bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 3704: Clinical efficacy and safety of bevacizumab monotherapy in patients with metastatic melanoma: predictive importance of induced early hypertension in a single-arm Phase II study
Authors: Straume Oddbjorn , Schuster Cornelia , Puntervoll Hanne , Eikesdal Hans P. , Heinrich Daniel , Geisler Stephanie B. , Geisler Jurgen , Molven Anders , Lønning Per E. , Akslen Lars 
Published: August 2012

Abstract
Purpose VEGF driven angiogenesis plays a key role in tumor growth. We determined clinical efficacy of bevacizumab monotherapy in unselected patients with metastatic melanoma. Patients and methods Thirty-five patients with metastatic melanoma in progression were enrolled in this phase II, single arm clinical trial. Each patient received bevacizumab monotherapy 10 mg/kg q14 d until intolerable toxicity or disease progression occurred. Clinical efficacy was evaluated by measuring objective response (OR), disease control (DC), and survival. We also evaluated potential predictive value of clinical parameters and BRAF/NRAS mutational status. Results We observed one complete (CR, 3%) and 5 partial (PR, 14%) responses. In addition, 5 patients experienced stable disease &gt; 6 months (SD, 14%), while 24 patients had progressive disease (PD, 69%), corresponding to a total disease control (DC) at 6 months in 11 out of 35 patients (31 %). Median progression free survival (PFS) was 2.14 months and median overall survival (OS) was 9 months (1.12-49). Seven of the 11 patients experiencing DC developed early hypertension (&lt; 2 months) after commencing bevacizumab compared to 3/24 of patients with PD (P= 0.001), and hypertension was associated with improved progression free survival (P= 0.005) and overall survival (P= 0.013). No correlation between BRAF and NRAS mutation status and response was recorded. Conclusion Bevacizumab monotherapy demonstrated promising clinical efficacy in patients with metastatic melanoma with disease control in 31% of the patients. The activity of the drug seemed particularly pronounced in patients developing by hypertension early during.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3704. doi:1538-7445.AM2012-3704
Abstract 3705: Multicenter phase II clinical trial of gemcitabine and liposomal paclitaxel combination chemotherapy in patients with advanced biliary cancer
Authors: Park Keon Uk , Kim Jin Young , Do Young Rok , Song Hong Suk , Ryoo Hun-Mo 
Published: August 2012

Abstract
OBJECTIVE: Advanced biliary tract cancer is associated with a poor prognosis due to wide resistance to chemotherapeutic agents. This phase II clinical trial was conducted to determine the safety and efficacy of weekly gemcitabine and liposomal paclitaxel (Genexol-PM®) in patients with unrectable or metastatic biliary cancer. METHODS: The eligibility criteria were patients 1) with pathologically proven unresectable or metastatic biliary cancer, 2) with an ECOG performance status 0 to 2, 3) aged more than 18, 4) with measurable lesions, 5) with adequate hematologic, renal and liver functions, and 6) who provided written informed consent. Each treatment cycle was consisted of gemcitabine 1000 mg/m*2 and liposomal paclitaxel 100 mg/m*2 on days 1, 8 followed by rest perioid of 14 days. It was repeated until the appearance of disease progression or unacceptable toxicity up to maximal 9 cycles. The primary end point of this study was reponse rate, and secondary end points included toxicity, progression free survival and overall survival. RESULTS: Thirty five patients were enrolled; median age was 63 years; male (n=30) and female (n-10). The median number of cycles administered was 3.5 (range, 1-10). Thirty patients were assessable for efficacy. Nine partial responses and 16 stable diseases were confirmed. Giving an overall response rate was 35.6% and disease control rate was 55.6% in per-protocol population. Median overall survival was 12.3 months (95% CI: 5.79-18.74) and median progression free survival was 4.07 months(95% CI: 3.12-5.01). The most frequent adverse events (AE) of all grades were anemia and neutropenia (n=17) followed by leucopenia (13). Grade 3/4 hematologic AEs: anemia (n=6), neutropenia (n=11), thrombocytopenia (n=1). Grade 3/4 non-hematologic AEs: elevated liver function tests (n=3), hyperbilirubinemia (n=1) hyponatremia (n=1). CONCLUSION: Weekly gemcitabine combined with liposomal paclitaxel appears to be effective against advanced biliary cancers. Further randomized trials are needed to confirm this finding.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3705. doi:1538-7445.AM2012-3705
Abstract 3713: Comparison of endpoints and data analysis methods for exposure of human tumor cells to dasatinib (NSC732517) and 6-MP (NSC755) in culture
Authors: Kaur Gurmeet , Kondapaka Sudhir B. , Teicher Beverly A. 
Published: August 2012

Abstract
Previous research using the NCI60 cell line combination screen suggested that dasatinib (NSC732517) and 6-mercaptopurine (6-MP; NSC755) may have greater than additive cytotoxicity in selected cell lines. We have conducted a detailed combination study using 6-MP and dasatinib in p53 wild type (MCF-7, H460, A498) and p53 mutant (MDA-MB-468, H23, 786-O) breast, lung and renal cell lines. These studies were performed measuring ATP as the endpoint using Cell Titer Glo after 72h exposure to 6-MP and dasatinib alone or in combination and measuring survival using colony formation after 72hr exposure to the compounds alone or in combination. As a single agent, the lung and renal mutant cell lines (H23, 786-O) were 2-10 fold more sensitive to 6-MP than wild type (H460, A498) with the exception of MDA-MD-468 (mutant), which was more resistant to 6-MP than MCF-7 (wild type). On the other hand all cell lines were sensitive to dasatinib with the IC50 ranging from 0.2-2 μM. For the combination studies, additivity/synergy was calculated using CompuSyn Software (Chou and Martin) or MacSynergy (Prichard and Shipman). Combination index (CI) analysis of the single agent and combination data for 6-MP and dasatinib was additive or antagonist in most of the cell lines. In A498, 786-0, MCF-7 and H460 cell lines a synergistic effect was observed at &gt;10 fold the clinical plasma levels of 6-MP (0.59 μM) or dasatinib (0.19 μM). NCI-H23 cell line demonstrated an additive effect at 0.3 μM of 6-MP and 0.2 μM of dasatinib (CI = 0.94). MDA-MB-468 cell lines demonstrated a strong synergy (CI = 0.2-0.4) for 6-MP (0.03-1 μM) and dasatinib (0.05 μM) at concentrations less than the clinical plasma levels. In a single agent colony formation assay, the H460 cells were sensitive to 6-MP (IC50= 0.21 μM) and resistant to dasatinib (IC50= &gt;10 μM). In a combination study, a synergistic effect (CI = 0.59-0.8) was observed in H460 cell line at concentrations below the clinical plasma level of 6-MP (0.2 μM-0.6 μM) and dasatinib (0.1 μM). These drug effects will be further evaluated in all cell lines by the determination of survival using colony formation assay.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3713. doi:1538-7445.AM2012-3713
Abstract 3724: Wogonin enhances tumor necrosis factor-related apoptosis-inducing ligand's antitumor activity in vivo through H2O2-mediated downregulation of X-linked inhibitor of apoptosis protein and cellular inhibitor of apoptosis protein 1 and 2
Authors: Yang Lan , Zheng Xuelian , Lin Yong , Wang Xia 
Published: August 2012

Abstract
Numerous malignant cells are resistant to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cytotoxicity, limiting value of TRAIL as an antitumor therapeutics. Combination of TRAIL with other agents is a promising strategy to overcome TRAIL resistance. Wogonin (5, 7-dihydroxy-8-methoxyflavone), a flavonoid originated from the root of the medicinal herb Scutellaria baicalensis Georgi, has been shown to enhance TRAIL-induced apoptosis in malignant cells in in vitro studies. However, whether wogonin enhances TRAIL's antitumor activity in vivo has never been studied. In this study, we first found that wogonin sensitized a variety of cancer cells including A549, HeLa and SKOV3 to TRAIL-induced apoptosis, as indicated by increased annexin V staining and enhanced activation of caspase-8 and -3 in TRAIL and wogonin cotreated cells, whereas having marginal effect on non-transformed bronchial epithelial cells and cervical epithelial cells. Then the effect of combination of TRAIL and wogonin was tested in a xenografted tumor model with A549 cells in nude mice. The results show that wogonin greatly enhanced TRAIL-induced suppression of tumor growth, which was accompanied with increased apoptosis in tumor tissues determined by a terminal deoxynucleotidyl-transferase -mediated dUTP nick-end labeling (TUNEL) assay. The protein levels of X-linked inhibitor of apoptosis protein (XIAP) and cellular inhibitor of apoptosis protein 1 and 2 (cIAP-1 and cIAP-2) were markedly reduced in both cultured cells and xenografted tumor tissues with co-treatment of wogonin and TRAIL. The down-regulation of these antiapoptotic proteins was likely mediated through proteasomal degradation and involved intracellular H2O2, as wogonin robustly induced H2O2 accumulation in A549 cells and the reactive oxygen species scavengers butylated hydroxyanisole (BHA) and N-acetyl-L-cysteine (NAC) and the proteasome inhibitor MG132 restored the expression of these antiapoptotic proteins and suppressed cytotoxicity in cells co-treated with wogonin and TRAIL. These results provide important in vivo evidence supporting the application of wogonin as TRAIL sensitizer for cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3724. doi:1538-7445.AM2012-3724
Abstract 3737: The PI3K/mTOR inhibitor PWT33597 regresses 786-0 renal xenografts
Authors: O'Farrell Marie , Ventura Richard , Tai Albert , Matthews David J. 
Published: August 2012

Abstract
PWT33597 is a balanced dual inhibitor of phosphatidylinositol 3-kinase alpha (PI3K alpha) and mTOR, currently in clinical development. Inhibition of signaling downstream of PI3K and mTOR by PWT33597 has been demonstrated, and PWT33597 is strongly efficacious in multiple xenograft models tested to date with different PIK3CA and PTEN genotypes. Inhibitors of mTORC1 (rapalogs) are approved for treatment of advanced renal cell carcinoma (RCC), but their effect is restricted to a subset of patients, and is not sustained. Inhibitors of VEGFR signaling such as sorafenib and sunitinib have also demonstrated clinical activity in RCC and are approved in this indication. Based on the proven role of rapalogs in RCC, we tested PWT33597 in a renal xenograft model with the hypothesis that inhibition of both mTORC1 and mTORC2, as well as PI3K, may offer increased efficacy by direct targeting of multiple signaling nodes including VEGFR signaling. Dual inhibition would also be expected to decrease release of negative feedback loops triggered by either mTOR or PI3K inhibition alone. PWT33597 was tested in 786-0 (VHL -/-, PTEN -/-) xenografts in comparison to rapamycin (mTORC1 inhibitor), and sorafenib (VEGFR/RAF inhibitor). While sorafenib and rapamycin showed tumor growth inhibition (TGI), the maximal effect with sorafenib was 64% TGI, and rapamycin had a largely cytostatic effect. The overall efficacy observed with PWT33597 was superior, with 93% TGI observed. PWT33597 was also tested in comparison to a pan-PI3K inhibitor (GDC-0941, 49% TGI) and demonstrated superior efficacy. Immunohistochemical analysis of tumors for cleaved caspase 3 (CC3) as an indicator of apoptosis showed that a single dose of PWT33597 induced a several fold increase in CC3 staining, and this effect was also apparent after 18 days of dosing. Based on these results we tested the ability of PWT33597 to regress large 786-0 tumors (approx. 500 mm3), and a rapid decrease in tumor size was observed in 100% of animals. Additional cellular and xenograft studies in RCC models are ongoing to further define the mechanism of action of PWT33597, and will be presented. Taken together, these data provide rationale for testing PWT33597 in patients with RCC.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3737. doi:1538-7445.AM2012-3737
Abstract 3749: Single agent activity of PIK3CA inhibitor BYL719 in a broad cancer cell line panel
Authors: Huang Alan , Fritsch Christine , Wilson Christopher , Reddy Anupama , Liu Manway , Lehar Joseph , Quadt Cornelia , Hofmann Francesco , Schlegel Robert 
Published: August 2012

Abstract
NVP-BYL719 is a p110α isoform-specific small molecule inhibitor that is currently in a Phase I clinical trial. To identify cancer populations that most likely to respond to BYL719 treatment, we initiated a comprehensive in vitro pharmacologic profiling screen across a large panel of cancer cell lines that have been previously characterized at the molecular level as part of the Cancer Cell Line Encyclopedia (CCLE) effort. We found that BYL719 responsive cell lines are enriched in indications such as Her2 positive and luminal breast cancer, while lacking in other indications such as Glioblastoma and Melanoma. Further exploration of the underlying genetic and pathway aberrations revealed that BYL719 sensitivity is positively associated with PIK3CA mutation, ERBB2 amplification and PIK3CA amplification/copy number gain. PTEN and BRAF mutations on the other hand, are associated with BYL719 insensitivities. KRAS mutation alone is neither associated with enhanced sensitivity nor insensitivity, however, co-commitant PIK3CA and KRAS mutants are more likely to be insensitive to BYL719 treatment. These findings will help to guide our clinical development plan.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3749. doi:1538-7445.AM2012-3749
Abstract 3750: The novel Akt inhibitor MK-2206, is cytotoxic in T-cell acute lymphoblastic leukemia: Therapeutic implications
Authors: Simioni Carolina , Cani Alice , Bressanin Daniela , Evangelisti Camilla , Chiarini Francesca , Capitani Silvano , Neri Luca M. , Martelli Alberto M. 
Published: August 2012

Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder arising within the thymus from the clonal proliferation of T-cell precursors. T-ALL accounts for 15% of ALL cases in children and 25% in adults. Although the prognosis of T-ALL has improved, due to the use of intensive polychemotherapy schemes, the outcome of relapsed and chemoresistant T-ALL is still poor, especially in adults, with a 35-40% survival at 5 years. Therefore, efforts are being made to develop targeted therapies against deregulated signaling cascades that sustain T-ALL cell proliferation, survival, and drug-resistance. A signaling pathway that is frequently upregulated in T-ALL, is the PI3K/Akt/mTOR network. To explore whether or not Akt could represent a potential target for therapeutic intervention in T-ALL, we evaluated the effects of the novel allosteric Akt inhibitor, MK-2206, on a panel of human T-ALL cell lines (MOLT-4, CEM, drug-resistant CEM) and primary cells from T-ALL patients, characterized by pathway upregulation. MK-2206 decreased T-ALL cell line viability as documented by MTT assays. IC50 for MK-2206 ranged from 1.0 to 4.8 μM at 48 hours. The drug was effective against drug-resistant CEM cells, overexpressing 170-kDa P-glycoprotein. MK-2206 blocked leukemic cells in the G1 phase of the cell cycle and induced caspase-dependent apoptotic cell death, as documented by Annexin V/propidium iodide staining and western blot analysis. In CEM cells, MK-2206 induced autophagy, as demonstrated by an increase in the 14-kDa form of LC3A/B. Western blotting documented a concentration-dependent dephosphorylation of Akt and its downstream targets, GSK-3β and FOXO3A, in response to MK-2206. mTORC1 downstream targets were also efficiently dephosphorylated by MK-2206, including p70S6K and 4E-BP1. MK-2206 decreased mTORC2 activity, as indicated by the downregulation of Ser 2481 p-mTOR levels, a readout for mTORC2 activity In MOLT-4 and CEM cells, MK-2206 strongly synergized (combination index: 0.1-0.33) with doxorubicin. Moreover, MK-2206 dephosphorylated Akt and induced apoptosis in a T-ALL patient cell subset (CD34+/CD4−/CD7−) which is enriched in leukemia initiating cells. Our findings indicate that Akt inhibition, either alone or in combination with chemotherapeutic drugs, represents a potential therapeutic target in T-ALL cells that require upregulation of the PI3K/Akt/mTOR signaling pathway for their proliferation and survival.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3750. doi:1538-7445.AM2012-3750
Abstract 3759: P7170, a novel inhibitor of phosphoinositide 3-kinase (PI3K)-mammalian target of Rapamycin (mTOR) and activin receptor-like kinase 1 (ALK1) as a new therapeutic option for Kras mutated non small cell lung cancer (NSCLC)
Authors: Agarwal Veena R. , Joshi Asavari , Venkataraman Magesh , Bhatia Dimple , Bose Julie , Kolla Lakshmi Sireesha , Gill Parkash , Sharma Somesh 
Published: August 2012

Abstract
Major breakthroughs in targeted cancer treatment have been achieved in last decade, but still some patient populations such as Kras mutated non small cell lung cancer (NSCLC), have no therapeutic options other than cytotoxic therapies. Therefore, development of targeted therapeutics is warranted in order to provide improved survival benefit for NSCLC patients with Kras mutation. P7170 is a small molecule inhibitor of PI3K (IC50 = 2.2 nM) and mTOR (IC50 = 4.4 nM). It also inhibits ALK1 and DNA-PK, two important enzymes involved in angiogenesis and DNA repair with IC50 of 47 and 1.5 nM, respectively. The structure, other in vitro, and in vivo efficacy of P7170 has been reported in the accompanying abstract submitted for AACR 2012. P7170 inhibited PI3K-mTOR pathway proteins pAKT, pS6 and p4EBP1 by 90 to 100 % in Kras mutated NSCLC cell line (H460) in a western blot assay. P7170 also exhibited potent cytotoxicity activity against two Kras mutated NSCLC (H460 and A549) cell lines with IC50 values of 7 and 5 nM. P7170 inhibited anchorage independent colony formation of tumor cells isolated from 10 different human tumor xenografts derived from NSCLC patient's tumors (Seven out of 10 samples had wild type Kras, and three had mutations in Kras). Moreover, P7170 induced apoptosis in H460 cell lines by inducing PARP cleavage. More interestingly, P7170 inhibited pAKT and pS6 in a dose dependent fashion in stem-like cells isolated from tumor samples of a Kras mutated NSCLC patient. P7170 demonstrated significant (p&lt;0.01) in vivo efficacy following oral administration, in NSCLC xenograft studies using Kras mutated H460 cancer cell line. P7170 treatment resulted in 66% tumor growth inhibition at a dose of 5 mg/kg, and stabilization of tumor growth (89% tumor growth inhibition) at a dose of 20 mg/kg. Evaluation of mechanism of action of P7170 in H460 xenografted tumors confirmed the inhibition of PI3K-mTOR (pAKT and p4EBP) and Ras-Raf (pERK) pathways. In addition, inhibition of ALK1 and DNA-PK activity with the treatment of P7170 was also confirmed in xenografts. Conclusion: P7170 by virtue of its unique profile represents an opportunity to deliver a first-in-class therapeutic option for patients saddled with Kras mutated non small cell lung cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3759. doi:1538-7445.AM2012-3759
Abstract 376: Limits of [18F]-FLT PET as a predictive imaging biomarker of proliferation in oncology
Authors: McKinley Eliot T. , Ayers Gregory D. , Smith Ralph A. , Washington Mary K. , Coffey Robert J. , Manning Henry C. 
Published: August 2012

Abstract
Background: Surrogate, non-invasive imaging biomarkers of cellular proliferation hold great promise for quantifying response to personalized medicine in oncology. An emerging imaging approach to assess tumor proliferation utilizes the positron emission tomography (PET) tracer 3′-deoxy-3′[18F]-fluorothymidine, [18F]-FLT. Though several studies have associated serial changes in [18F]-FLT-PET with elements of therapeutic response, the degree to which [18F]-FLT uptake quantitatively reflects proliferative index has been continuously debated for more that a decade. The goal of this preclinical study was to elucidate quantitative relationships between [18F]-FLT-PET and cellular, proteomic, and genomic metrics proliferation in treatment naive tumors. Methods and Findings: [18F]-FLT-PET imaging was conducted in mice bearing human colorectal or breast cancer cell line xenografts. Quantitative relationships between PET imaging, thymidine kinase 1 (TK1) protein and RNA levels, and immunostaining for proliferation markers (Ki67, TK1) were evaluated using imaging-matched tumor specimens. Overall, we found that [18F]-FLT-PET reflects TK1 protein levels in tumors. However, the cell cycle specificity of TK1 expression and the variable degree to which tumors utilize thymidine salvage for DNA synthesis tend to decouple [18F]-FLT-PET data from estimates of proliferation by standard, clinically employed means. Conclusions: Our findings illustrate that [18F]-FLT-PET reflects tumor proliferation as a function of thymidine salvage pathway utilization. Therefore, unlike more generalizable proliferation markers, such as Ki67 immunostaining, tumor uptake of [18F]-FLT reflects proliferative indices to variable and potentially unreliable extents. [18F]-FLT-PET can not discriminate moderately proliferative, thymidine salvage driven disease from highly proliferative tumors that rely primarily upon de novo thymidine synthesis. For those reasons, the magnitude of [18F]-FLT uptake in treatment naive tumors should not be considered a surrogate of proliferative index. These data provide rationale for the diversity of correlative results reported, both positive and discordant, comparing [18F]-FLT-PET and tumor proliferation across numerous single-center clinical studies and provide a basis for future clinical best-practices when this imaging biomarker is employed in oncology.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 376. doi:1538-7445.AM2012-376