, forming a dinitrophenyl-GSH adduct, with the daizeniumdiolate ion by-product ultimately releasing nitric oxide (NO). A consequence of this metabolism and NO-generation is a rapid and pronounced depletion of cellular GSH concurrent with a rise in oxidized glutathione (GSSG). The GSH/GSSG redox couple, considered to be the major redox buffer of the cell, helps maintain a reducing environment under basal conditions. The depletion of GSH through drug conjugation and subsequent oxidation results in a rapid rise in the oxidation potential of the cellular environment, an increase of 30 mV in the first 30 min of treatment, initiating the stress signaling pathways which lead to extrinsic/intrinsic apoptosis. Preventing this rise in the oxidation potential by pre-treating cells with known antioxidant N-acetylcysteine inhibited the downstream signaling events leading to apoptosis. These data indicate that depletion of the glutathione pool is a crucial first step in the mechanism of JS-K cytotoxicity.
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 C180.